NEUROBIOLOGICALANDBEHAVIORALPHENOTYPESANDCOCAINESELF‐ADMINISTRATIONINADULTRHESUSMONKEYS

EXPOSEDTOCOCAINETHROUGHOUTGESTATION

BY

LINDSEYR.HAMILTON

ADissertationSubmittedtotheGraduateFacultyof

WAKEFORESTUNIVERSITYGRADUATESCHOOLOFARTSANDSCIENCES

InPartialFulfillmentoftheRequirements

FortheDegreeof

DOCTOROFPHILOSOPHY

PrograminNeuroscience

August2010

Winston‐Salem,NorthCarolina

ApprovedBy:

MichaelA.Nader,Ph.D.,Advisor____________________________________

ExaminingCommittee:

JosephR.Tobin,M.D.,Chair____________________________________

PaulW.Czoty,Ph.D. ____________________________________

AnthonyLiguori,Ph.D. ____________________________________

LindaJ.Porrino,Ph.D. ____________________________________

ii

ACKNOWLEDGEMENTS

Althoughthisdissertationwillhaveonlymynameonthecover,a

greatnumberofpeoplehavecontributedtoitsproduction.Iowemany

thankstoallthosepeoplewhohavemadethisdissertationpossible.

Firstandforemost,Iwouldliketoexpressmydeepestgratitudetomy

advisor,Dr.MikeNader,whohasgivenmethefreedomtoexploreonmy

ownand,atthesametime,theguidancetobetterrefinemyideas.Hehas

impresseduponmealltheimportanttraitsnecessarytobecomeabehavioral

pharmacologist:perseverance(“Staythecourse!”),properterminology

(“Don’tcallitaDRLschedule.”),criticalanalysis(“Thedataarethedata.”),

andhighcaffeineintake(“Isdecafcoffeeareinforcer?”).

Ialsogreatlyappreciatethepeoplethatmadecomingtowork

everydayatreat,notachore:mylabmateswithwhomIsharedanoffice,

frustrations,successes,andmanygreatconversations,Dr.MattBanks,Dr.

JennMartelle,Dr.NatalliaRiddick,RobGould,andBrandiBlaylock;andmy

colleagueswhotrainedmeandwerealwaysavailabletoassistmeinanyway,

SueNader,TonyaCalhoun,MichelleIcenhower,SusanMartelle,Michael

Coller,andWhitneyWilson.IalsowouldberemissifIdidnotthankmy

presidentialmonkeyswhotaughtmepatienceandalwaysgavemeagood

laugh.

iii

Iamgratefultomydissertationcommitteefortheirhelpful

suggestions,comments,critiques,andalternateviewpoints:Dr.PaulCzoty,

Dr.TonyLiguori,Dr.LindaPorrino,andDr.JoeTobin.

Finally,Iwholeheartedlythankmyfriendsandfamilyfortheir

support,patience,andloveduringmygraduateschoolyears.Myparents

havealwaysbeenmybiggestcheerleadersandIdeeplyappreciatetheir

beliefinme.Thefriendswhomakeupmyextendedfamilyhavegivenme

strengththroughoutdifficulttimes,celebratedwithmeinhappytimes,and

helpedmestayfocusedoncompletingthisdissertation.Itrulyvaluetheir

friendship.

ThisresearchwassupportedbyGrantR01DA025120,R37DA

10584,andanIndividualPredoctoralNationalResearchServiceAwardF31

DA024485fromtheNationalInstituteonDrugAbuse.

iv

TABLEOFCONTENTS

PAGE

ACKNOWLEDGEMENTS

ii

LISTOFABBREVIATIONS

v

LISTOFTABLESANDFIGURES

viii

ABSTRACT

x

CHAPTERS:

I.

Introduction 1

II.

Characterizationofthedopaminereceptorsysteminadultrhesusmonkeysexposedtococainethroughoutgestation.PublishedinPsychopharmacology,acceptedMarch2010

86

III.

Increasedimpulsivityinmale,butnotfemale,adultrhesusmonkeysexposedtococainethroughoutgestation.SubmittedtoPsychopharmacology,April2010

115

IV.

Increasedvulnerabilitytoself­administercocaineinadultrhesusmonkeysexposedtococainethroughoutgestation.TobesubmittedtoScience,May2010

156

V.

Discussion 182

SCHOLASTICVITAE 218

v

LISTOFABBREVIATIONS

5‐HIAA 5‐hydroxyindoleaceticacid

5‐HT Serotonin

ACC AnteriorCingulateCortex

ANOVA AnalysisofVariance

BSID BayleyScaleofInfantDevelopment

COMT Catechol‐O‐methyltransferase

CSF CerebrospinalFluid

DA Dopamine

DAT DopamineTransporter

DVR Dopamine

E EmbryonicDay

EDTA Ethylenediaminetetraaceticacid

e.g. ExempligratiaorForexample

FCP Fluoroclebopride

FR FixedRatio

HV HighlyVulnerable

HVA Homovanillicacid

i.e. idestorThatis

i.m. Intramuscular

IQ IntelligenceQuotient

i.v. Intravenous

vi

LV LowVulnerable

MAO Monoamineoxidase

MDI MentalDevelopmentIndex

MRI MagneticResonanceImaging

nM Nanomole

NAc NucleusAccumbens

NBAS NeonatalBehavioralAssessmentScale

NE Norepinephrine

NHP NonhumanPrimates

NIDA NationalInstituteonDrugAbuse

NMDA N‐methyl‐D‐aspartate

NSDUH NationalSurveyonDrugUseandHealth

OTB OperantTestBattery

PCP Phencyclidine

PR ProgressiveRatio

ROI RegionofInterest

SAMHSA SubstanceAbuseandMentalHealthServicesAdministration

SEM StandardErroroftheMean

SN SubstantiaNigraParsCompacta

TH Tyrosinehydroxylase

TO Timeout

vii

VR VariableRatio

VTA VentralTegmentalArea

viii

LISTOFTABLESANDFIGURES

CHAPTERI PAGE

Table1. SubjectDemographics 40

CHAPTERII

Figure1. DistributionVolumeRatiosof[18F]FCPintheCaudate,Putamen,andAmygdala

104

Figure2. A) YawningElicitedbyQuinpiroleinFemalePrenatallyCocaineExposedandControlMonkeys

B) YawningElicitedbyQuinpiroleinMalePrenatallyCocaineExposedandControlMonkeys

C) GroupComparisonforYawningElicitedbyQuinpirole

105

106

Figure3. CorrelationofPeakYawnsElicitedbyQuinpiroleandMaximalDailyDoseofInUteroCocaine

107

Figure4. A) EffectsofSKF81297onEye‐BlinkingRatesinControlMonkeys

B) EffectsofSKF81297onEye‐BlinkingRatesinPrenatallyCocaineExposedMonkeys

C) GroupComparisonoftheEffectsofSKF81297onEye‐BlinkingRates

108

109

CHAPTERIII

Table1. ComparisonofCSFConcentrationsof5‐HIAAandHVA

139

Table2. ResponseRatesDuringtheDelayDiscountingTask 140

Figure1. A) LatencytoTouchaNovelObjectPlacedintheHomeCage

B) GridCrossingsinaNovelEnvironment

141

Figure2. NumberofSessionstoExtinguishFood‐ReinforcedBehavior

142

Figure3. RepresentativeDelayValue–PercentageChoicefortheDelayedReinforcerCurvesforaPrenatallyCocaineExposedMonkeyandaControlMonkey

143

Figure4. IndifferencePointsontheDelayDiscountingTask 144

ix

Figure5. OverallImpulsivityScoreMeasuredAcrossFourImpulsivityMeasures

145

CHAPTERIV

Figure1. PercentageofMonkeysReachingCriteriatoAcquireCocaineSelf‐AdministrationatVariousDosesofCocaine

174

Figure2. AmountofCocaineIntakePriortoReachingCriteriatoAcquireCocaineSelf‐AdministrationinPrenatallyCocaineExposedandControlMonkeys

175

Figure3. AmountofCocaineIntakePriortoReachingCriteriatoAcquireCocaineSelf‐AdministrationinHighlyandLessVulnerableMonkeys

176

Figure4. A) ComparisonofImpulsivityScoresBetweenHighlyandLessVulnerableMonkeys

B) PeakYawnsElicitedbyQuinpiroleinHighlyandLessVulnerableMonkeys

C) RelationshipBetweenPeakYawnsandAmountofCocaineIntakePriortoReachingCriteriatoAcquireCocaineSelf‐Administration

177

178

CHAPTERV

Figure1. RepresentativeResponseRatesforFoodandDrugUnderanFR30ScheduleofReinforcement

185

Figure2. AcquisitionandMaintenanceCocaineDose‐ResponseCurvesforPrenatallyCocaine‐ExposedandControlMonkeys

187

Figure3. AlterationsinD2andD3ReceptorsCouldResultinSimilarFCPDVRsinPrenatallyCocaineExposedandControlMonkeys

200

Figure4. PercentageofMaleandFemaleMonkeysReachingCriteriatoAcquireCocaineSelf‐AdministrationatVariousDosesofCocaine

206

x

ABSTRACT

Hamilton,LindseyR.

NEUROBIOLOGICALANDBEHAVIORALPHENOTYPESASSOCIATEDWITHVULNERABILITYTOCOCAINESELF‐ADMINISTRATIONINADULTRHESUS

MONKEYSEXPOSEDTOCOCAINETHROUGHOUTGESTATION

DissertationunderthedirectionofMichaelA.Nader,Ph.D.,ProfessorofPhysiologyandPharmacology

Maternalcocaineaddictionisasignificantpublichealthproblemyet

theeffectsofcocaineuseduringpregnancyonlong‐termpostnataloutcomes

havenotbeenwellestablished.Thisdissertationutilizedananimalmodelof

prenatalcocaineexposureinrhesusmonkeystoevaluatethelong‐term

neuropharmacologicalconsequences,behavioralimpulsivity,and

vulnerabilitytostimulantself‐administration.Theseadultmonkeyshadbeen

exposedtococainethroughoutgestationandwerecomparedtoapopulation

ofcontrolmonkeys.

InChapterII,thedopamine(DA)receptorsystemwascharacterized

usingseveralinvivomodels.Therewerenodifferencesbetweengroupsin

D2‐likereceptoravailability,asdeterminedwithpositronemission

tomographyimaging,orinD1‐likereceptorfunction,asassessedby

unconditionedbehaviorselicitedbyanagonist.Prenatallycocaine‐exposed

monkeyshadhigherD3receptorfunctioncomparedtocontrols,asassessed

byquinpirole‐elicitedyawning.Additionally,arelationshipwasfound

xi

betweengestationalcocainedoseandD3receptorfunction,demonstrating

thatprenatalcocaineexposurehadlong‐lastingneurobiologicaleffects.

ThestudiesinChapterIIIexaminedseveralmeasureshypothesizedto

assessimpulsivity.Ingeneral,unconditionedbehaviorsdidnotshow

differencesinimpulsivity,whilebehaviorsinvolvingschedule‐controlled

respondingweremoresensitive.Overall,maleprenatallycocaine‐exposed

monkeysweremoreimpulsivethancontrolswhiletherewerenodifferences

inoverallimpulsivityobservedinfemales.

ChapterIVwasaimedatdeterminingwhethertheneurobiological

andbehavioraloutcomesobservedearlierwouldresultinalteredsensitivity

tothereinforcingeffectsofcocaine.Prenatallycocaine‐exposedmonkeys

acquiredcocaineself‐administrationatlowerdosesthancontrols.

Vulnerabilitytoself‐administercocainewasfoundtoberelatedtoan

individualphenotypeinvolvingincreasedD3receptorfunctionandincreased

impulsivity.

Inconclusion,theresearchpresentedinthisdissertationsuggeststhat

cocaineuseduringpregnancycanhavelong‐lastingneurobiologicaland

behavioraleffects.Theseresultsindicatethatavulnerablephenotypefor

cocainereinforcementexistsandthatprenatalcocaineexposuremay

predisposeindividualstowardsthisphenotypeinadulthood.Greater

understandingofthisphenotypecouldleadtoidentificationof

pharmacologicalandbehavioraltargetsforpreventionandtreatmentof

cocaineabuse.

1

CHAPTERIINTRODUCTION

COCAINEABUSE

Cocaineisapowerfulcentralnervoussystemstimulantthatinhibitsthe

synapticuptakeofdopamine(DA),norepinephrine(NE),andserotonin(5‐HT)

bybindingtothetransportersfortheseneurotransmitters(Benowitz,1993).

Cocainealsoactivatestheperipheralsympatheticnervoussystemandhaslocal

anestheticeffects(Krug,1989).Physicalandpsychologicalsymptomscanarise

frombothacuteandchroniccocaineuse.Physicalconsequencesinclude

myocardialinfarctions,ischemiccomplications,arrhythmias,seizures,lossof

consciousness,andmigraineheadaches(Gradman,1988;Klonoffetal.,1989;

Romeroetal.,2002).Theacutebehavioraleffectsofcocaineuseinclude

irritability,impairedjudgment,aggressiveness,sexualdisinhibition,increased

impulsivity,andmanicexcitement(TaylorandHo,1977;EstroffandGold,1985;

Hurlbut,1991;Das,1993).Chronicuseofcocainehasbeenassociatedwith

somaticcomplaints,depression,anxiety,paranoia,memoryloss,andproblems

withexecutivefunction(Jovanovskietal.,2005;Minnesetal.,2008).

ThepeakofthecocaineepidemicintheUnitedStatesoccurredinthe

mid‐1980s,whenabout8millionAmericanswereusingcocaineregularly

(CreglerandMark,1986).The1988NationalHouseholdSurveyonDrugAbuse

(NHSDA)foundthatthenumberofheavycocaineusersincreasedsignficantly

from1985to1988(SAMHSA,1988).Duringthis3yearperiod,therewasa33%

increaseamongthoseusingcocaineonceaweekormore(SAMHSA,1988).The

2

numberofAmericanswhousedcocainewithintheprecedingmonthwasatan

alltimehighof7.1millionin1985(SAMHSA,1986)and1in3youngadults

reportedusingcocaineatleastonce(O’Malleyetal.,1991).Today,cocaineuseis

stillwidespreadintheUnitedStateswith2.4millionAmericansconfirming

currentcocaineuse(SAMHSA,2006).Additionally,epidemiologicdatasuggest

thatcocainedependencemaybegrowinginWesternEuropeandAfrica,

evidencedbythelargestrecentincreaseincocaineseizures(UnitedNations,

2007),makingthisaglobalpublichealthproblemaswell.

Cocaineuseamongfemalesofchildbearingageissignificantpublic

healthconcern.ThemostrecentNationalSurveyonDrugUseandHealth

(NSDUH)foundthatin2006‐2007,5.6%ofpregnantwomenages15to44

reportedusingillicitsubstancesinthepastmonthandalmost1.0%reported

currentuseofcocaine(SAMHSA,2008).Ofalltheillicitsubstances,cocaine,

secondonlytomarijuana,remainsoneofthemostwidelyusedillicit

substancesamongwomenduringpregnancyandiscommonlyused

concurrentlywithtobaccoandalcohol(NIDA,1996;SAMHSA,2006).Infact,

inthe1990s,typicallyupto10‐20%oflivebirthsinsomeurban,primarily

lowsocioeconomicstatusareas,testedpositiveforcocaineexposure(Church

etal.,1991;Kandeletal.,1998;WetheringtonandRoman,1998)althoughit

wasreportedashigh40%inonestudy(Ostreaetal.,1992).Reportsfromthe

mostrecentNationalPregnancyandHealthSurvey(NPHS)estimatethat

45,000infantsprenatallyexposedtococainearebornannually(NIDA,1996).

However,sincetheNPHSisbasedonself‐report,itislikelythatitisan

3

underestimateofthescopeoftheproblem(Markovicetal.,2000;Savitzet

al.,2002,Bessaetal.,2010).

Evenwithconservativeestimates,widespreaduseofcocaineinthe

UnitedStateshasresultedinupwardsof1.5millionchildrenprenatally

exposedtococaine,manyofwhomarenowenteringadolescenceoryoung

adulthood,atimewhenmanyexperimentwithdrugsofabuse.Young

adolescentswithparentswhoabusedrugsare2‐3timesmorelikelytotry

substances(Newcombetal.,1983;Jacksonetal.,1997;Kaplowetal.,2002).

Furthermore,thesechildrenare2‐4timesmorelikelytohavedevelopeda

substanceusedisorderduringadolescence(Biedermanetal.,2000).Since1

in5Americansages21‐25yearsoldhavetriedcocaineatleastonceintheir

lifetime(SAMHSA,2008),thisisalargepublichealthproblemifprenatal

exposuretococaineincreasesvulnerabilitytodrugdependence.Thefocusof

theresearchinthisdissertationisonthelong­termeffectsofprenatal

cocaineexposure,specificallyvulnerabilitytoself­administerdrugsof

abuse.

DOPAMINE

Thebehavioralandreinforcingeffectsofcocainearethoughttobe

primarilymediatedbytheDAsystem(Robertsetal.,1977,1980;Wise,1984;

Ritzetal.,1987;Bergmanetal.,1989;Madrasetal.,1989;Kuharetal.,1991).DA

neuronsarewidelydistributedintheadultcentralnervoussystemandDA

4

servesavarietyoffunctionsinthematurebrain,includingcontrolofmovement

andtheregulationofendocrine,cardiovascular,andlimbicsystems.

DAissynthesizedfromconversionofL‐tyrosineintoL‐dopabytyrosine

hydroxylase,therate‐limitingenzyme.L‐dopaisconvertedtoDAbyactivityof

DOPAdecarboxylase.DAreceptorsarecharacterizedbyanintracelluarC‐

terminusregion,anextracellularN‐terminusregion,andsevenmembrane

spanningregions.Thereceptorsarecoupledintracellularlytoguanine

nucleotidebindingproteinsthatinduceintracellularsignalingcascades,which

caninfluenceregulationofcalciumandpotassiumchannelsonthepostsynaptic

membrane.

TheDAreceptorscanbedividedintotwosuperfamiliesbasedontheir

pharmacologicalprofilesandsequencehomology:D1‐likereceptorsandD2‐like

receptors.D1‐likereceptors,includingtheD1andD5receptorsubtypes,catalyze

thesynthesisofcyclicadenosinemonophosphate(cAMP)fromtheactionof

adenylatecyclaseonadenosinetriphosphate.StimulationofD2‐likereceptors,

includingtheD2,D3,andD4receptorsubtypes,hasoppositeeffects,inhibiting

cAMPsynthesis(KebabianandCalne,1979;Missaleetal.,1998).DAtransmitter

actionisterminatedbyre‐uptakeintothepresynapticterminalbyahighaffinity

plasmamembranedopaminetransporter(DAT)andenzymaticallydegradedby

monoamineoxidase(MAO)orcatechol‐O‐methyltransferase(COMT).

Thereareseveralmajordopaminergicpathways.Thenigrostriataltract

consistsofdopaminergicneuronsinthesubstantianigra(SN)parscompacta

thatterminateinthestriatum,amajorDA‐containingareaofthebrain.The

5

striatumisacomponentoftheextrapyramidalmotorsystemandplaysan

essentialroleinthecoordinationoflocomotoractivity.Themesolimbicand

mesocorticalDApathwaysaretwomidbraindopaminergicpathwaysimplicated

inbehaviorsassociatedwithmotivation,reward(bothendogenoussystemsand

drugabuse),andreinforcement.Bothpathwaysbegininthemidbrainventral

tegmentalarea(VTA)andprovideinputtothenucleusaccumbens(NAc)and

frontalcortex(bothmedialprefrontal(mPFC)andanteriorcingulate(ACC)),

respectively(Olsonetal.,1973).Inmonkeys,ithasalsobeenobservedthata

subsetofVTAneuronsprovideinnervationtothecaudatenucleusofthe

striatum(Lynd‐BaltaandHaber,1994a,1994b;Haberetal.,1995).Itisthought

thatstimulationofDAreceptorsinmesolimbicpathwayisinpartresponsible

forthereinforcingeffectsofcocaine(WiseandRompre,1989;Volkowetal.,

1999).Thesubjectiveeffectsofcocainearealsothoughttobemediatedthrough

thissamepathway(DiChiaraandImperato,1988;WiseandRompre,1989;

Wise,1996).

D1‐likereceptorsarepositivelycoupledtoadenylylcyclasethrough

stimulatoryGαproteins,resultinginanincreaseincAMPconcentrations.DAD1

receptorsareprimarilylocalizedinthenucleusaccumbens,olfactorytubercles,

andtheamygdala,whileDAD5receptorsareprimarilylocalizedinthe

hippocampus,hypothalamus,andparafascicularnucleus.ItisthoughtthatD1‐

likereceptorsmayplayaroleinthereinforcingeffectsofcocaine.Several

groupshavedemonstratedthatantagonismofD1‐likereceptorsresultsin

increasesincocaineself‐administrationunderafixed‐ratio(FR)scheduleof

6

reinforcementinrats(Koobetal.,1987;CorrigallandCoen,1991;Hubnerand

Moreton,1991;RanaldiandWise,2001).

D2‐likereceptorsarenegativelylinkedtoadenylatecylasethrough

inhibitorGi/oproteinsandstimulationresultsininhibitionofcAMP

concentrations.Thesereceptorsarefoundthroughoutthebrainincludingthe

caudatenucleus,putamen,nucleusaccumbens,olfactorytubercles,andcerebral

cortex.AprominentroleforD2‐likereceptorsinthereinforcingeffectsof

psychostimulantshasbeenestablished.D2‐likereceptorantagonistsattenuate

thereinforcingeffectsofself‐administeredcocaine(Bergmanetal.,1990;

Brittonetal.,1991;CorrigallandCoen,1991;HubnerandMoreton,1991;Caine

andKoob,1993;Campbelletal.,1999;Naderetal.,1999).

Additionally,Volkowetal.(1999)determinedthatpeoplewithlowD2‐

likereceptoravailabilityasassessedwithpositronemissiontomography(PET)

foundmethylphenidatetobemorepleasantthanpeoplewithhighD2‐like

receptoravailability.Additionally,cocaineabusershavelowerD2‐likereceptor

availabilitycomparedtoage‐matched,non‐drugabusingindividuals(Volkowet

al.,1993;Martinezetal.,2004).MonkeywithlowerD2‐likereceptoravailability

self‐administercocaineathigherratesthanmonkeyswithhigherD2‐like

receptoravailability(Morganetal.,2002;Naderetal.,2006).Itappearsthat

theremaybeopposingeffectsofD1‐likeandD2‐likereceptorsonthereinforcing

effectsofcocaine.

7

DOPAMINERGICRECEPTORSYSTEMDURINGGESTATION

Sincethefocusofthisdissertationisonthelong‐termeffectsofprenatal

cocaineexposure,itisimportanttounderstandthedevelopmentoftheDA

systemduringgestation.Tyrosinehydroxylase(TH),therate‐limitingenzymein

DAsynthesis,isausefulmarkerforidentifyingDAneurons.THisfirstapparent

atEmbryonicday(E)12‐13ofanapproximate21daygestationalperiodinthe

ratmidbrain,andispresentbyE14ofanapproximate30daygestationalperiod

intherabbit.DAisalsolikelytohaveearlybiologicalactivityintheprimate

brain.Inthemonkey,DAneuronsoftheSN/VTAareproducedbetweenE36and

E43ofa165daygestationalperiod(LevittandRakic,1982).Inhumans,

midbrainDAneuronsappearduringthefirsttrimesterinthesecondmonthof

gestation(OlsonandSeiger,1972).Thisinputisthusalreadypresentinthe

cortexevenwhilemoresuperficialcorticallayers(II‐IV)arebeginningtoform,

consistentwithamorphogenicroleofDA.

Axonsofdopaminergiccellsreachthecortexafewdaysaftertheirinitial

detectioninthemidbraininmonkeys(Lambeetal.,2000).Limbiccortical

regions,suchastheACCandmPFCreceivethedensestdopaminergic

innervation.Thedensityoftyrosinehydroxylase‐positiveaxonsinthecortex

increasesgraduallyoverdevelopmentthendeclinespostnatallytoreachadult

levelsduringpuberty(Lambeetal.,2000).

TranscriptsfortheD1,D2andD3receptorscanbedetectedinthe

striatumandcortexbyE14intheratandbyE12inthemouse(Jungand

Bennett,1996;Arakietal.,2007).D1‐likeandD2‐likereceptorsaremeasurable

8

attheseearlyprenataltime‐pointsandincreaseingreatquantitythroughout

prenatalandearlypostnataldevelopmenttoreachadultlevelsofexpression

betweenpostnatalday14and21inrodents(Salesetal.,1989;Raoetal.,1991;

Schambraetal.,1994;Cailleetal.,1995).Inthemonkey,DAreceptorsappearin

targetregionsofDAinputbyweek12ofgestation(Lidowetal.,1991;Lidow,

1995a)andinhumansDAreceptorbindingsiteshavebeendetectedbyweek

twelveofgestation(Aubertetal.,1997).Inallspeciesexamined,DAreceptors

arepresentveryearlyinprenataldevelopment,consistentwitharoleforDAin

regulatingneuronaldifferentiationandcircuitformation.Therefore,theDA

systemisapotentialmodulatorytargetforcocainetoactonduringprenatal

developmentwhenthedrugisusedduringpregnancy(MalangaandKosofsky,

2003;StanwoodandLevitt,2004).

“CRACKBABIES”

Inthe1980s,the'warondrugs'associatedwiththecrackcocaine

epidemicfocusednationalattentionontherelationshipbetweendruguseand

socialandeconomicproblemsinsociety.AnearlyreportinTheNewEngland

JournalofMedicinesuggestedthatprenatalcocaineexposurecouldcause

behavioralandlearningproblems(Chasnoffetal.,1985)andamediafrenzy

over"crackbabies"ensued.DespiteChasnoffandcolleagues’warningsthat

moreresearchwasneededtodeterminethelong‐termeffectsofprenatal

cocaineexposure,mediareportsdescribedchildrenexposedtococaineinutero

asa"bio‐underclass"andforecastedthat"theirswillbealifeofcertainsuffering,

9

ofprobablydeviance,ofpermanentinferiority”(Krauthammer,1989).Therising

trendsofcocaineuseamongpregnantwomen,coupledwiththesetypesofdire

reportsinthepopularpress,resultedinarushtojudgementwithregardtothe

fateofprenatallycocaineexposedchildren(Leshner,1998).

Thepersistenceofthemythologythatprenatallycocaine‐exposed

childrensufferfromamyriadofdevastatingeffectsmaynegativelyshapeclinical

investigations.Observersofchildrenwhoarecocaine‐exposedmaybe

influencedbymediareportsthatfrequentlyover‐generalizefromanecdotal

descriptions.Mediaanecdotaldescriptionshavebeenusedinamannerthat

impliesthatthesechildrenarerepresentativeofallchildrenwhoarecocaine‐

exposed(Neuspiel,1993;DayandRicharson,1993;ElyerandBehnke,1995;

O’NeillandCarter,1999;Will,1999;Rotzoll,2000).Thelabelcocaine‐exposed

maythenimpacttheexpectationsofcliniciansandresearchersworkingwith

children.

Woodsetal.(1998)designedastudythatexaminedtheassociation

betweenthelabelcocaine‐exposedandobservers’perceptions.Collegestudents

fromeducation,nursing,generaleducation,andpsychologyprogramswere

askedtoratebehavioralparametersfromvideotapesofhealthyinfantswho

were,infact,notcocaine‐exposed.Onegroupofobserverswastoldthatthechild

theywereabouttowatchwas“bornwithoutanyknownproblems.”Asecond

groupwastoldthatthesamechildwas“bornwithoutanyknownproblems

otherthanthathermotherusedcocaineduringpregnancy.”Theresultsofthe

studyshowedthatthesameinfantsinthesametapeswhenlabeledascocaine‐

10

exposedduringpregnancywereratedmorenegativelythanwhentheyhadnot

beenlabeledascocaine‐exposed.Thisprejudiceisdamaginginclinicalsettings

andhighlightsthecrucialneedforresearchonthesubjecttobedonethoroughly

andwithoutbias.Prenatalcocaineexposureinanimalmodelsallowsforsuch

objectiveassessmentsacrossawiderangeofbehaviors.

PRENATALCOCAINEEXPOSURE:HUMANSTUDIES

Maternalcocaineuseduringpregnancycontinuestobeofgreat

concernforhealthcareprofessionals.Ithasbeensuggestedthatgestational

exposuretodrugsofabuseisthesinglelargestpreventablecauseofinutero

developmentalcompromiseofinfantsintheUnitedStatestoday(Lesterand

Twomey,2008).Findingsintheliteraturedemonstrateinconsistenciesin

regardtothephysiologicanddevelopmentaloutcomesofinfants/young

childrenprenatallyexposedtococaine.Furtherresearchiswarranted,asitis

evidentfromstudiesthatnotallinvestigatorsarecontrollingforconfounding

variablessuchaspoly‐druguse,whichisnecessaryinordertoisolate

cocaine'seffects.However,themajorityofresearchonthetopicpointstoa

myriadofclinicalmanifestationsthatpresentintheinfant/youngchild.

Cocaineuseduringpregnancyposesarisktobothmotherandfetus

andhasbeenassociatedwithsignificantobstetriccomplications.Pregnant

womenwhousecocainehavebeenfoundtohaveahigherincidenceofpoor

weightgainandcardiaccomplications,suchashypertension,arryhythmia,

11

cardiacischemia,andhemorrhagicstroke(PlessingerandWoods,1998;

Kuczkowski,2003;VidaeffandMastrobattista,2003).Cocaineisknownto

haveanegativeadditiveeffecttothealreadystressedcardiovascularsystem

ofthepregnantwoman(Wagneretal.,1998).Duringpregnancy,thetoxicity

ofcocaineisincreased,thusincreasingtheriskforcardiovascularevents

suchasstrokeandseizures(PlessingerandWoods,1998).Otheradverse

effects,includinguterinerupture,hepaticrupture,placentalabruptionand

maternaldeath,areknowntooccurmorefrequentlyinthoseusingcocaine

(PlessingerandWoods,1998;Kuczkowski,2003).

Prenatalcocaineexposureishypothesizedtodirectlyaffectthe

developmentofthefetalcentralnervoussystemthroughteratologiceffectson

braingrowthanddevelopment.Thefetusisatsignificantriskfromcocaine

exposuresecondarytomaternaluse.Cocainehasalowmolecularweightandis

bothhydrophilicandlipophilic.Thesepropertiesallowsignificantlevelsof

cocainetocrosstheplacentaandpassthroughthebloodbrainbarrier.Fetal

cocaineconcentrationsareequivalenttomaternalcocaineconcentrationswithin

1‐2minutes,raisingfetalheartrate,anddecreasinginternalandplacentalblood

flow(Woodsetal.,1987).Themetabolismofcocaineinthefetusisknowntobe

considerablyslowerthanthatoftheadult.Thus,fetalexposuretococaineis

prolonged(Schenkeretal.,1993;Wagneretal.,1998).AstudybyMahoneand

colleagues(1994)foundcocaineanditsderivativestonotonlybetransferredto

thefetusviadiffusionintotheumbilicalcordandwithintheplacentalvessels,

butalsotobeintheamnioticfluidandthenswallowedbythefetus.Infact,

12

amnioticfluidcanactasarepositoryforcocaineexposuretothefetus.Sanberg

andOlsen(1992)demonstratedthatcocaineconcentrationsinamnioticfluid

were3‐4timesgreaterthaninfetalblood.Cocainecanthenenterthefetalblood

atarateof3%fromtheamnioticfluid(Mahoneetal.,1994).Ifcocaineenters

theamnioticfluidearlyinpregnancy,whenwatertransportacrossfetalskinis

unrestricted,fetalexposuremaybemarkedlyenhancedatacriticaltimeperiod

duringwhichneurotransmitterdevelopmentisbeinginitiated(Woods,1998).

Thedose,thedurationofdrugingestion,andthepointingestationatwhichthe

fetusisexposedtococainedeterminestheeffectthedrugmayhaveonthefetus.

Oneofthemajordifficultiesinstudyingprenatalcocaineexposurein

humansistheproblemofcontrollingforconfoundingandmoderatingvariables.

Forexample,pregnantwomenwhousecocainealsotendtouseotherillicit

substanceslikemarijuanaaswellaslicitsubstancesthatcanhavetoxiceffects

likenicotineandalcohol(Franketal.,1988;ZuckermanandFrank,1989;Hurtet

al.,1995).Therearealsomanybiologicalandsocialconfoundsthatmustbe

takenintoaccount,includingfactorsthatprecedeconceptionlikematernalage,

educationalstatus,nutritionalstatus,anddiseasestatus(Franketal.,1988).

Determiningcriteriaforwhetherprenatalcocaineexposurehasoccurreddiffers

fromstudytostudy.Ascertainmentofcocaineuseduringpregnancyis

commonlydonebyself‐report,althoughthatisnotthemostreliablemethod

(Zuckermanetal.,1989).Moreaccurateascertainmenttechniquesincludeurine

toxicology(Ambreetal.,1982;WeissandGawin,1988),hairradioimmunoassay

13

(Grahametal.,1989;Klineetal.,1992),andmeconiumanalysis(Ostreaetal.,

1989;Lewisetal.,1995).

Thedoseofcocainethefetuswasexposedtoisalsochallengingto

determineinhumanstudies.Aninterestindosehasemerged,though,asitis

thoughtthatgreatercocaineexposurecandisruptbraindevelopmentmoreso

andmayhavegreaterbehavioralandphysiologicalconsequences.Oneissuein

thehumanliteratureisthatthereisnoconsensusforwhatdefinesheavyuseof

cocaine(Franketal.,1998).Itisnotclearwhetherheavyusersinonepopulation

arecomparabletoheavyusersinanotherpopulationbecauseofvariabilityin

potency,routeofadministration,andmodesofascertainmentofdoseofprenatal

cocaineexposure.Infact,someoftheinterviewsdesignedtoidentifyprenatal

cocaineexposureuseacriteriaofheavyuse(usingmorethantwodaysaweek

ormorethanonelineofcocaineaday)thatdoesnotdistinguishbetween

frequencyandquantity(Richardsonetal.,1993;Singeretal.,1994;Jacobsonet

al.,1996).Also,thedoseusedduringpregnancymayvarythroughoutgestation,

astherehavebeenreportsthatwomen’susedecreasesasthepregnancy

progresses(Richardsonetal.,1993).Beyondtheissueofdeterminingdoseof

cocaineexposure,itisnotyetknownwhethertheprimarydeterminantof

adverseoutcomesiscumulativedoseormaximumdoseusedonasingle

occasion(Franketal.,1998).Despitethesechallenges,itdoesappearthatthere

isacocainedoseeffectonneonatalsizeatbirth,onneonatalbehavior,andon

infantinformationalprocessing(Jacobsonetal.,1996;Hurtetal.,1997;

Chiribogaetal.,1999;BatemanandChiriboga,2000).However,thesestudies

14

needtobemorethoroughlyinvestigatedwhilecontrollingforconfounding

biologicalandsocialvariables.

PHYSIOLOGICEFFECTSOFPRENATALCOCAINEEXPOSUREINNEONATES

Cocaine'sphysiologicaleffects,suchasvasoconstriction,

hypertension,andtachycardiaduringpregnancy,mayhaveprofoundeffects

onthefetus.Duringpregnancy,cocainecausesvasoconstrictionofthe

maternaluterinebloodvesselscausinganincreaseinuterinevascular

resistanceanddecreaseduterinebloodflow(Woodsetal.,1987).Oxygen

andnutrientsnormallytransferredtothefetusviathesevesselsareunable

toreachtheplacentaandfetusresultinginuteroplacentalinsufficiencyand

fetalhypoxemia(Woodsetal.,1987).Thisuterinevasoconstrictionmaybe

theprimarycauseforsuchcomplicationsasspontaneousabortion,

prematurelaboranddelivery,abruptioplacentae,andfetalintracranial

hemorrhage(Ackeretal.,1983;Bingoletal.,1987;Cohenetal.,1991;

WoottonandMiller,1994;PlessingerandWoods,1998;Fajemirokun‐

OdudeyiandLindow,2004).

Although,oneofthemetabolitesofcocaine,benzoylecgonine,does

notcrosstheplacentaveryreadily,theplacentaisstilladirecttargetfor

cocaine.Therefore,theplacentaltransfersystemsareadverselyaffectedfor

essentialnutrientsaswell.Placentalperfusioncanbecompromisedbyas

muchas50%inmotherswhoingestcocaine(Woodsetal.,1987).Decreased

15

fetaloxygenlevelshavealsobeennotedwithmaternalcocaineexposure

(Chao,1996).Inanimalstudies,adecreasedlevelofoxygenationwasnot

seenwithdirectadministrationofcocainetothefetus(Chao,1996).

Therefore,thisproblemsuggestsdecreasedoxygenationresultsfrompoor

placentalperfusion.

Ithasrecentlybeenshownthatcocaineispharmacologicallyactivein

thenonhumanprimatefetalbrain(Benvenisteetal.,2010).Thisindicates

thatprenatalcocaineexposuremaynotjusthaveharmfuleffectsonafetus

duetoplacentalcirculationbutalsoduetococainedirectlyactingonthe

developingbrain.Therefore,deleteriouseffectsofcocaineonbrain

developmentcanoccureitherdirectly,byinfluencingbothstructuraland

functionalaspectsoffetalbraindevelopment,orindirectly,throughhypoxic

stateswhichcanalterneuraldevelopment.Directteratologicmechanisms

canaffecttheneurogenesisofneuralsystems,includingalterationson

monoaminergicsystemdevelopmentandneuralgrowthfactors,destruction

ofionchannelandmonoaminesystems,andpossiblealterationofgene

expression(Mayes,2002).

Recentanimalandhumanimagingdatahavebeguntorevealevenmore

specificareasofinsultattributabletoprenatalcocaineexposure.Leeetal.

(2008)haveisolatedamechanism(down‐regulationofthecellcycleregulatory

proteincyclinA)fortheinhibitionofneuralprogenitorcellproliferation

observedinfetalrodentsexposedtococaineinutero.Physiologicchangesto

16

humanbrainsafterfetalcocaineexposurehavebeenidentifiedasreduced

cerebralbloodflow(Raoetal.,2007),reducedcorpuscallosum(Singeretal.,

2006),andsmallercaudate(Avantsetal.,2007)incocaine‐exposedindividuals

comparedtocontrols.

Monamineshavebeenthefocusofseveralstudiesastheyhaveatrophic

influenceondevelopingbraincells.Blockadeofmonoaminesmayalsobea

mechanismbywhichprenatalcocaineperturbsthebrainarchitecture(Cabrera‐

Veraetal.,2000).Severalstudieshaveexaminedareasofthebrainthatare

monoamine‐richinprenatallycocaineexposedanimalsandhavefoundevidence

ofalterationsinbraincelldevelopment,includingthematurationand

progressionofbraindevelopmentbeyondthefetalperiod(Renetal.,2004;

Morrowetal.,2005;Leeetal.,2008).Therefore,monoaminecircuitrythat

influencesrisk‐takingbehaviorandregulatessubstanceuse,emotionaland

behavioralreactivitytostress,attention,andexecutivefunctioningisof

particularrelevancetothestudyofprenatallycocaine‐exposedadolescenceand

youngadults.InChapterII,thelong‐termeffectsofprenatalcocaineexposure

onthedopaminereceptorsystemwereexamined.

PHYSIOLOGICALEFFECTSOFPRENATALCOCAINEEXPOSUREININFANTS

Humanresearchinvolvingverylargesamplesizes,multivariatestatistical

analyses,andcontrolforimportantconfoundshasfoundconsistentpatternsof

deficitamongnewbornsandinfantsexposedtococaine.Intrauterinegrowth

17

retardation,prematurity,lowbirthweight,anddeficitsinbirthlengthandhead

circumferenceforgestationalagehavebeenconsistentlyrelatedtofetalcocaine

exposureininfantsdespitedifferingmethodologies(Singeretal.,1994,2002;

Chiribogaetal.,1999;Richardsonetal.,1999;BatemanandChiriboga,2000;

Kuhnetal.,2000;Bandstraetal.,2001;Badaetal.,2002,2005;Behnkeetal.,

2006).Singerandcolleagues(2002)compared218infantswhowereprenatally

exposedtococaineto197whowerenotandreportedthatcocaineuseduring

pregnancywasassociatedwithanincreaseinprematurelaboranddelivery,

lowerbirthweight,smallerheadcircumference,adecreaselengthatbirth,and

shortergestationalage.Similarly,Bandstraetal.(2001)notedcocaine‐

associateddeficitsinbirthweightandlengthbutnotheadcircumference.

PrematuritywasnotfoundbyBandstraetal.(2001),astheinfantsstudiedwere

full‐term.BothSingeretal.(2002)andBandstraetal.(2001)includedatarget

populationofprimarilyAfrican‐Americanpregnantwomenoflow‐

socioeconomicstatuswithcocaineuse,identifiedconfoundingvariables

includingpoly‐druguse(i.e.,alcohol,marijuana,tobacco,etc.),andcontrolledfor

thesevariablesincomparisongroups.

Inastudyexamining295infantsprenatallycocaine‐exposedwhose

motherreceivednoprenatalcareascomparedto98infantswhosemother

didreceiveprenatalcarebythefifthmonthofpregnancy,Richardsonetal.

(1998)notedthatduringearlypregnancyinfantsfrombothgroupsexhibited

lowergestationalage,birthweight,length,andheadcircumference.The

authorsconcludedprenatalcocaineexposurewasassociatedwithrestricted

18

intrauterinegrowthregardlessofprenatalcare.Confoundingfactors

(alcohol,tobacco,marijuana,otherillicitdrugs,maternalandinfant

variables)werecontrolledandattheendofeachtrimesterbothgroupswere

questionedabouttheiruseofcocaine/crack,alcohol,marijuana,tobaccoand

otherdruguse.

BatemanandChiriboga(2000)investigatedtherelationshipbetween

birthweightandheadcircumferencewiththequantityofcocaineexposure

in240non‐randomizedfull‐terminfantsfromasingleinner‐cityhospital.

Levelsofcocaineexposureweremeasuredusingradioimmunoanalysesof

hairinthethirdtrimesterofpregnancy.Measurementsindicatedno

exposure(136infants),lowexposure(52infants),andhighexposure(52

infants).Adjustmentsweremadefortheconfoundingvariablesofuseof

alcohol,tobacco,marijuana,andopiatesduringpregnancyaswellasinfant

andmaternalcharacteristics.Adose‐responseeffectofcocaineonthe

neonates'headcircumferencewasonlyfoundinthehigh‐exposuregroup.

Chiribogaetal.(1999)andKuhnetal.(2000)reportedsimilarfindings.

Chirbogaetal.(1999)alsofoundadecreaseinbirthlengthsamonginfants

prenatallyexposedtococaineathighlevelsofexposure.Insummary,

researchindicatesprenatalexposuretococainemayaffecttheinfant's

gestationalageatbirth,length,weight,andheadcircumference.Asdescribed

inmoredetaillaterinthischapter,theprenatallycocaineexposedmonkeys

usedinthisdissertationshoweddecreasedinfantbodyweight,bodylength,

andcrowncircumferenceatbirthcomparedtocontrols(Morrisetal.,1997).

19

However,therewerenodifferencesinpostnatalgrowthoftheoffspringover

thefirst18monthsbetweenthetwogroups(Morrisetal.1996).Themean

weightofthetwogroupshasnotbeendifferentsince12monthsofage.

NEUROBEHAVIORALANDNEUROLOGICALOUTCOMES

Ininfantsandpreschoolers,apatternofneurocognitiveprocesses

(Azumaetal.,1993;Mayesetal.,1993;Jacobsonetal.,1996;Lesteretal.,1998;

Singeretal.,2000)hasbeenshowntobenegativelyaffectedbyfetalcocaine

exposureinthedomainsofattention(Singeretal.,2000;Gaultneyetal,2005),

arousalmodulation(Morrowetal.,2001;Mayes,2002),cognitiveandlanguage

processing(Alessandrietal.,1993;1998;Singeretal.,2001;Morrowetal.,

2003;Lewisetal.,2004),andtoneandmotorfunction(Arendtetal.,1999).

However,someoftheseneurobehavioralreportsareconflicting.

Inanearlystudy,Mayesetal.(1993)administeredtheBrazeltonNeonatal

BehavioralAssessmentScale(NBAS)to56newborns(24‐48hoursold)

prenatallyexposedtococaineand20matchednewbornswhowerenotexposed.

Theauthorsfoundtheinfantsprenatallycocaine‐exposedonlydemonstrateda

lowerscoreonthehabituationclusteroftheNBAS,whichindicatesthatthe

infantsrequiredmorestimulusexposuresbeforetheydemonstratedadecreased

responsetothatstimulation.A1995studyexaminedtheassociationbetween61

3‐month‐oldinfantsprenatallyexposedtococaineand47non‐exposedinfants

(Mayesetal.,1995).Controllingforpoly‐druguse,theauthorsdocumentedno

20

differenceininformationalprocessingbyhabituationandresponsetonovelty

relatedtoprenatalcocaineexposureassessedbyavisualhabituationand

noveltyresponsivenessprocedure.Aretrospectivestudyfound464infants

heavilyexposedtococaineprenatallytohavepoorerscoresonthenovelty

preferencetestat6.5and12monthsandfasterreactivityonthevisual

expectancyparadigmat6.5months(Jacobsonetal.,1996).

Whileexaminingneonatesprenatallycocaine‐exposed,Morrowetal.

(2001)andDelaney‐Blacketal.(1996)found,aftercontrollingforcovariates,

significantdifferencesinallNBASclusterscores.However,Morrowetal.

(2001)foundnodifferenceinabnormalreflexesandDelaney‐Blacketal.

(1996)reportednodifferenceinhabituationintheneonatesprenatally

cocaine‐exposed.Delaney‐Blacketal.(1996)alsofoundinfantswithhigher

meconiumconcentrationsofcocainemetaboliteshadpoorermotorskillsand

regulationofstate.Tronicketal.(1996)examined251full‐terminfants

prenatallycocaine‐exposedandfoundpoorerregulationarousal(state

regulationandexcitability)amongonlytheinfants"heavily"cocaine‐exposed

at3weeks,butnotat3daysofageontheNBASwhilecontrollingfor

covariates.Infantsheavilycocaine‐exposedwerealsofoundbySingeretal.

(2000)tobefourtimesaslikelytobe"jittery"andhavemoremovementand

toneabnormalitiesandsensoryasymmetriesthanthelightlyornon‐exposed

neonates.Theauthorsstatisticallycontrolledforotherdrugexposures.

21

Kingetal.(1995)foundneurobehavioralabnormalities(increased

jitteriness,hyperactiveresponses,andexcessivesucking)onday1and2of

lifeinneonatesexposedtococaineinutero,evenwhilecontrollingfor

confoundingvariables.WhileKingetal.(1995)identifiedtheseresultsas

consistentwithwithdrawal,areportfromtheAmericanAcademyof

Pediatrics(1998)suggestedthatthesesignsofneurobehavioraland

neurologicalalterationswerearesultofthetoxiceffectsofcocaineitself

ratherthanevidenceofwithdrawal.Overall,itdoesappearthatprenatally

cocaine‐exposedinfantshavedeficitsinarousalandnoveltyresponsiveness.

Inthisdissertation,severalmodelsofimpulsecontrol,includingreactionto

novelty,wereexaminedinadultmonkeysprenatallycocaineexposedto

cocaineandcontrols(ChapterIII).

COGNITION

Theresultsofstudiestodetermineanassociationbetweenacognitive

delayandprenatalcocaineexposureareconflicting.Severalstudies

documentednostatisticallysignificantdifferencesoncognitivedevelopment

assessedbytheBayleyScaleofInfantDevelopment's(BSID)Mental

DevelopmentIndex(MDI)amonginfants/youngchildrenexposedtococaine

prenatallywhentestedat6‐24months(Jacobsonetal.,1996;Kilbrideetal.,

2000;Franketal.,2002;Messingeretal.,2004).

22

Similarly,Korenetal.(1998)investigatedtheintelligencequotient

(IQ)of21/2‐year‐oldchildrenprenatallycocaine‐exposed(n=23)and

adoptedatbirthintomiddletoupperclassfamiliestoacontrolgroup(n=

23).Theauthorsclaimthattheirdesignprovidedexclusionofpostnatal

environmentinfluencesonthecognitivefunctioningofinfantsprenatally

exposedtococaine.AfteradministeringtheBayleyandMcCarthyIQtests,

theyfoundnodifferencesinglobalIQbetweenthetwogroups;however,

theyreportedatrendtowardslowerIQofthechildreninthecocaine‐

exposedgroup.

Incontrast,Singerandcolleagues(2002)reportedinfantsprenatally

exposedtococaineweretwiceaslikelytohavesignificantcognitivedelays

throughouttheirfirst2yearsoflifethannon‐exposedinfants.Alessandrietal.

(1998)andLewisetal.(2004)reportedlowerMDIscoresamonginfants/young

childrenheavilyprenatallycocaine‐exposed.Alessandriandcolleagues(1998)

examinedthecognitivefunctioningofinfantsprenatallycocaine‐exposed

(heavilyexposed[n=30)andlightlyexposed[n=30]toamatchedcontrol

group[n=169]at8and18monthsofage)usingtheBSID’sMDI.They

documentedadecreaseinMDIscoresonlyat18monthsofageamongallinfants

prenatallycocaineexposed,buttheinfantsheavilyexposedhadthepoorest

scores.Lewisandassociates(2004)examinedtheeffectsofprenatalcocaine

exposureandcognitivedevelopmentat12,18,24,and36monthsof147young

childrenwhowereexposedand89whowerenot.Aftercontrollingfor

confoundingfactorssuchassocioeconomicstatusandmaternaleducational

23

levelandusingtheBSID’sMDI,theauthorsfoundtheyoungchildrenwithhigher

meconiumconcentrationsofcocainemetaboliteshadlowertestscoreswitha

declineat18monthsonmentaldevelopment.

Withregardtoolderchildren,prenatalcocaineexposureappearedto

resultinmorespecificratherthangeneralcognitiveeffects.Forexample,seven

yearoldprenatallycocaineexposedchildrenweredeterminedtobe2.8times

morelikelytoexperiencelearningdisabilitiesthancontrolsubjects(Morrowet

al.,2006).Singerandcolleaguesfoundthatprenatallycocaineexposedchildren

atages4and9yearsoldperformedmorepoorlyontasksrequiringvisual

perceptualreasoningthannon‐cocaineexposedchildrendespitenoFullScaleIQ

differencesbetweengroups(Singeretal.,2004;Singeretal.,2008).Additionally,

decreasedvisualmotorskills(Arendtetal.,2004),visualspatialworking

memory(Schroderetal.,2004;Mayesetal.,2007),anddeficitsinvisualspatial

integration(Singeretal.,2004)havebeenobservedinprenatallycocaine‐

exposedchildren.Whilenotexaminedinthisdissertation,bothgroupsof

monkeyswillbestudiedincognitiontasksinthecomingyears.

ATTENTION/EXECUTIVEFUNCTION

Attentionandexecutivefunctiondomainshavebeenextensively

investigatedinprenatallycocaineexposedchildrenandapatternofdifficulties

withsustainedandselectiveattention(Bandstraetal.,2001;Savageetal.,2005;

Linaresetal.,2006)havebeenrevealed.Instudiesofselectiveattention,

childrenexposedtococaineprenatallymademorecommissionerrors(Noland

24

etal.,2005)andomissionerrors(Accorneroetal.,2007)comparedtocontrols.

TheStroopTaskhasbeenusedtoinvestigateexecutivefunctioninthese

childrenaswell.Prenatallycocaineexposedchildrengeneratedlonger

responsestowordsinthistaskthannon‐exposedchildren,suggestingthatearly

cocaineexposuremayinhibitthespecializationandefficiencyoffrontal

functioning(Mayesetal.,2005).Attheageoffouryearsold,increasedratesof

commissionerrors,whichindicategreaterimpulsivity,werefoundusingan

adaptedversionoftheConnors’ContinuousPerformanceTest(Minnesetal.,

2010).Inthesamecohortat6yearsold,theprenatallycocaineexposedchildren

werereportedtodemonstratemoresymptomsofinattentionthanacontrol

group(Linaresetal.,2006).

ANTISOCIAL/AGGRESSIVEBEHAVIOR

Behavioralproblemshavebeenreportedinprenatallycocaine‐exposed

childreninseverallargewell‐controlledstudies.Studiesusingavarietyof

measuresincludingselfreport(Linaresetal.,2006),caregiverreport(Soodet

al.,2005;Accorneroetal.,2006;Warneretal.,2006;Badaetal.,2007;Minneset

al.,2008),teacherreport(Delaney‐Blacketal.,2000;NordstromBaileyetal.,

2005),oracombination(Benderskyetal.,2006),haverevealedapatternof

behaviordisturbancesinvolvinginhibitorycontrol,externalizing,aggressiveand

delinquentbehaviorproblemswithspecificgendereffectsrevealedinsome

studies(Delaney‐Blacketal.,2000;2004;NordstromBaileyetal.,2005;Soodet

al.,2005;Benderskyetal.,2006;Minnesetal.,2008).Forexample,withregard

25

toimpulsivity,BenderskyandLewis(1998)foundthat2year‐oldprenatally

cocaine‐exposedchildrenhadlessimpulsecontrolcomparedtothoseexposedto

othersubstancesbutnotcocaineinutero.Childrenwereseatedatatableupon

whichanexperimenterhadplacedacookieandweretoldnottotakethecookie

untiltheexperimenterreturned.Theexperimentergavethechildanoveltoy,

lefttheroom,andretunedaftertwominutes.Itwasfoundtheprenatallycocaine

exposedchildrenhadshorterlatenciestoreachfor,totake,andtoeatthecookie

comparedtocontrols(BenderskyandLewis,1998),indicatingthatgestation

cocaineexposurealtersimpulsecontrol.However,therehavebeenalimited

numberofstudiesthatfoundeithernodifferences(Accorneroetal.,2006)or

attributedthenegativebehavioralfindingstopoorenvironments,maternal

psychopathology,gestationalweaknesses,and/orenvironmentalleadexposure

ratherthanthedirecteffectsofcocaine(Accorneroetal.,2002;Warneretal.,

2006).

Earlyresearchfocusingoncaregiverreportsindicatedhigherratesof

behavioralproblemsinchildrenprenatallyexposedtococainecomparedtonon‐

cocaine‐exposedchildren(Richardson,1998;Chasnoffetal.,1998).Several

studieshaverecentlyfoundanincreaseinhyperactivityandexternalizing

behaviorsinprenatallycocaine‐exposedchildren(Linaresetal.,2006;

Benderskyetal.,2006).Thesebehavioralissuesappeartobeexaggeratedin

malechildrenexposedtococaineinutero,withprenatallycocaine‐exposedboys

oftendemonstratingmoreaggression,hyperactivity,anddisruptivebehavior

thannon‐exposedboys,whereasgirlsdonotshowthesedifferences(Bendersky

26

etal.,2006;Bennettetal.,2007;Delaney‐Blacketal.,2004).However,arecent

studyindicatestheincreasedoddsofdelinquentbehaviorassociatedwith

prenatalcocaineexposuretobefoundonlyingirls(Minnesetal.2010).This

discordancewithearlierstudieshasbeenattributedtoatrendtowardsgreater

easeofreportingantisocialandaggressivebehavioramongfemales,especially

amongthoseknowntobeatsomebiologicrisksuchasprenatalcocaine

exposure.

Insummary,importantpatternsofdifferenceshaveemergedbetween

prenatallycocaine‐exposedchildrenandcontrolsinhumancohortstudies.

Developmentaldifferenceshavebeenwelldocumentedandincludedeficitsfrom

prenatalcocaineexposureonvisualrecognitionandmemory(Singeretal.,1999;

2005),attention(Singeretal.,2000;Nolandetal.,2005;Linaresetal.,2006),

birthoutcomes(Singeretal.,2002),earlycognitiveandlanguagedevelopment

(Singeretal.,2001;2002),perceptualreasoning(Singeretal.,2004;2008),and

aggression/impulsecontrol(Linaresetal.,2006).Thedifferencesthathavebeen

observedbetweenprenatallycocaineexposedchildrenandnon‐exposed

childrenhavemeaningfulimplications.Whilethedevelopmentaloutcomesin

whichdifferenceshavebeenfoundinthehumancohortstudieshavesmallto

moderateeffectsizes(rangingfrom0.2‐0.5),thesedifferencescontinuetobe

observedasaconsistentpatternofdeficitsattributedspecificallytoprenatal

cocaineexposure.Additionally,ithasbeenreportedthatevensmalldifferences

andsubtleeffectshavebeenshowntoresultinasubstantialnumberofcocaine‐

27

exposedchildrenrequiringspecialeducationortherapeuticintervention(Lester

etal.,1998).

Todate,therearenostudiesthathavedocumentedthepersistenceof

earlycognitiveimpairmentandbehavioralproblemsduetoprenatalcocaine

exposurethroughtheadolescentandyoungadultperiod.Yetsignificant

disruptioninprenatalneuronaldifferentiationandinthedevelopmentof

neuronalcircuitryandanatomy(Dow‐Edwardsetal.,2006;Singeretal.,2006)

canhavepermanenteffectsonlong‐termoutcomes.Additionally,somelong‐

termoutcomes,likesubstanceabuseandmentalillness,maynotemergeuntil

laterinlife.Itishypothesizedthatbehaviorssuchasimpulsivity,sensation

seeking,andcognitiveimpairmentsindecision‐makingmaymanifestin

adolescenceandyoungadulthoodinsuchactivitiesasdrugabuse,riskysexual

behaviors,criminality,teenpregnancy,andschooldrop‐out.Forexample,some

cognitiveeffectsofprenatalcocaineexposuremaynotappearuntilthese

children’scognitiveabilitiesalongcertaindimensionsarechallengedasthey

advanceintheirschooling.Ifpervasivecompensatoryadjustmentsoccurforthe

impactofprenatalcocaineexposure,theremaybesubstantialrecoveryinany

compromisedbrainsystemsallowingforretentionorreturnoffunction.

However,along‐termcostofsuchcompensatoryneuralreorganizationmaybea

decreaseinadaptability(HughesandSparber,1978;Spear,1996).Some

behavioralandphysiologicalfunctionsmayappearnormalunderbasaltesting

conditionsanddeficitsmayonlybecomeunmaskedwhentheserectifiedneural

systemsaretaxedbystressorsorotherchallenges.Forexample,self‐regulating

28

problemsobservedininfantsandchildrenprenatallycocaineexposedmaybe

earlymarkersforthedevelopmentofmentalhealthconcerns,notapparentuntil

onsetofdruguseorstressfultransitionsassociatedwithadolescent

development.

Centraltotheproblemofrisk‐takingbehavioramongprenatallycocaine‐

exposedadolescentsandyoungadultsiswhetheritisrelatedtopredisposition

towarddrugseekingandaddictioninthisgroup.Researcheffortsthatidentify

earlyriskandprotectivefactorsforsubstancedependenceamongprenatally

cocaine‐exposedchildrencanultimatelypreventhumansufferingandreduce

publichealthexpenditures.Itcanalsobearguedthatthepatternsofdifferences

found,ratherthanthenumberofdifferencesfound,haveimportantimplications

fordisruptionsinadultbehavior.Forexample,attentionandexternalizing

behaviorproblemshaveconsistentlybeenfoundamongprenatallycocaine‐

exposedchildren.Thispatternofbehaviorhasbeenassociatedwiththe

developmentofsubstanceusedisordersandconductproblems.Researchefforts

focusingonexamininggroupdifferencesinsubstanceuseriskandprotective

factorsamongprenatallycocaineexposedadolescenceandyoungadultshelp

provideafoundationforpreventionandinterventionofdrugabuse.Currently,

thehumancohortstudieshaveonlyfollowedtheprenatallycocaine‐exposed

childrenandnon‐exposedcontrolsthroughage13years.Itisnotyetknown

whetherprenatalcocaineexposureisassociatedwithincreasedriskofspecific

typesofsubstancedependence,mentalhealthproblems,orotherhigh‐risk

behaviors.Additionally,researcherswithhumans,unlikethoseusinganimal

29

models,struggletorefinetheirmethodstoascertainaccuratelywhethercocaine

exposureoccurredaswellastodeterminegestationaltimingofexposure,the

acuteandcumulativedosestowhichthefetuswasexposedto,andtocontrol

otherpotentiallyconfoundingvariables.Therefore,thestudiesinthisdissertation

investigatingthelong­termeffectsofprenatalcocaineexposureonriskfactorsfor

drugabuseinadultmonkeysofferanimportantcomplementtothehumanstudies.

PRENATALCOCAINEEXPOSURE:ANIMALSTUDIES

Parallelingthehumanlongitudinalstudies,theanimalliteratureindicates

thatprenatalcocaineexposurehaspersistent,specific,negativeeffectsonbrain

anatomy,organization,andneurotransmitterfunction.Learning,memory,

attention,emotionalreactivitytostress,andvulnerabilitytosubstanceabuse

havebeeninvestigatedinprenatallycocaine‐exposedanimals.Differentanimal

models,designedtomimichumandruguseduringgestation,confirmthat

prenatalcocaineexposureresultsinspecificandlong‐lastingbehavioral,

cellular,andmolecularchanges(Mayes,2002;Lidow,2003;Harvey,2004;

StanwoodandLevitt,2004).However,theextentandnatureofthecellular

alterationsvaryacrossmodelsystems.Deficitsrangefromalterationsinbasic

processesofneocorticaldevelopmentthatresultinalteredcellproduction,

migration,andgeneticregulation(Lidow,1995a,1995b;LidowandSong,2001a,

2001b;Crandalletal.,2004;Renetal.,2004;Guerrieroetal.,2005;Leeetal.,

2008;Novikovaetal.,2008),tomoresubtlechangesincellularmorphology,and

molecularsignalingcascadeswithinDA‐richregionsofthecerebralcortex

30

(Jonesetal.,1996;2000;Stanwoodetal.,2001;StanwoodandLevitt,2003;

2007).

MolecularanalyseshavedeterminedthattheDAD1receptorexhibits

permanentreducedcouplingtoitsG‐proteinfollowingprenatalcocaine

exposure(Wangetal.,1995;Friedmanetal.,1996;Jonesetal.,2000).This

reductionincouplingisaresultofDAD1receptorremaininginternalizedand

nottraffickingproperlytothecellmembrane(StanwoodandLevitt,2007).Adult

rabbitsexposedtococaineprenatallyalsoexhibitgreatlyreduced

psychostimulant‐inducedstereotypies,consistentwithdiminishedD1receptor

signaling(SimanskyandKachelries,1996;StanwoodandLevitt,2003).Itis

importanttoemphasizethatotherreceptorsignalingdoesnotappeartobe

altered,norisD2couplingalteredintheDA‐richbrainregions(Wangetal.,

1995;Friedmanetal.,1996).ThisselectivereducedcouplingoftheD1receptor

hasbeenimplicatedinthecellular,morphological,andbehavioralchanges

observedfollowingprenatalcocaineexposureinthisteratologicmodel.

AdditionalevidencetosupportaroleforalteredD1receptorsignalingatthe

cellularlevelcomesfromstudiesoftheD1receptorknockoutmouse,which

exhibitssimilarcellularandmorphologicalchangestotheprenatalcocaine

exposedrabbits(Stanwoodetal.2005).

Incontrasttotherelativelyfewcellulareffectsdetected,consistent

behavioralchangesincludingdeficitsinattentiontasks,emotionalreactivity,and

thereinforcingeffectsofdrugsofabusethatcorrespondwiththehumanclinical

literatureareobservedinavarietyofanimalmodelsofprenatalcocaine

31

exposure(Morrowetal.,2002;Rochaetal.,2002;Gabrieletal.,2003;Stanwood

andLevitt,2003;Thompsonetal.,2005;Malangaetal.,2008).Prenatallycocaine

exposedrodentswerefoundtohavelong‐termalterationsinworkingmemory,

spatialmemory(Inman‐Woodetal.,2000),non‐spatialshort‐termmemory

(Morrowetal.,2002),andlearningimpairmentsinawater‐mazetest

(Bashkatovaetal.,2005).Additionalevidenceforenduringeffectsofprenatal

cocaineexposureinratsonvisualattention(Gendleetal.,2004)andsustained

attention(Gendleetal.,2003)canbefoundintheanimalliterature.Inresponse

toenvironmentalorsocialstress,prenatallycocaine‐exposedratshaveshown

suppressedlevelsofplay(Woodetal.,1994),lessbehavioraladaptation

(Campbelletal.,2000),andmoreaggressivebehavior(WoodandSpear,1998).

Increasedaggression(Johnsetal.,1994;McMurrayetal.,2008)andanxietywith

decreasedsocialization(Overstreetetal.,2000)aswellasalterationsin

regulatoryandcopingbehaviorwithelevatedresponsivitytoacuteandchronic

stress(Woodetal.,1994;1995)hasbeenobservedinprenatallycocaine‐

exposedrodents.

Prenatallycocaine‐exposedrodentsalsoshowanalteredpropensityto

becomeinvolvedinself‐administrationofdrugsorresponddifferentlyto

cocainethanrodentsnotexposedtococaine(Heyseretal.,1992a,1992b;Keller

etal.,1994,1996;Hechtetal.,1998;Rochaetal.,2002;Crozatieretal.,2003;

Guerrieroetal.,2005;Malangaetal.,2009),raisingquestionsregarding

increasedsensitivitytodrugsandincreasedsubstanceabuseriskforprenatally

cocaine‐exposedhumans.Kosofskyandcolleagueshavedocumentedthat

32

prenatallycocaine‐exposedmicedonothabituatetonoveltyandinresponseto

repeatedcocaineinjections,showbluntedlocomotorsensitization,increased

stereotypicbehavior,andincreasedDAreleaseinthenucleusaccumbens

(Crozatieretal.,2003;Guerrieroetal.,2005;Malangaetal.,2009).Thissuggests

thatprenatalcocaineexposurealterstheadaptationofbrainrewardsystemsto

chronicpsychostimulantexposureinadulthood.

Othergroupshaveexaminedinrodentsthereinforcingeffectsofcocaine

inadulthoodfollowingprenatalcocaineexposure.Heyseretal.(1992a,1992b)

foundthatprenatallycocaine‐exposedratsdidnotacquirecocaineconditioned

placepreferencesuggestingareductionincocainereward.Incontrast,Kelleret

al.(1994,1996)determinedthatprenatallycocaine‐exposedratshadhigher

basalDAlevelsandhadsignificantlyhigherratesofrespondingcomparedto

controlsforalowdoseofcocainemadeavailableunderaFR1scheduleof

reinforcement.Thedoseofcocainewasactuallysolowthatitdidnotappearto

functionasareinforcerincontrolanimals(Kelleretal.,1996).Inanimportant

controltothisstudy,nodifferenceswereobservedinacquisitiontoacquire

water‐reinforcedrespondingundertheFR1scheduleofreinforcement.This

findingsuggeststhatprenatallycocaine‐exposedratsaremoresensitiveto

reinforcingeffectsofcocainebutnottootherreinforcers.

Hechtetal.(1998)extendedtheworkofthepreviousgroupstomeasure

thereinforcingstrengthofcocaineusingaprogressive‐ratio(PR)scheduleof

reinforcement.Prenatallycocaine‐exposedratshadsignificantlylowerbreak

pointsthancontrolssuggestingthattheseanimalswerelesssensitivetothe

33

reinforcingstrengthofcocaine.However,Rochaetal.(2002)reported

conflictingdatainmice.Differentdosesofcocaine(0.25‐2.0mg/kg/injection)

weremadeavailableunderanFR1scheduleofreinforcementtoexamine

vulnerabilitytoself‐administercocaine.Whiletherewerenodifferences

betweenprenatallycocaine‐exposedandcontrolmiceinacquisitionoffood‐

reinforcedrespondingortococaineself‐adminstration,agreaternumberofthe

prenatallycocaine‐exposedmicereachedthecriteriaforacquisitionatallthe

dosestested(Rochaetal.,2002).Thissuggeststhatprenatallycocaineexposed

subjectsmaybemorevulnerabletococainereinforcement.

NONHUMANPRIMATEMODELS

Thisdissertationworkutilizeslaboratoryanimalsandbehavioral

pharmacologymethodologytostudythelong‐termeffectsofprenatalcocaine

exposureandvulnerabilitytoself‐administrationofcocaine.Humanstudies

involvingprenatalcocaineexposurehaveresultedininconsistentfindingsthat

canbeattributedtodifficultiesincontrollingforpotentiallyconfounding

variables,suchaslevelofpre‐andpost‐natalcare,inadequatenutritionduring

pregnancy,multipledruguseduringpregnancy,anddrugdosage(Karmeland

Gardner,1996;Richardsonetal.,1996;GingrasandO'Donnell,1998;Dow‐

Edwardsetal.,1999;Mayesetal.,2003;Singeretal.,2004);thesevariablescan

becontrolledinanimalstudies.

Womenwhousecocainewhilepregnantusegreateramountsofother

drugs(Singeretal.,2000;2001),indicatingthatsimultaneouscontrolforother

34

prenataldrugexposuresisimportantwhenevaluatingthedirecteffectsof

cocaineondevelopmentaloutcomeslaterinlife.Forexample,attentional

measures,whichhavebeenexaminedinprenatalcocainestudies,havebeen

showntobevulnerabletotheeffectsofprenatalalcohol(Friedetal.,1992),

marijuana(Leechetal.,1999),andtobacco(Friedetal.,1992).Inaddition,

prenataltobaccoexposurehasbeenassociatedwithconductdisorderinboys

(WakschlagandHans,2002)andexternalizingbehaviors,anxiety,and

depression(Corneliusetal.,2001).Researchonfetalalcoholexposurehasalso

shownarangeofcognitiveandbehavioraleffectswithexposedchildrenhaving

moreinternalizingandexternalizingbehaviorproblems(Baileyetal.,2004;

Soodetal.,2001)andpsychiatricdisorders(O’Connoretal.,2002).Further

obfuscatingthedirecteffectsofprenatalcocaineexposure,caregiverswhouse

drugsmayexposetheirchildrentochaoticrearingenvironmentsand/orpassive

drugexposurethroughsecondhandtobacco,marijuana,orcocainesmoke.The

behavioraloutcomeevaluationsofchildrenexposedtococaineinuterohave

generatedequivocalresultsregardingthedomainsaffected,whichhighlightsthe

needforlongitudinalstudiesthatcontrolforconfoundingenvironmentaland

biologicfactorssuchasprenatalexposuretootherdrugsandalcohol.

Therefore,investigatingtheneurobiologicalandbehavioralconsequences

ofprenatalcocaineexposureinhighlycontrolledanimalmodelsisanimportant

complementtothehumanstudies.Nonhumanprimates(NHP),especiallyrhesus

macaques(Macacamulatta),offernumerousadvantagescomparedtoother

animalsforthestudyofprenatalcocaineexposure.Forinstance,NHParevery

35

similartohumansinphysiologyandbrainorganization(Goldman‐Rakicand

Brown,1982;SchneiderandSuomi,1992;Silketal.,1993).NHPhave

approximately95%genehomologytohumans(Haciaetal.,1998)andgreater

homologyinDA,5‐HT,andNEsystemsthanrodents(Weertsetal.,2007).

Additionally,NHPhavesimilarinuterodevelopmentashumansoveralong

gestationperiod(24‐26weeks)(Silketal.,1993),makingthemespecially

valuableforprenatalcocaineexposurestudies.Anotherlineofevidencethat

NHPmaybepreferentialcomparedtorodentsforprenatalcocaineexposure

studiesisthatthebehavioralandneurochemicalresponsetopsychostimulants

maybedifferentbetweenthespecies.Thereisevidencesuggestingspecies

differencesbetweenNHPandrodentsinthemetaboliceffectsofcocaine(Lyons

etal.,1996),thebehavioraleffectsofpsychostimulants(Robertsetal.,1999;Lile

etal.,2003),andtheDAreceptordistribution(Richfieldetal.,1987;Campsetal.,

1990).Finally,NHPcanbeutilizedforlongitudinalstudiesduetotheir

relativelylonglifespancomparedtorodentssothelong‐termeffectsofprenatal

cocaineexposurecanbefullyexamined.Therefore,themajorstrengthsofthe

studiesinthisdissertationarethatNHPmodelsaremoreanalogoustothe

humanconditionthananyotheranimalmodel,thatNHPallowforthestudyof

long‐termeffectsinadults(beginning13yearsaftergestationalcocaine

exposure),thatNHPhavesimilarneurochemical,hormonal,and

neuroanatomicalfunctions,andthatNHPallowforthestudyofmultiple

behaviors,makingtheseextremelytranslationalstudies.

36

PRENATALCOCAINEEXPOSURE:NONHUMANPRIMATES

Therehavebeenfourresearchgroupsthathaveexaminedtheeffectsof

prenatalcocaineexposureinNHP.Themajorityoftheworkwithprenatally

cocaine‐exposedNHPhasconcentratedexclusivelyonthephysiological

consequences.Ronnekleivandcolleaguesmainlyfocusedonfetalbrain

developmentduringinuterococaineexposure.Briefly,3.0mg/kgcocainewas

administeredi.m.tothemothersfourtimesdailywhilecontrolsubjectsreceived

salineinjectionsfourtimesdaily.Thetreatmentregimenbeganonday18of

pregnancyandcontinueduntilresearchersremovedthefetusatday60.

RonnekleivandNaylor(1995)reportedthatTHmessengerribonucleicacid

(mRNA)content,asmeasuredbyquantitativeinsituhybridization,wasreduced

inthesubstantianigraandventraltegmentalareasafter60daysofprenatal

cocaineexposure,whichsuggestsreducedDAsynthesis.Also,increasesinDAD1,

D2,andD5receptorsubtypemRNAlevelsinthefrontalcortexandstriatalareas

wereobserved(ChoiandRonnekleiv,1996).Invitroreceptorautoradiography

laterrevealedsignficantincreasesinD1‐andD2‐likereceptordensitiesinthe

striatumandsubstantianigra(Fangetal.,1997)andsignificantincreasesinDA

transportermRNAanddensities(FangandRonnekliev,1999).WhileRonnekleiv

andcolleagueshavenotreportedanyfunctionalconsequencesofthisprenatal

cocaineexposureregimen,theyhavenotedthatthesealterationsinDA

neurocircuitrycouldaffectmotivationandreward(Fangetal.,1997).

AsecondresearchgrouphasexaminedprenatalcocaineexposureinNHP

usingadifferenttreatmentregimen.Lidowandcolleaguestreatedpregnant

37

monkeyswith10mg/kgcocainep.o.twiceadayfromE40‐E102andallowed

themtodelivertheoffspringatfull‐term.Nodifferencesinweightofoffspring,

signsofatrophy,orhemorrhageswereseenbetweentheprenatallycocaine

exposedinfantsandsaline‐treatedcontrols(Lidow,1995b).However,the

volumeandweightofthebrainsofthecocaine‐treatedinfantswereabout20%

lowercomparedtothebrainsofthesaline‐treatedinfants(Lidow,1995b).Other

studiesfromthisgrouphavedescribedhigherincidenceofcelldeathinthe

developingcerebrumofcocaine‐exposedinfants(Heetal.,1999)andabnormal

neurocorticalcytoarchitecture(LidowandSong,2001a,2001b).BoththeLidow

andRonnekleivresearchgroupshaveshownthatprenatalcocaineexposurehas

detrimentaleffectsonthedevelopingbraininNHP.

Athirdgroupthathasexaminedtheeffectsofcocaineexposureduring

gestationusedosmoticminipumpstoinfusecocaine(0.3mg/kg/hr)orsaline

continuouslyinpregnantrhesusmonkeys(Howelletal.,2001).Comparedtoa

pair‐fedcontrolgroup,signficantlylowersurvivalrateswerefoundforthe

cocaine‐exposedfetuses(Howelletal.,2001),whichisconsistentwiththe

documentationofincreasedstillbirths,spontaneousabortions,andinutero

deathfromhumanstudies(Chasnoffetal.,1985;Bingoletal.,1987;Lutigeret

al.,1991).Ofthemonkeysthatsurvivedtofull‐term,therewerenophysiological

differencesobservedbetweenprenatallycocaineexposedandcontrolsubjects,

includingbodyweight,bodylength,andheartrate(Howelletal.,2001).

NoneofthesestudiesinNHPhaveinvestigatedthelong‐term

consequencesofthegestationalcocaineexposure.Themonkeysusedinthe

38

experimentsincludedinthisdissertationarethefirstprenatallycocaineexposed

NHPtobeexaminedforbiologicalorbehavioraleffectsbeyondinfancy.The

twentymonkeysusedinthesedissertationstudieshavebeenpartofresearchby

Pauleandcolleaguessinceinception(fordescriptionsseeMorrisetal.,1996,

1997).Femalerhesusmonkeyswereadministered1.0mg/kgcocainei.m.three

timesaday,fivedaysaweek.Thisdosingbeganpriortomating.Thedoseof

cocainewasincreasedweeklysothatbytheendofgestation,thepregnant

monkeyswerereceivingbetween4.5‐8.5mg/kg/injectioncocainethreetimes

perday.Themeancumulativeintakeofmonkeysinthisgroupwas1131.5

mg/kg(Table1).Thedoseandfrequencyofcocaineoverthepregnancywas

carefullycontrolledandrigorouscontrolsforfactorssuchasnutritionalstatusof

themothers,stressfromdruginjections,andpostnatalrearingwereinplace

increasingthelikelihoodthatprenatalcocainewastheprimaryindependent

variableinfluencinglong‐termbehavioralassessments.

Comparedtocontrols,nodifferenceswereobservedinthematernal

characteristicsofbodyweight,foodintake,andlengthofpregnancy.However,

decreasedinfantbodyweight,bodylength,andcrowncircumferencewerenoted

intheprenatallycocaineexposedmonkeysatbirthcomparedtocontrols

(Morrisetal.,1997).Nodifferenceswereobservedbetweengroupsthoughwith

respecttopostnatalgrowthoftheoffspringoverthefirst18months(Morriset

al.,1996)andthemeanweightofthetwogroupshasnotbeensignificantly

differentsince12monthsofage.

39

Morrisandcolleaguesinvestigatedthebehavioralconsequencesof

prenatalcocaineexposureusinganOperantTestBattery(OTB),whichhasbeen

describedindetail(Morrisetal.,1996).TheOTBconsistsoffivecomponents:1)

motivationasassessedbyPRrespondingmaintainedbybanana‐flavoredfood

pellets;2)colorandpositiondiscrimination;3)short‐termmemoryusinga

delayedmatching‐to‐sampletask;4)timingbehaviorwhichwasassessedwitha

temporalresponsedifferentiationtask;and5)learningusingarepeated

acquisitiontask(Pauleetal,2000).Nodifferencesintheacquisitionofanyofthe

fivebehavioralcomponentswereobservedbetweentheprenatallycocaine

exposedmonkeysandcontrols(Morrisetal.,1996).Infact,theonlybehavioral

differencePauleandcolleagueseverdocumentedbetweenthetwogroupswas

thattheprenatallycocaineexposedmonkeysperseveratedonthesimplevisual

discriminationtasklongerthancontrolmonkeyswhenthestimulionthistask

werereversedaftersixyearsofperformingthetask(Chelonisetal.,2003).This

deficitintaskperformancewasstillapparent2.5yearsaftertherulereversal

indicatingthatprenatalcocaineexposuremaypermanentlyimpairtheabilityof

thesubjectstorespondtoenvironmentalchanges(Chelonisetal.,2003).

ThemonkeysfromPauleandcolleagues’laboratorycametoWakeForest

Universityin2006aroundtheageof12yearsoldandbegantestinginthe

experimentsdescribedinthisdissertationatthispoint.Fromthetimethey

begantesting,therewerenodifferencesinweightbetweenthetwogroups

(Table1).

40

TABLE1.SUBJECTDEMOGRAPHICS

CONTROLS PRENATALLYCOCAINEEXPOSED

ID Sex Weight(kg)

InuteroCocaine(mg/kg)

ID Sex Weight(kg)

InuteroCocaine(mg/kg)

1553 F 5.9 0.0 1554 F 6.1 982.51556 F 6.3 0.0 1555 F 5.0 912.01558 F 7.3 0.0 1557 F 6.4 1248.01559 F 6.0 0.0 1560 F 6.0 1132.51561 F 5.6 0.0 1563 M 8.2 1084.51564 M 7.6 0.0 1565 M 8.7 1138.51566 M 8.4 0.0 1567 M 7.5 1404.01661 M 9.0 0.0 1568 M 8.1 885.01662 M 7.2 0.0 1569 M 7.3 1147.51663 M 8.2 0.0 1570 M 8.5 1380.0

Mean(±SEM)

7.15(±0.37)

0.0(±0.00)

Mean(±SEM)

7.18(±0.39)

1131.45(±56.10)

Approximatelyhalfofthesubjectsineachgroup(prenatallycocaine

exposedandcontrols)arefemalemonkeys.Itisknownthathormonalchanges

acrossthemenstrualcyclemayhavealargeeffectonstimulantdrugs,

particularlycocaine.Aconsistentandgreatermood‐alteringeffectofstimulant

useduringthefollicularphaseofthemenstrualcyclehasbeenobserved(for

review,seeTerneranddeWit,2006)anditisthoughtthatprogesteronelevel

fluctuationsmayaccount,inpart,forthismenstrualphasedifference(Evansand

Foltin,2006;Evans,2007).Evansetal.(2002)foundthatcocaineeffectson

heartrateandratingsof“gooddrugeffect”wereincreasedmoreinthefollicular

phasethaninthelutealphase,demonstratingthatcocaine’seffectscanvaryasa

functionofmenstrualcyclephase.Additionally,Czotyetal.(2009)foundthatD2

41

–likereceptoravailabilityvariedacrossthemenstrualcycleinmacaqueswith

D2‐likereceptoravailabilityinthestriatumbeinglowerinthefollicularphase

thaninthelutealphase.Therefore,specificconsiderationsweretakeninto

accountandtheexperimentsinthisdissertationweredesignedtoexaminethe

dopaminergicsystem(ChapterII)andacquisitionofcocaineself‐administration

(ChapterIV)infemalesubjectsinthefollicularphaseofthemenstrualcycle.

IMPULSIVITY

Animalstudiesandhumanmagneticresonanceimaging(MRI)have

documentedspecificregions(caudatenucleus,corpuscallosum,prefrontal

andposteriorcortices)(Avantsetal.,2007;Raoetal.,2007;Singeretal.,

2006)andmechanisms(Buxhoevedenetal.,2006;Leeetal.,2008;Morrow

etal.,2005;Renetal.,2004)ofbraindamagerelatedtofetalcocaine

exposure.Thesedata,combinedwithearlypatternsofcognitivedeficitsand

behavioralproblemsinhumans,indicatethatprenatalcocaineexposure

exertsspecificteratologiceffectsonhumandevelopmentduringearly

childhoodyearsthroughitseffectonareasofthebrainrelatedtohigher

orderthinking,impulsecontrol,andsensationorpleasureseeking.Ithas

beenhypothesizedthatsomenegativeeffectsofcocaine,particularlythose

governedbymonoaminerichareasofthebrainsuchasemotionalregulation

andimpulsecontrol(Bandstraetal.,2007),willultimatelyleadtohigher

ratesofsubstancedependence.Itispossiblethattheearlydeficitsin

42

attentionandexecutivefunctionseeninthehumancohortstudiesatages4,

6,and9yearsoldmaybeassociatedwithdisturbancesininhibitorycontrol

inadolescenceandadulthood.Reducedimpulsecontrolcouldindicatethat

prenatalexposuretococainemaypredisposeadolescentstogreaterdruguse

experimentationandatrajectorytowardsubstancedependence.

Highimpulsivityhasbeenstronglyassociatedwithdrugaddiction

(JentschandTaylor,1999;BickelandMarsch,2001;deWitandRichards,

2004).However,thecauseandeffectrelationshipsbetweenimpulsivityand

substanceabusehavebeenchallengingtodetermine.Prospectivestudiesin

bothhumansandanimalsindicatethatpreexistingimpulsivetraitsmay

predisposeindividualstodruguse(Tarteretal.,2003;Perryetal.,2005,

2008;Dalleyetal.,2007;Diergaardeetal.,2008;MarusichandBardo,2009).

However,otherstudiesinanimalshavefoundthatchronicstimulantusemay

causedeficitsinimpulsecontrol(Simonetal.,2007;Stanisetal.,2008;

DandyandGatch,2009).

Someofthedifficultyinevaluatingimpulsivityisduetoitbeing

conceptualizedasabroadspectrumofbehaviorsratherthanasingletrait.

Duetothemultidimensionalaspectofimpulsivity,ithasbeendifficultto

classifyinthescientificliteraturealthoughacommondefinitionis‘a

predispositiontowardrapid,unplannedreactionstointernalorexternal

stimuliwithdiminishedregardtothenegativeconsequencesofthese

reactionstotheimpulsiveindividualortoothers’(Moelleretal.,2001;

ChamberlainandSahakian,2007).Althoughitiswellacceptedthat

43

impulsivityisnotaunitaryconstructbutratheraspectrumofbehaviors,

thereisnotmuchagreementonhowtomeasureimpulsivityinanimal

models.Inhumanstudies,impulsivityistypicallyassessedbyquestionnaires.

Severaldistinctmeasureshavebeendevelopedtoassessimpulsivityin

animals,including1)choosinganimmediate,lowmagnituderewardovera

delayed,largemagnitudereward,2)lackofbehavioralinhibition,and3)

exaggeratedresponsetonovelty.Thesemeasuresarethefocusofstudiesin

ChapterIII.

Impulsivechoiceismostcommonlyassessedinhumanstudiesusinga

delaydiscountingtaskinwhichsubjectsaresurveyedandaskedtochoose

betweenasmall,immediatereinforcerandalarger,delayedreinforcer.The

subjectivevalueofthelargerreinforcerisdecreased(e.g.discounted)asthe

lengthoftimethesubjectmustwaittoreceiveitincreases.Byusingaseries

ofchoicesbetweenvaryingdelayvalues,theindifferencepointcanbe

calculatedasthedelayvalueatwhichthesmaller,immediatereinforceris

chosenasoftenasthelarger,delayedreinforcer.

Delaydiscountinghasbeenadaptedforanimalstudiesbypresenting

delaydiscountingchoicesasdifferingreinforcementschedules.Animalsare

trainedtomakeanoperantresponseononemanipulandumtoobtainasmall

magnitudereinforcerandtorespondonanothermanipulandumtoobtaina

largermagnitudereinforcerafterasetdelay.Ithasbeenshownthatdrug

usersdiscountthevalueofbothrealandhypotheticaldelayedreinforcers

moresothannonusers(Maddenetal.,1997;Bickeletal.,1999;Kirbyetal.,

44

1999;Coffeyetal.,2003),whichindicatesapossiblerelationshipbetween

impulsivechoiceanddrugabuse.

Demonstratingtheutilityofdelaydiscountingproceduresinassessing

therelationshipbetweenimpulsivechoiceanddrugabuse,Perryetal.

(2005)useddelaydiscountingmeasuresinratstoshowthatimpulsiveness

wasdirectlyrelatedtovulnerabilitytoacquirecocaineself‐administration.

Ratsweredividedintohighandlowimpulsivechoicegroupsbasedontheir

percentageofresponsesontheleverassociatedwiththelarger,delayed

reinforcer.Whencocaineacquisitionwasexamined,thehighimpulsiveness

ratsacquiredself‐administrationmorerapidlyandathigherlevelsthanthe

lowimpulsivenessrats.

Delaydiscountingstudieshavebeenextendedtononhumanprimates

(Newmanetal.,2008;Woolvertonetal.,2007;WoolvertonandAnderson,

2006;AndersonandWoolverton,2003).Woolvertonetal.(2007)

demonstratedthatrhesusmonkeysself‐administeringcocaineintravenously

showsimilardiscountingratescomparabletohumans,suggestingtheymay

beanidealmodeltostudythelong‐termeffectsofdrugabuseonimpulsivity.

ThestudiesinChapterIIIarethefirsttouseNHPinfood‐reinforceddelay

discountingstudies.

Responseperseverationisthetendencytocontinuerespondingfora

reinforcerdespitetheresponsescurrentlybeingeitherunrewardedor

punished(McCleary,1966).Responseperseverationtasksfirstestablisha

dominantresponsesetforaninitialhighrateofrewardthatsubjectsthen

45

havetoalterastheresponsesetbecomesunrewardedorpunishedmore

thanitisrewarded(Matthysetal.,2004).Itisthoughtthatincreased

responseperseverationisameasureofbehavioralinhibitionbecausein

thesetaskssubjectsmuststoptheirongoingbehavior(Matthysetal.,1998).

Increasedbehavioralinhibition,asassessedbyresponseperseverationtasks,

hasbeenshowninstudieswithpatientswithexternalizingdisorderswhere

impulsivityisoftenasymptom.Innonhumanprimates,perseverative

respondingcanbeassessedinavarietyofways.Oneofthesimplest

measuresistoexaminecontinuedrespondingduringextinguishingoffood‐

reinforcedbehavioronasimpleFRschedule.Asubjectthattakesmany

sessionstoextinguishresponding(unrewardedresponding)wouldbe

consideredmoreimpulsivethanasubjectthattakesonlyafewsessionsto

extinguishresponding,asdescribedinChapterIII.

Differentialbehavioralresponsetonovelstimulihasbeenattributed

toimpulsivity(Goldber,1990;Zuckerman,1996).Inrodents,astrong

correlationbetweennoveltypreferenceandimpulsivereactivitywithboth

self‐administrationratesandrewardingefficacyofpsychomotorstimulants

hasbeenobserved(Hooksetal.,1991;Abreu‐Villaçaetal.,2006;Davisetal.,

2008).Measuringimpulsivitybyexposingsubjectstoanovelobjecthasalso

beenusedsuccessfullyinnonhumanprimatestudies(Boligetal.,1992;

reviewedinClarkandBoinski,1995;Colemanetal.,2005).Responsiveness

inanopenfieldisanothermethodcommonlyusedtoassessimpulsivity.

Piazzaandcolleaguesdemonstratedthatresponsivenessinanopenfieldwas

46

associatedwithvulnerabilitytostimulantself‐administration(Piazzaetal.,

1989;1990;reviewedinPiazzaandLeMoal,1998).Ithasbeenproposed

thatlocomotorresponsetoanovelfieldiscloselyrelatedtobehavioral

disinhibition(StoffelandCunningham,2008).Humanshavealsobeenshown

todisplaydifferencesinreactivitylevelswhenexposedtoanovel

environment(Alessietal.,1999).InChapterIII,theeffectofprenatal

cocaineexposureonmultiplemeasuresofimpulsivity,includingboth

unconditionedandconditionedbehaviors,willbediscussed.

ACQUISITIONOFCOCAINESELF­ADMINISTRATION

Althoughanumberofprospective,longitudinalstudiesarecurrently

investigatingtheroleofcocaineincontributingtoadverseoutcomesin

prenatallyexposedchildren,theimpactofprenatalcocaineexposureregarding

vulnerabilityforaddictionhasnotbeensystematicallyexamined.Childrenwho

werebornduringthecrackcocaineepidemicofthemid‐1980sandearly1990s

arenowenteringyoungadulthood,atimewhenexperimentationwithdrugsof

abusetypicallyoccurs.Giventheapparentlinksbetweenprenatalcocaine

exposureandlong‐termbehavioralandneuraloutcomesthatareostensibly

involvedindeterminingsensitivitytococaine,itisreasonabletoexaminethe

possiblerelationshipbetweencocaineexposureduringgestationandthe

acquisitionofcocaineself‐administration.Itisimpossibletoethicallystudy

acquisitionofdrugtakingbehaviorincocaine‐naïvehumans.Therefore,animal

47

modelsareextremelyvaluableinallowingresearcherstoexaminevariables,like

prenatalcocaineexposure,thatmayenhanceorimpedetheinitiationofdrug‐

takingandpredictvulnerabilityfordrugabuse.

Acquisitionstudieshaveprimarilybeenconductedinrodents,dueto

theprohibitiveexpenseofbetween‐subjectdesignsusingNHP.However,

therehavebeenafewstudiesexaminingdrughistoryvariablesinacquisition

ofself‐administrationofaseconddruginmonkeys(Pickensetal.,1973;

YoungandWoods,1981;Carrolletal.,1984;Beardsleyetal.,1990;Nader

andMach,1996;WojnickiandGlowa,1996;Lileetal.,2000).Forexample,

acquisitionoftheselectivedopaminereuptakeinhibitorGBR12909self‐

administrationwasstudiedindifferentgroupsofrhesusmonkeysthatwere

eitherexperimentallynaïveorhadahistoryofcocaineself‐administration.It

wasdeterminedthatself‐administrationwasmaintainedunderamultiple

FR30schedulewithalternatingcomponentsofeitherfoodordrug

presentationonlyinthemonkeyswithpreviouscocaineself‐administration

history(WojnickiandGlowa,1996).However,experimentallynaïve

monkeysfailedtoacquireGBR12909self‐adminstrationatlowdoses

(WojnickiandGlowa,1996).Similarly,Beardsleyetal.(1990)demonstrated

thatMK‐801,theN‐methyl‐D‐aspartate(NMDA)receptorantagonist,was

self‐administeredbyrhesusmonkeyspreviouslytrainedtoself‐administer

phencyclidine(PCP),adifferentNMDAreceptorantagonist,butwasnotself‐

administeredbyrhesusmonkeyspreviouslytrainedtoself‐administer

cocaine.Thisfindingsupportsthegeneralconclusionthatpriorexposuretoa

48

drugwithsimilarpharmacologicalactionsfacilitatesacquisitionofself‐

adminstrationinNHP.Thesestudiesalsoimplythatinuterococaine

exposure,actingasapriorexposure,mayincreasevulnerabilitytoself‐

administercocainelaterinlife.

Inrodentstudies,manytypesofvariableshavebeenidentifiedas

affectingrateofacquisitionofdrugself‐adminstration.LikeinNHP,drug

historyisanimportantvariable.Pretreatmentwithamphetamine(Piazzaet

al.,1989;1990),cocaine(Horgeretal.,1990;Childsetal.,2006),naltrexone

(Carrolletal.,1986),andcaffeine(Horgeretal.,1991)canenhance

acquisitionofpsychomotorstimulantself‐administration.Environmental

conditionssuchasrestrictedaccesstofood(DeVryetal.,1989)andahistory

ofrestrictedfeeding(Speckeretal.,1994),physicalstress(Shahametal.,

1992;GoedersandGuerin,1994),orsocialstress(Haneyetal.,1995)have

allbeenshowntoenhanceacquisitionofdrugtakinginrats.Additionally,

characteristicsoftheanimalshavebeennotedaspredictiveoffaster

acquisitionofstimulantself‐administration.Forexample,highrateof

novelty‐inducedlocomotoractivity(Piazzaetal.,1989),preferenceofsweets

(Gosnelletal.,1995),andincreasedimpulsivityasassessedbyadelay‐of‐

rewardparadigm(Poulosetal.,1995,Perryetal.,2005)haveallbeen

determinedtopredictacquisitionofself‐administrationofstimulants.

Whileacquisitionstudiestypicallyholdthedoseofthedrugconstantat

lowormoderatelevelsandmanipulateothervariables,anothermethodof

examiningacquisitionistotestmultipledosesofthedruganduserateof

49

acquisitionorprobabilityofacquisitionatvariousdosesasthedependent

measure(vanReeetal.,1978;GerritsandvanRee,1995;CarrollandLac,1997;

ZhaoandBecker,2009).ThefocusofChapterIVwastodetermineifprenatal

cocaineexposurewouldfacilitaterateofacquisitionofself‐administrationof

cocaineinadulthood.Sinceithasbeenarguedthattherateofacquisitionofdrug

self‐administrationmayserveasapredictoroflaterdrug‐takingbehavior,

possiblyinfluencingthetransitionfromdrugusetoaddition(Rochaetal.,2002;

2005),thestudiesinChapterIVweredesignedtotestacquisitionbyexamine

multipledosesofcocaineandfocusingonrateofacquisition.Importantly,two

factorsthatarethoughttopredictvulnerabilitytoself‐administrationdrugsof

abuse,basaldopaminergicfunction(ChapterII)andimpulsivity(ChapterIII),

werealsoexamined.

50

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CHAPTERII

CHARACTERIZATIONOFTHEDOPAMINERECEPTORSYSTEMINADULTRHESUSMONKEYSEXPOSEDTO

COCAINETHROUGHOUTGESTATION

LindseyR.Hamilton,PaulW.Czoty,H.DonaldGage,MichaelA.Nader

ThefollowingmanuscriptwasacceptedforpublicationbyPsychopharmacologyMarch2010.Stylisticvariationsareduetotherequirementsofthejournal.LindseyR.Hamiltonperformedtheexperiments,analyzedthedata,andpreparedthemanuscript.H.DonaldGageaidedintheanalysisofthepositronemissiontomographydata.PaulW.CzotyandMichaelA.Naderactedinanadvisoryandeditorialcapacity.

87

ABSTRACTRATIONALE:Cocaineuseduringpregnancyisassociatedwithalterationsin

thedopamine(DA)systeminthefetalbrain.However,littleisknownabout

theeffectsofprenatalcocaineexposureonthepostnataldopaminergic

system.OBJECTIVES:TheobjectiveofthestudywastoexamineDAreceptor

functioninadultmonkeysthatwereprenatallyexposedtococaine.

MATERIALSANDMETHODS:Maleandfemalerhesusmonkeys

(approximately13yearsold)thathadbeenprenatallyexposedtococaine(n

=10)andcontrols(n=10)wereusedinallstudies.First,DAD2‐like

receptoravailabilitywasassessedusingpositronemissiontomographyand

theD2‐likereceptorradiotracer[18F]fluoroclebopride(FCP).Next,D3

receptorfunctionwasassessedbymeasuringquinpirole‐inducedyawning

(0.03‐0.3mg/kg).Finally,D1‐likereceptorfunctionwasexaminedby

measuringeyeblinkingelicitedbythehigh‐efficacyD1‐likereceptoragonist

SKF81297(0.3‐3.0mg/kg).RESULTS:Therewerenodifferencesbetween

groupsorsexesinD2‐likereceptoravailabilityinthecaudatenucleus,

putamenoramygdala.However,quinpiroleelicitedsignificantlymoreyawns

inprenatallycocaine‐exposedmonkeyscomparedwithcontrolmonkeys.A

significantcorrelationbetweengestationaldoseofcocaineandpeakeffects

ofquinpirolewasobserved.Inallmonkeys,administrationofSKF81297

eliciteddose‐dependentincreasesineyeblinksthatdidnotdifferbetween

groups.CONCLUSIONS:Thesefindingssuggestthatprenatalcocaine

exposurecanhavelong‐termeffectsonDAD3receptorfunctioninadults.

KEYWORDS:Prenatalcocaine­D2receptors­PETimaging­Quinpirole–SKF81297­Rhesusmonkey

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Ithasbeenestimatedthatover45,000infantsborneachyearhave

beenprenatallyexposedtococaine(NationalPregnancyandHealthSurvey

1996).Cocaineuseduringpregnancyisassociatedwithseveralphysical

deficitsincludingreducedbodyweight,bodylength,andheadcircumference

atbirth(NairandWatson1991).However,theeffectsofcocaineuseduring

pregnancyonpostnataldevelopmentandlong‐termneurobiologicaland

behavioraloutcomeshavebeenlessthoroughlyinvestigated.Thepresent

studycomparedapopulationofrhesusmonkeysthatwereprenatally

exposedtococainethroughoutgestationtocontrolmonkeyswithnearly

identicalpharmacologicalandexperimentalhistories(Morrisetal.1996,

1997).Atthestartofthepresentstudy,thesemonkeyswereadults(13years

old),withminimaldrugexposuresincebirth(seePauleetal.1996,2000;

Morrisetal.1996).Despitetheescalatingcocaineintakesofthemothersand

thelowerinfantweightsatbirth(Morrisetal.1997),overthefirst18

months,nodifferenceswereobservedbetweencocaineandcontrolgroups

withrespecttopostnatalgrowth(Morrisetal.1996).Aparticularadvantage

ofusingnonhumanprimatesinprenatalcocaineexposurestudiesisthe

relativelylonggestationalperiod.Inrhesusmacaques,theaverage

gestationalperiodisapproximately24weeks(Silketal.1993).Despitethis

advantage,therearenostudiesinvolvingprenatalcocaineexposurein

rhesusmonkeysthathaveexaminedtheconsequencesofgestationaldrug

exposureinadults.

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Forthepresentstudies,thedopamine(DA)neurotransmittersystem

wasexaminedusingseveralinvivomeasures.WithintheDAsystem,there

aretwosuperfamiliesofDAreceptors,theD1‐likereceptorswithtwo

receptorsubtypesD1andD5andD2‐likereceptorswithD2,D3andD4

receptorsubtypes.BothD1‐andD2‐likereceptorshavebeenshowntobe

affectedbychroniccocaineexposureinadulthumansandnonhuman

primates(e.g.,Mooreetal.1998a,1998b;Martinezetal.2004;Naderetal.

2002;Volkowetal.1999).Asitrelatestoeffectsonthefetus,elevationof

extracellularmonoamineconcentrationsduringdevelopmentmayleadto

alterationsinreceptorsignalingmechanismsatbirthandperhaps

throughoutlife.SinceDAisamongthefirstneurochemicalpathwaysto

developinthefetalbrain(reviewedinBhide2009),thelong‐lastingeffectsof

cocaineexposureonthedopaminergicsystemduringthiscrucial

developmentstageareofparticularinterest.

Inthepresentstudy,DAD2‐likereceptoravailabilitywasassessed

usingpositronemissiontomography(PET)andthetracer

[18F]fluoroclebopride(FCP),whichdoesnotdifferentiatebetweenD2‐like

receptorsubtypes(Machetal.1996).Inadultrhesusmonkeys,D2‐like

receptoravailabilityhasbeenshowntodecreaseasaconsequenceofchronic

cocaineexposure(Naderetal.2006).WehypothesizedthatD2‐likereceptor

availabilitywouldbelowerinadultmonkeyswhohadbeenexposedto

cocainethroughoutgestation.WhiledatasuggestthatD2‐likereceptorsare

reducedduetococaineexposure,post‐mortemstudiesfoundD3receptorsto

90

behigherincocaineoverdosevictimscomparedtoage‐matchedcontrols

(StaleyandMash1996).Thus,weusedtheD3/D2agonistquinpiroleandthe

unconditionedbehavioryawningtoassessD3receptorfunctioninvivo.

Earlierworkinrodentshasshownthattheascendinglimbofthequinpirole‐

elicitedyawningdose‐responsecurve,includingthepeakofthecurve,is

mediatedbyD3receptors(Collinsetal.2005).

AsitrelatestoD1receptors,Jonesetal.(2000)demonstratedthat

prenatalcocaineexposureinducedearlydesensitizationofDAD1‐like

receptorsinfetalrabbitanteriorcingulatecortexandcaudatenucleusthat

occurredwithoutalterationsofthereceptorproteinitself,suggestingthat

theD1‐likereceptorsbecomeuncoupledfromtheirG‐protein(Lidow1998;

Jonesetal.2000).Importantly,D1‐likereceptoralterationsinrabbitsand

rodentsprenatallyexposedtococainehavebeenshowntopersistinto

adolescenceandadulthood(Bayeretal.2000;StanwoodandLevitt2007).

Therefore,inthepresentstudy,D1‐likereceptorfunctionwasinvestigated

byassessingtheabilityofthehigh‐efficacyagonistSKF81297toeliciteye

blinking(JutkiewiczandBergman2004).Forthesestudies,therewasanear

equaldistributionofmaleandfemalemonkeys,sotheeffectsofprenatal

cocaineexposureandsexwerefactorsinallanalyses.

MATERIALSANDMETHODS

SUBJECTS. Twentyadultrhesusmonkeys(Macacamulatta),bornbetween

1993and1995andraisedattheFDAfacilityinLittleRock,ARuntiltheir

91

arrivalatWakeForestUniversityin2007,servedassubjects.Tenmonkeys

(6male,4female)wereprenatallyexposedtococaineand10monkeys(5

male,5female)werecontrols,asdescribedpreviously(Morrisetal.1996,

1997).Briefly,mothersofcocaine‐exposedmonkeysreceivedintramuscular

injectionsofescalatingdosesofcocainethreetimesperdayfortheentire

courseofgestation;themeancumulativecocaineintakewas1131.5(±56.1

SEM)mg/kg(Morrisetal.1996).At6monthsofage,allmonkeyswere

housedindividuallyinthesamecolonyroomandbeganbehavioraltraining

involvinganoperanttestbattery(Morrisetal.1997).Otherthantheir

prenataldrughistories,allmonkeyshadidenticalexperimentalhistories,

includingacuteexposuretococaine,amphetamine,haloperidol,quinpirole,

SCH‐23390,spiperone,andMK‐801(seePauleetal.1996;Morrisetal.1997;

personalcommunicationfromM.Paule).Atthetimeofthepresentstudies,

therewerenosignificantdifferencesbetweentheprenatallycocaineexposed

andcontrolmonkeysinage(12.4±0.3yearsvs.12.9±0.3years,

respectively)orweight(7.8±0.7kgvs.6.4±0.4kg,respectively).

Monkeyswereindividuallyhousedinstainless‐steelcageswithwater

availableadlibitumandhadvisualandauditorycontactwitheachother.

Duringa2‐monthquarantine,afree‐feedingweightwasdeterminedand

monkeys’bodyweightsweremaintainedatapproximately95%ofthatvalue

throughoutthesestudies(LabDietMonkeyChowandfreshfruit).Each

monkeywasfittedwithanaluminumcollar(PrimateProducts,Redwood

City,CA)andtrainedtositcalmlyinastandardprimatechair(Primate

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Products)usingaspeciallydesignedstainless‐steelpolethatattachedtothe

collar.Allexperimentalandenvironmentalenrichmentprotocolswere

approvedbytheWakeForestUniversityInstitutionalAnimalCareandUse

Committee.Theexperimentsarelistedintheorderthateachanimalwas

tested.

MENSTRUALPHASEDETERMINATION. Sincewehavepreviouslyshownthat

D2receptoravailabilitydiffersacrossthemenstrualcycle(Czotyetal.2009),

allexperimentswereconductedinthefollicularphase.Menstrualcyclewas

assessedbydailyvaginalswabs.Daysofbleedingwererecordedas

indicativeofmenses.PETscanswerescheduledtooccurduringthefollicular

phase(days2‐12).Toconfirmcyclephase,onthedayofaPETstudy,3mlof

bloodwasdrawnfromthefemoralveinandanalyzedforprogesteroneatthe

BiomarkersCoreLaboratoryoftheYerkesNationalPrimateResearchCenter

ofEmoryUniversityinAtlanta,GA(seeCzotyetal.2009fordetails).

EXPERIMENT1:EFFECTSOFPRENATALCOCAINEEXPOSUREOND2

RECEPTORAVAILABILITY.Magneticresonanceimaging(MRI)scanswere

acquiredforeachmonkey.TwentyminutesbeforetheMRI,subjectswere

anesthetizedwithketamine(15‐20mg/kg,i.m.)andtransportedtotheMRI

facility.Anesthesiawasmaintainedduringthescanningprocedurewith

ketaminesupplementswhennecessary.T1‐weightedimagesoftheentire

brainwereacquiredwitha1.5‐TeslaGESignaNRscanner(GEMedical

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Systems).Imageswereusedtoanatomicallydefineregionsofinterest(ROIs),

includingthecaudatenucleus,putamen,amygdala,andcerebellum,forlater

co‐registrationwithPETimages.

PETdatawereacquiredusingaGEAdvanceNXiPETscanner(~4.8

mm3resolution)andtheradiotracer[18F]fluoroclebopride(FCP),which

bindswithhighaffinitytoD2‐likereceptors(Machetal.1993)witha

test/retestvariabilityof~2%(Naderetal.1999).Methodologicaldetails

regardingthedataacquisitionprotocol,bloodsamplingandmetabolite

analysisforFCPhavebeendescribedpreviously(Machetal.1996;Naderet

al.1999).Approximately30minbeforethescan,monkeyswereanesthetized

withketamine(10mg/kg,i.m.),intubated,andmaintainedthroughoutthe

scanbyinhaledisoflurane(1.5%).ThisinductionprotocoldoesnotalterD2

receptoravailabilityasmeasuredwithFCP(Naderetal.1999).Catheters

wereplacedinanexternalarteryandveinbypercutaneoussticksandsaline

wasdeliveredtothemonkeythroughoutthescan.Bodytemperaturewas

maintainedat38°Candvitalsigns(heartrate,bloodpressure,respiration

rate,andtemperature)weremonitoredthroughoutthescanningprocedure.

Aparalytic(0.07mg/kgvecuroniumbromide)wasadministeredi.v.and

respirationwasmaintainedbyaventilator.Supplementaldosesof

vecuroniumbromide(0.1mg/h)wereadministeredthroughoutthestudy.

A5‐mintransmissionscanwasacquiredin2Dmode.Next,the

monkeyreceivedabolusdoseof[18F]FCP(2‐5mCi)followedbya3mlflush

withheparinizedsalineanda180mindynamicacquisitionscanwas

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acquired.Twenty‐sixframeswereacquiredover3hr(5x1min,5x2min,5

x5min,8x10min,3x20min)in3Dmode(i.e.,septaretracted).Image

reconstructionof3Ddatawasdoneusingthe3D‐reprojectionmethod

(Rogersetal.1987)withfullquantitativecorrections.Oncethescanningwas

compete,thetransmissionscandataweresmoothedtransaxiallyusinga4‐

mmGaussianfilterandsegmented(Bettinardi1999).Emissiondatawere

correctedforattenuationandreconstructedinto129x128matricesusinga

Hanningfilterwitha4‐mmcutofftransaxiallyandarampfilterwithan8.5‐

mmcutoffaxially.

Thefirstfiveframesofeachstudy'sPETimagedatawerethenadded

together.Thissummedimagerepresentstraceruptakeintheearlypartof

thestudyandapproximatesabloodflowimage.Theimagewasthen

registeredtotheanimal’sMRIusingtheAIRalgorithm(Woodsetal.1993)

afterextractingthebrainimagefromtheMRI,usingthemethodofSmith

(2002).Time‐activitycurvesweregeneratedforradiotracerconcentrations

inROIsdefinedoneachsubject’sco‐registeredMRI.Distributionvolume

ratios(DVR)werecalculatedforeachROIusingthecerebellumasthe

referenceregionandthegraphicalmethodofLoganetal.(1996).TheDVR

thusservedasanindexofspecificFCPbindingineachROI.Forallregions,

therightandleftsides’DVRsdidnotdifferandwereaveraged.

EXPERIMENT2:EFFECTSOFPRENATALCOCAINEEXPOSUREON

QUINPIROLE­INDUCEDYAWNING.Aquinpiroledose‐responsecurvewas

95

determinedforeachmonkey.Beforeeachexperimentalsession,themonkey

wasplacedinaprimatechairandgivenaninjectionofsaline(1.0ml)or

quinpirole(0.03,0.1,or0.3mg/kg,i.m.);dosesweretestedinrandomorder

withatleast2daysbetweentesting.Thesedosesofquinpiroledonotinduce

hypothermiainourmonkeys(unpublishedobservations),aneffectdescribed

asD2receptor‐mediatedeffectobservedinrodents(Boulayetal.1999a,b;

Chaperonetal.2003;Collinsetal.2007).Immediatelyaftertheinjection,

occurrencesofyawningwerecountedfor30minutes.Fullextensionofthe

jaws,withdrawalofthelips,andexposureoftheteethcharacterizedyawning

(CodeandTang1991).Sessionswerevideotapedandtwopeoplewhowere

blindtothemonkeys’prenatalhistoryscoredthesesessionswithaninter‐

observervariabilityof<5%.

EXPERIMENT3:EFFECTSOFPRENATALCOCAINEEXPOSUREONSKF

81297­INDUCEDEYEBLINKING.Monkeyswereseatedinaprimatechairin

atestingroom.Followinga15minuteacclimationperiod,saline(1.0ml)was

administeredintothesaphenousveinandblinkingwascountedduringthe

last2.5minutesofthefollowing15minuteperiod.Subsequently,cumulative

dosesofSKF81297(0.3,1.0,and3.0mg/kg,i.v.)wereadministeredand

blinkingwascountedinthelast2.5minutesofthe15minuteperiod

followingeachdose.Totalsessionlengthwas75minutes.Sessionswere

videotapedandtwopeople,oneofwhomwasblindtothemonkeys’prenatal

drughistory,scoredthesesessionswithaninter‐observervariabilityof<8%.

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Drugs.Quinpirole(Sigma‐Aldrich,St.Louis,MO)wasdissolvedinsterile

salinetoaconcentrationof1.0mg/ml.SKF81297(Sigma‐Aldrich,St.Louis,

MO)wasdissolvedinsterilesalinetoaconcentrationof5.0mg/ml.Alldoses

areexpressedasthesalt.

STATISTICALANALYSIS.InExperiment1,foreachROI,datawereanalyzed

usingatwo‐wayrepeatedmeasuresANOVAwithgroup(prenatalcocaine

andcontrol)andsexasfactors.InExperiments2and3,three‐wayrepeated

measuresANOVAswithgroup,sexanddose(quinpiroleorSKF81297)as

factorswereconducted.Inallcases,significancewasacceptedatthe95%

levelofconfidence(p<0.05).

RESULTS

EXPERIMENT1:EFFECTSOFPRENATALCOCAINEEXPOSUREOND2

RECEPTORAVAILABILITY.Forallmonkeys,therewasahighlevelofuptake

of[18F]FCPinallthreeregionsofinterestandalinearrateofwashout,as

shownpreviously(e.g.Morganetal.2002).Inthecerebellum,[18F]FCP

uptakewaslowwitharapidrateofwashout(notshown).Forbothgroupsof

monkeys,[18F]FCPDVRsinthecaudatenucleusandputamenwerehigher

thanDVRsobservedintheamygdalainallmonkeys(Fig.1).Therewereno

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significantmaineffectsofprenatalcocaineexposureorsexandnogroupx

sexinteractionsforanyROI.

EXPERIMENT2:EFFECTSOFPRENATALCOCAINEEXPOSUREON

QUINPIROLE­INDUCEDYAWNING.Usinga3‐wayrepeatedmeasuresANOVA,

therewasasignificanteffectofquinpiroledose[F(3,48)=7.13,p<0.001],and

group[F(1,16)=8.51,p<0.01]andasignificantsexxquinpiroledose

interaction[F(3,48)=3.42,p<0.05](Fig.2).Allquinpiroledoseselicitedmore

yawnsintheprenatalcocaine‐exposedmonkeyscomparedtocontrols(Fig.

2,rightpanel).Malemonkeys,irrespectiveoftheirprenatalcondition,

yawnedmorefollowing0.03mg/kgquinpirolecomparedtofemalemonkeys

whosequinpirolecurvepeakedat0.1mg/kg(Fig.2,leftandmiddlepanels).

Forcontrolandprenatallycocaine‐exposedmonkeys(maleandfemale),all

quinpiroledoseselicitedmoreyawnsthansaline,butthedose‐response

curveswererelativelyflat(Fig.2,rightpanel).Finally,combiningthedatafor

allprenatallycocaine‐exposedmonkeys(Fig.3)revealedasignificant

positivecorrelationbetweenthemaximaleffectofquinpiroleandmaximal

dailyinuterococaineexposure(r2=0.84,p<0.0005).However,when

cumulativegestationalcocainedosewasusedintheanalysis,thecorrelation

wasnotsignficant.

EXPERIMENT3:EFFECTSOFPRENATALCOCAINEEXPOSUREONSKF

81297­INDUCEDEYEBLINKING.Followingsalineadministration,ratesof

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blinkingrangedfrom4.8‐17.2blinksperminutebutdidnotdifferbetween

prenatallycocaineexposedandcontrolmonkeys(Fig4).Arepeated‐

measuresthree‐wayANOVArevealedasignificantmaineffectofSKF81297

dose[F(3,39)=45.80,p<0.001]andSKF81297dosexsexinteraction

[F(3,39)=3.11,p<0.05].ForbothgroupsandacrossallSKF81297doses,

malesblinkedmorethanfemales.

DISCUSSION

Thepurposeofthepresentstudieswastodetermineiftherewere

long‐termalterationsindopaminefunctioninadultmonkeysthatwere

exposedtococaineinutero.Tenmonkeys(maleandfemale)prenatally

exposedtococainewerecomparedto10age‐matchedcontrolmonkeyswho

hadnearlyidenticalpostnatalexperimentalhistories.Therewereno

differencesbetweengroupsinD1‐likereceptorfunction,asassessedbySKF

81297‐elicitedeyeblinks,orinD2‐likereceptoravailabilityasdetermined

withPETimaging.Incontrast,theD3/D2receptoragonistquinpiroleelicited

significantlymoreyawnsinmonkeysprenatallyexposedtococaine

comparedtocontrolmonkeys.Furthermore,asignificantcorrelationwas

observedbetweenmaximaldailygestationaldoseofcocaineandpeakeffects

ofquinpirole.Thesefindingssuggestlong‐lastingeffectsofprenatalcocaine

exposureonDAD3receptorfunction.

Accumulatingevidencesuggeststhatchroniccocaineexposurecan

producesignificantreductionsinDAD2‐likereceptoravailabilityinadult

99

humansandanimals(e.g.,Volkowetal.1999;Martinezetal.2004;Naderet

al.2002,2006).However,earlierworksuggestedthattheeffectsofchronic

cocaineonfetalDAreceptordensitiesmaybedifferentfromthoseobserved

inadults.Forexample,Fangetal.(1997)observedsignificantlyhigherlevels

ofD2‐likereceptordensitiesinthefetalmonkeystriatumfollowing

gestationalcocaineexposure.DatafromthepresentPETimagingstudy

suggestthatanychangesinD2‐likereceptoravailabilitythatmayhave

occurredinuteroorinthedevelopingbrainhaverecoveredinadulthood.

ComparedtotheFangetal.(1997)rhesusmonkeystudy,thepresentstudy

involvedlongerinuterotreatments(approximately6months),full‐term

pregnancyand13yearsofabstinence.FuturelongitudinalPETimaging

experimentsconductedatmultiplepointsduringamonkey’slifespan

followinginuterococaineexposurewoulddirectlyaddressthetimecourse

ofrecovery.

NosignificantsexdifferenceswereobservedinD2‐likereceptor

availabilityinanyoftheregionsofinterest.Thisisconsistentwiththelackof

sexdifferencesseeninstriatalD2/D3receptorbindingusing[18F]‐fallypride

inadolescentrhesusmonkeys(Christianetal.2009)andwithprevious

reportsofwomenandmenshowingequivalentD2‐likereceptoravailability

(Fardeetal.1995;Pohjalainenetal.1998;Munroetal.2006).However,it

hasbeensuggestedthatfemalesexhormonesmayenhancepresynaptic

dopamineturnover(Laaksoetal.2002)andtheradiotracerusedinthis

experiment(FCP)issensitivetofluctuationsinmenstrualcyclephase(Czoty

100

etal.2009).Inaddition,sexdifferenceshavebeenreportedinastudyusing

[11C]racloprideandPETinhealthymenandwomenofagesrangingfrom19‐

82yrsold(Pohjalainenetal.1998).Therefore,itremainspossiblethat

differencesinD2‐likereceptoravailabilityinmalesandfemalesmayhave

beenobservedatearliertimepointsormayyetbeseenasthesemonkeys

age.

ThePETradiotracerusedinthepresentstudydoesnotdifferentiate

betweenD2,D3andD4subtypesoftheD2‐likereceptorsuperfamily.Thus,it

isconceivablethatprenatalcocaineexposurecouldhavelong‐termeffectson

subtypesofthissuperfamilywhichwouldbeobscuredbyopposite

adaptationsinanothersubtype.Forexample,invitroreceptor

autoradiographystudieshaveshownlowerD2‐likereceptordensities(e.g.,

Mooreetal.1998;Naderetal.2002)andhigherD3receptordensities(e.g.,

StaleyandMash1996)incocaine‐exposedindividualscomparedtoage‐

matchedcontrols.TodetermineifthereweredifferencesinD3receptor

function,theD3receptoragonistquinpirolewasusedtoexaminethe

sensitivityofbehaviorrelatedtothissubtypeinbothgroupsofmonkeysand

asafunctionofsex.Collinsetal.(2005,2007)haveshownthattheascending

limbofthequinpiroledose‐responsecurveismediatedbyD3receptorswhile

thedescendinglimbismediatedbyD2receptors.Basedonprevious

experimentsinrhesusmonkeys(Martelleetal.2007)thedoserangeof

quinpiroleadministeredinthepresentstudyissituatedontheascending

limbofthedose‐responsecurveandthereforeisthoughttoassessprimarily

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D3receptorfunction.Thegreaterabilityofquinpiroletoelicityawninginthe

prenatallycocaine‐exposedmonkeysissimilartoresultsfromMoodyetal.

(1992),whodemonstratedthatratpupsexposedtococainethroughout

gestationexhibitedasupersensitivitytothestimulatingeffectsofquinpirole

withrespecttobehaviorssuchasforwardlocomotion,rearinganddirected

oralmovementscomparedtocontrolpups.Additionally,whenallmonkeys

prenatallyexposedtococainewereusedintheanalysis,wefoundthatD3

receptorsensitivitycorrelatedwiththemaximumdoseofcocaineeach

individualmonkeyreceivedinutero.Takentogether,thepresentresults

provideevidenceforlong‐termneuropharmacologicalconsequencesof

prenatalcocaineexposureonD3receptorfunctionunderconditionsinwhich

nodifferenceinD2‐likereceptorswasobservedusingPETimaging.The

combinationofeffectsleadtointerestinghypothesesregardingdifferential

sensitivitytothereinforcingeffectsofcocaine.Forexample,becausePET

imagingstudiesinmonkeyshaveshownarelationshipbetweenD2receptor

availabilityandcocainereinforcement(seeNaderetal.2008),thePET

imagingdatawouldsuggestnodifferencesbetweenprenatalcocaine

exposedandcontrolmonkeysinvulnerabilitytococainereinforcement.

However,D3receptorsensitivityhasbeenassociatedwithimpulsivity(e.g.

Doddetal.2005;Sokoloffetal.2006),whichwouldsuggestdifferential

sensitivityofcocaine‐exposedmonkeyscomparedtocontrolsinacquisition

ofcocaineself‐administration.Additionalbehavioralstudiesinthese

monkeys,includingassessingthereinforcingeffectsofcocaine,willprovide

102

importantinformationastothelong‐termconsequencesofprenatalcocaine

exposureandtheroleofD2‐likereceptorsubtypesinthesebehavioral

outcomes.

InanefforttomorefullycharacterizeDAreceptoractivityinvivo,

functionalstudiesoftheD1‐likereceptorwerealsoundertakeninthese

samemonkeys.D1‐likereceptordensitieshavepreviouslybeenshowntobe

affectedbychroniccocaineexposureinadultmonkeys(Mooreetal.1998)

andnotnecessarilyinamannersimilartotheeffectsofcocaineonD2‐like

receptors(Naderetal.2002).Fangetal.(1997)reportedthatcocaine

treatmentfromgestationalday22to70resultedinsignificantincreasesin

D1‐likereceptordensitiesinday‐70fetalmonkeystriatum.Inrodentand

rabbitmodels,severalstudiessuggestthatprenatalcocaineexposure

uncoupledtheD1receptorfromitsG‐proteinresultinginanattenuationofD1

receptorsignaling(Friedmanetal.1996;Wangetal.1995;Lidow1998;

Jonesetal.2000;Unterwaldetal.2003).However,therearenodata

assessingD1‐likereceptorfunctioninadultswhohadbeenprenatally

exposedtococaine.Inthepresentstudy,nodifferencesinpotencyoreffects

ofSKF81297‐elicitedeyeblinkswereobservedinadultmonkeysprenatally

exposedtococaineversuscontrols.Becauseithasbeenarguedthatthis

unconditionedbehaviorisasensitivemeasureofD1‐likesignaling

(JutkiewiczandBergman2004),thesedatasuggestthatanyfunctional

differencesinD1receptorsensitivityobservedinprenatallycocaine‐exposed

animalsshortlyafterbirtharenolongerapparentintheseanimalsasadults.

103

Itshouldbenotedthatunderotherconditionsinsociallyhousedmonkeys,

SKF81297‐elicitedeyeblinkingdidnotdifferentiatemonkeysbasedon

socialrank(Czotyetal.2004),eventhoughdifferencesinsensitivityto

cocainereinforcementwereobserved(Czotyetal.2005).Itremainspossible

thatotherfunctionalmeasuresofD1‐likereceptoractivity(e.g.,drug

discriminationordrugself‐administration)mayyielddifferentialsensitivity

duetoprenatalcocaineexposure.Thepresentfindingsarealsothefirstto

notesexdifferencesinsensitivitytotheD1‐likeagonisteffectselicitedby

SKF81297.ItisimportanttonotethatD3receptorfunction(quinpirole‐

elicitedyawning)wasalsodifferentiallyaffectedbysex.Thepresentfindings

addtoagrowingbodyofevidenceforsexdifferencesinthebehavioral

effectsofdrugs.Takentogether,thesefindingsindicatethatprenatalcocaine

exposurecanhavelong‐lastingeffectsonDAreceptorfunctionandthat

malesandfemalesareequallysensitivetotheseperturbations.

ACKNOWLEDGMENTS

ThisresearchwassupportedbyNationalInstituteonDrugAbusegrantsR01

DA25120,R37DA10584,andK31DA024485.Theauthorsreportnoconflict

ofinterestandwouldliketoacknowledgethetechnicalassistanceofTonya

Calhoun,KimberlyBlack,HollySmithandWhitneyWilson.Theauthorsalso

thankDr.MerlePauleforprovidinginformationrelatedtothehistoriesof

thesemonkeysandDr.AnthonyLiguoriforstatisticalconsultation.

104

FIGURE1.Distributionvolumeratios(DVRs)of[18F]FCPincontrol(open

symbols)andprenatallycocaine‐exposed(shadedsymbols)monkeysinthe

caudatenucleus,putamen,andamygdala.Eachbarrepresentsmean±SEM

valuesfrom10monkeys.

105

106

FIGURE2.Yawninginducedbyquinpirole(0.03‐0.3mg/kg)infemale(A)

andmale(B)control(opensymbols)andprenatallycocaine‐exposed(closed

symbols)adultrhesusmonkeys.PanelCrepresentsmeandata(maleand

female)foreachgroup.Dataarerepresentedasthemean±SEMnumberof

yawnsina30‐minobservationperiod.

107

FIGURE3.Relationshipbetweenpeaknumberofyawnselicitedby

quinpiroleandmaximaldailydoseofcocainereceivedinutero(fromMorris

etal.,1996).Differentsymbolsrepresentmales(triangles)andfemales

(circles).

108

109

FIGURE4C.EffectsofSKF81297onrateofeyeblinkingincontrol(A)and

prenatallycocaine‐exposed(B)male(filledsymbols)andfemale(open

symbols)monkeys.PanelCrepresentsmeandata(maleandfemale)foreach

group.Eachpointrepresentsmean±SEMvalues.

110

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CHAPTERIII

INCREASEDIMPULSIVITYINMALE,BUTNOTFEMALE,ADULTRHESUSMONKEYSEXPOSEDTOCOCAINE

THROUGHOUTGESTATION

LindseyR.Hamilton,PaulW.Czoty,MichaelA.Nader

ThefollowingmanuscriptwassubmittedtoPsychopharmacologyinApril2010.Stylisticvariationsareduetotherequirementsofthejournal.LindseyR.Hamiltonperformedtheexperiments,analyzedthedata,andpreparedthemanuscript.PaulW.CzotyandMichaelA.Naderactedinanadvisoryandeditorialcapacity.

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ABSTRACT

RATIONALE:Inuterococaineexposurehasbeenassociatedwithalterations

inthedopamine(DA)systeminmonkeys.However,thebehavioraloutcomes

ofprenatalcocaineexposureinadulthoodarepoorlyunderstood.

OBJECTIVES:Toassessbehavioralmeasuresofimpulsivityin14year‐old

rhesusmonkeysexposedtococaineinuteroandcontrols(n=10pergroup).

MATERIALSANDMETHODS:Toassessimpulsivity,twounconditioned

behavioraltasks,novelobjectreactivityandlocomotoractivity,andtwo

conditionedbehavioraltasks,responseextinctionanddelaydiscounting,

wereexamined.Inaddition,cerebrospinalfluid(CSF)sampleswereanalyzed

forconcentrationsofthemonoaminemetaboliteshomovanillicacid(HVA)

and5‐hydroxyindoleaceticacid(5‐HIAA).RESULTS:NodifferencesinCSF

concentrationsof5‐HIAAandHVA,latenciestotouchanovelobjector

locomotoractivitywereobservedbetweengroupsorsexes.However,

prenatallycocaine‐exposedmonkeysrequiredasignificantlygreaternumber

ofsessionstoreachcriteriaforextinctionoffood‐reinforcedbehaviorthan

controlmonkeys.Onthedelay‐discountingtask,maleprenatallycocaine‐

exposedmonkeyshadasignificantlylargermeanindifferencepointthan

malecontrolmonkeys;nodifferenceswereobservedinfemales.Whenan

overallimpulsivityscorewasdeterminedtakingintoaccountthetwo

unconditionedandtwoconditionedbehavioralmeasures,maleprenatally

cocaine‐exposedmonkeysweremoreimpulsivethanmalecontrolmonkeys.

Nodifferencesinoverallimpulsivitywereobservedinfemales.Asignificant

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negativecorrelationbetweenCSFconcentrationofHVAandoverall

impulsivityscorewasobserved.CONCLUSIONS:Thesefindingssuggestthat

prenatalcocaineexposurehaslong‐termneurobehavioraldeficitswith

neurobiologicalcorrelatesthatareinfluencedbysexoftheindividual.

KEYWORDS:Prenatalcocaine–Impulsivity–Delaydiscounting–CSF–HVA–

Rhesusmonkey

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Maternalcocaineaddictionisasignificantpublichealthproblemwith

almost50,000infantsborneachyearhavingbeenexposedtococainein

utero(NationalPregnancyandHealthSurvey1996).Severalinvestigators

haveexaminedthephysiologicalconsequencesofcocaineusethroughout

gestationinnonhumanprimatemodels(e.g.Howelletal.2001;Lidow2003).

Thepresentstudyutilizedprenatalcocaineexposureinrhesusmonkeysin

ordertoevaluatethebehavioralandneurochemicalconsequencesofinutero

drugexposureinadults.Theseanimalshadbeenexposedtococaine

throughoutthe25weeksofgestationorwerecontrols(Morrisetal.1996,

1997)andwerestudiedasadults(14‐15yearsold).Werecentlyexamined

dopamine(DA)receptorfunctionintheseadultmonkeys(Hamiltonetal.

2010)usingagonist‐elicitedbehaviorsandPETimaging.Therewereno

differencesinDAD1‐andD2‐likereceptorfunction,butdifferenceswere

notedinthebehavioraleffectsoftheD3/D2agonistquinpiroleinmonkeys

prenatallyexposedtococaine.Inthepresentstudy,weextendedthe

examinationofneurobiologicalcharacteristicstoincludeCSFconcentrations

oftheDAmetabolitehomovanillicacid(HVA)andtheserotoninmetabolite

5‐hydroxyindoleaceticacid(5‐HIAA),andextendedbehavioralassessments

tomeasuresthoughttoreflectaspectsofimpulsivity.

Cocaineuseduringpregnancyhasbeenassociatedwithphysical

deficitsintheoffspringincludingreducedbodyweight,bodylength,and

headcircumferenceoftheinfantsatbirth(NairandWatson1991)and

developmentaldeficitsincludingmemory(Singeretal.2005,2008),

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attention(Singeretal.2000;Nolandetal.2005;Linaresetal.2006),

cognition(Singeretal.2001;Morrowetal.2006),andimpulsecontrol

(Savageetal.2005;Linaresetal.2006;Accorneroetal.2007;Pulsiferetal.

2008).Investigatingthedifferencesinimpulsecontrolinahighlycontrolled

animalmodelisanimportantcomplementtothehumanstudies.However,

someofthedifficultyinevaluatingimpulsivityisduetoitbeing

conceptualizedasabroadspectrumofbehaviorsratherthanasingletrait

(Moelleretal.2001;ChamberlainandSahakian2007).Whileresearchwith

humanshastypicallyassessedimpulsivityusingstandardizedquestionnaires

(Evenden1999),thereisnoagreementonhowtomeasureimpulsivityin

animalmodels.Severaldistinctmeasureshavebeendevelopedtoassess

impulsivityinanimals,includingresponsetonovelty,locomotoractivity,

behavioralinhibition,andchoicebetweenanimmediate,low‐magnitude

rewardoveradelayedlarge‐magnitudereward.Inthepresentstudy,eachof

thesedependentvariableswasassessedtodirectlycomparethesevarious

measuresofimpulsivity.

Thefirstsetofbehavioralmeasurestoassessimpulsivityusedinthe

presentstudyinvolvedtheunconditionedbehaviorsofresponsetoanovel

object(Delluetal.1996;Zuckerman1996)andlocomotoractivityinanopen

field.Reactivitytoanovelobjecthasbeenusedasameasureofimpulsivityin

rodents(Hookseta.1991;Sutoetal.2001;Davisetal.2008)andnonhuman

primates(Boligetal.1992;reviewedinClarkeandBoinski1995;Colemanet

al.2005;Czotyetal.2010).Regardinglocomotoractivity,Piazzaand

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colleaguesdemonstratedthatresponsivenessinanopenfieldwasassociated

withvulnerabilitytostimulantself‐administration(Piazzaetal.1989;1990;

reviewedinPiazzaandLeMoal1998).InterestinglyDalleyetal.(2007)did

notfindarelationshipbetweenlocomotoractivityandothermeasuresof

impulsivity.Inthepresentstudy,wedirectlycomparedlocomotoractivityof

adultrhesusmonkeyswithseveralothermeasureshypothesizedtoassess

impulsivity.

Athirdmeasureofimpulsivityisresponseperseveration,whichisthe

tendencytocontinueemittingaformerlyreinforcedresponsedespitethe

responsecurrentlybeingeitherunrewardedorpunished(McCleary1966).It

isthoughtthatresponseperseverationisameasureofdeficientbehavioral

inhibitionbecauseinthesetaskssubjectsmuststoptheirongoingbehavior

(Matthysetal.1998).Inthepresentstudy,perseverativerespondingwas

assessedbyexaminingrespondingduringextinctionofpreviouslyfood‐

reinforcedfixed‐ratio(FR)respondinginmonkeysandsubjectsrequiringa

greaternumberofsessionstoextinguishresponding(unrewarded

responding)wasclassifiedasmoreimpulsivethansubjectsthattookfewer

sessionstoextinguishresponding.

Asafinalmeasureofimpulsivity,weassessedchoicebehavior

involvingdelays.Impulsivechoiceismostcommonlyassessedinhuman

studiesusingadelay‐discountingtaskinwhichsubjectsareaskedtochoose

betweenasmall,immediatereinforcerandalarger,delayedreinforcer.The

subjectivevalueofthelargerreinforcerisdecreased(i.e.,discounted)asthe

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lengthoftimethesubjectmustwaittoreceiveitincreases.Byusingaseries

ofchoicesbetweenvaryingdelayvalues,anindifferencepointcanbe

calculatedasthedelayvalueatwhichthesmaller,immediatereinforceris

chosenasoftenasthelarger,delayedreinforcer.Delaydiscountinghasbeen

adaptedforanimalstudies(e.g.Perryetal.2005;Woolvertonetal.2007).

Althoughseveralstudieshaveexamineddelaydiscountinginmonkeys

(AndersonandWoolverton2003;WoolvertonandAnderson2006;

Woolvertonetal.2007;Newmanetal.2008),thesestudieshaveinvolved

choicebetweendrugreinforcers.Thepresentstudyextendedthisworkto

delaydiscountinginvolvingdifferentmagnitudesofnon‐drugreinforcers.

Suchinformationallowsforthegeneralassessmentofimpulsivityandallows

fordelaydiscountingvaluestobecomparedtoothernon‐drugrelated

behavioralmeasuresofimpulsivity.Finally,inadditiontothesebehavioral

measures,weexaminedtherelationshipbetweenmeasuresofDAreceptor

functionandmonoaminemetabolitelevelsandthevariousmeasuresof

impulsivityinbothmaleandfemalemonkeys.

MATERIALANDMETHODS

SUBJECTS.Twentyadultrhesusmonkeys(Macacamulatta),bornbetween

1993and1995andraisedattheFDAfacilityinLittleRock,ARuntiltheir

arrivalatWakeForestUniversityin2007,servedassubjects.Tenmonkeys

(6male,4female)wereprenatallyexposedtococaineand10monkeys(5

male,5female)wereprenatallyexposedtosaline,asdescribedpreviously

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(Morrisetal.1996,1997).Briefly,themothersofthemonkeysusedinthis

studyreceivedintramuscularinjectionsofsalineorescalatingdosesof

cocainethreetimesperdayfortheentirecourseofgestation,withmean

cumulativecocaineintakeof1131.3(±56.1SEM)mg/kg(Morrisetal.1996).

Whenthemonkeyswere6monthsofage,theywerehousedindividuallyin

thesamecolonyroomandbeganbehavioraltraininginvolvinganoperant

testbattery(Morrisetal.1997).Otherthantheirprenataldrughistories,all

monkeyshadnearlyidenticalexperimentalhistories(seePauleetal.1996;

Morrisetal.1996).Atthestartofthisexperiment,monkeyswere

individuallyhousedinstainless‐steelcageswithwateravailableadlibitum

andhadvisualandauditorycontactwitheachother.Sincewehave

previouslyshownthatmonoaminefunctionisinfluencedbymenstrualcycle

(Czotyetal.2009),wemonitoredmenstrualcyclephasethroughoutthe

experimentbydailyvaginalswabs.Daysofbleedingwererecordedas

indicativeofmenses.Duringquarantine,afree‐feedingweightwas

determinedandmonkeys’bodyweightsweremaintainedatapproximately

95%ofthatvaluethroughoutthesestudies(LabDietMonkeyChowandfresh

fruit).Eachmonkeywasfittedwithanaluminumcollar(PrimateProducts,

RedwoodCity,CA)andtrainedtositcalmlyinastandardprimatechair

(PrimateProducts)usingaspeciallydesignedstainless‐steelpolethat

attachedtothecollar.Allmanipulationswereperformedinaccordancewith

the2003NationalResearchCouncilGuidelinesfortheCareandUseof

MammalsinNeuroscienceandBehavioralResearchandwereapprovedbythe

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WakeForestUniversityInstitutionalAnimalCareandUseCommittee.The

orderofexperimentsaccuratelydepictstheorderoftestingforeachmonkey.

APPARATUS.Theapparatusconsistedofaventilated,sound‐attenuating

chamber(1.5x0.74x0.76m;MedAssociates,EastFairfield,VT)designedto

accommodateaprimatechair.Tworesponsekeys(5cmwide)werelocated

ononesideofthechamberwithahorizontalrowofthreestimuluslights14

cmaboveeachresponsekeyandafoodreceptaclewaslocatedbetweenthe

responsekeys.Thereceptaclewasconnectedwithtygontubingtoapellet

dispenser(GerbarandsCorp.,Arlington,MA)locatedonthetopofthe

chamberfordeliveryof1‐gbanana‐flavoredfoodpellets(P.K.NoyesCo.,

Lancaster,NH).Aninfusionpump(Cole‐Palmer,Inc.,Chicago,IL)waslocated

onthetopofthechamber.

SURGERY.Eachmonkeywaspreparedwithachronicindwellingvenous

catheterandsubcutaneousvascularport(AccessTechnologies,Skokie,IL)

understerilesurgicalconditions.Anesthesiawasinducedandmaintained

withketamine(15mg/kg)andbutorphanol(0.025mg/kg).Vitalsignswere

monitoredforthedurationofthesurgery.Briefly,acatheterwasinserted

intothefemoralveintothelevelofthevenacava.Thedistalendofthe

catheterwaspassedsubcutaneouslytoapointslightlyoffthemidlineofthe

back,whereanincisionwasmade.Theendofthecatheterwasthenattached

tothevascularaccessportandplacedinapocketformedbybluntdissection.

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Eachportandcatheterwasfilledwithheparinizedsalinesolution(100

Units/ml)aftereveryexperimentalsessiontoprolongthepatency.Priorto

eachsalineself‐administrationsession,thebackoftheanimalwascleaned

withbetadineand95%EtOHandtheportwasconnectedtotheinfusion

pumplocatedoutsidethechamberviaa20‐gaugeHuberPointNeedle

(AccessTechnologies).Thepumpwasoperatedforapproximately3sectofill

theportandcatheterlinewithsalinepriortostartingthesession.

CEREBROSPINALFLUID(CSF)MEASURESOF5­HIAAANDHVA.Monkeys

wereanesthetizedwith10mg/kgketamine,thealuminumcollarwas

removedandtheneckandthebackoftheskullwereshavedandcleaned

withbetadineand95%EtOH.A25‐gauge,1.5‐inchneedleattachedtoa3‐ml

syringewasinsertedthroughthecisternamagnaandapproximately2mlof

CSFwasremovedwithin10minofinductionofanesthesia.Femaleswere

studiedonlyduringthefollicularphase.Thesampleswereimmediately

transferredtovacutainertubesonice.Sampleswerecentrifugedat4ºCfor

30minat3000rpmandthenaliquotedintomicrocentrifugetubesfor

storageat‐30ºCuntiltheywereanalyzedusinghigh‐pressureliquid

chromatographywithelectrochemicaldetection.Themobilephaseconsisted

of9.6gcitricacid,11.2gsodiumphosphatemonobasicand0.7g1‐

octanesulfonicacidin860mlofultra‐purewater.100microlitersof0.5M

ethylenediaminetetraaceticacid(EDTA)wasaddedandthepHofthe

solutionwasadjustedto3.Next,6dropsoftriethylamineand140ml

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acetonitrilewereaddedandthemobilephasewasfilteredtwice.Mobile

phasewasdeliveredtothesystematarateof0.2ml/minusinganESA582

solventdeliverymodule(ESAInc.,Chelmsford,MA).Three30‐microliter

aliquotsofeachsamplewereloadedintoaESA542autoinjectorand20

microliterswereinjected.SeparationwasachievedwithaC‐18column(150

mmlength,3.2mmi.d.,3micrometerparticlesize;ESA,Inc.)and5‐HIAAand

HVAweredetectedinsamplesusinganESACoulochemIIdetector.

Concentrationsof5‐HIAAandHVAweredeterminedbyinterpolationusinga

standardcurvethatwasgeneratedusingstandardsolutionscontaining

knownamountsofthemetabolites.Eachsamplewastestedintriplicateand

averagevalueswereusedfordataanalysis.

EXPERIMENT1:EFFECTSOFPRENATALCOCAINEEXPOSUREON

IMPULSIVITYUSINGUNCONDITIONEDBEHAVIORS.Approximately2‐6

monthsafterquarantineended,monkeyswerecharacterizedontwo

measuresofimpulsivitythatutilizedunconditionedbehaviors.Forthenovel

objectreactivitytest,themonkeyinthecageadjacenttothesubject’shome

cagewasremoved,thepartitionwasremovedfrombetweenthecages,and

thesubjectwasmovedtotheadjacentcage.Next,thepartitionwasreplaced

andanopaqueblackPlexiglasboxmeasuring30.5x20.3x20.3cmwas

placedinthemonkey’semptyhomecage.Thepartitionwasremovedagain

andthelatencytotouchtheobjectwasrecorded.Ifthemonkeydidnottouch

theobjectwithin15min,ascoreof900secwasassigned.Allsessionswere

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videotapedandscoredbyanobserverblindtothemonkey’sprenatal

condition.The900‐secmaximumdurationwasbasedondatafromour

laboratory(Riddicketal.2009).

Toassesslocomotoractivity,eachmonkeywasplacedina3.0x2.0x1.75m

enclosurewiththefielddividedinto9equalgridzones.Overthe30minute

testperiod,themonkeys’activitywasvideotapedusingacameramounted

overhead.Theprimarydependentmeasurewascrossingsbetweenthe

zones,definedas>50%ofthemonkey’sbodycrossingintoanewgrid

section,andwascountedbyanobserverblindtotheprenatalconditionof

themonkey.

EXPERIMENT2:EFFECTSOFPRENATALCOCAINEEXPOSUREONRESPONSE

EXTINCTION.Monkeyswereinitiallytrainedtorespondontheleftandright

keysbyreinforcingeachresponsewitha1‐gbanana‐flavoredpellet;a30‐sec

timeoutfollowedeachfoodpresentation.Thelightabovetheresponsekey

signaledfoodavailability;onlyonekeywasactiveduringasession.Overthe

courseof2‐3weeks,thenumberofresponsesrequiredwasincreaseduntila

FR30scheduleoffoodpresentationwasachieved.Sessionsendedafter30

reinforcershadbeendeliveredor60minhadelapsed.Whenrespondingwas

reliablymaintained(i.e.,meanresponserate±20%for3consecutive

sessions)onbothkeysandmaximalfoodreinforcementwasobtained

consistently,intravenouscatheterswereimplanted.

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Afterimplantationofthecatheter,baselinefoodreinforcementrateswerere‐

establishedover5sessions,butonlyontheresponsekeyassociatedwiththe

highestrates.Forcontrolmonkeys,4hadhigherratesontheleftkeyand6

ontherightkeyandforprenatallycocaine‐exposedmonkeysthedistribution

was3ontheleftkeyand7ontherightkey.Salineinjectionswere

substitutedforfoodpelletsforatleast5consecutivesessionsanduntil

respondingwasdeemedextinguished.Thecriteriaforextinguishingfood‐

reinforcedrespondingwere3consecutivesessionsinwhichresponserates

werereducedbyatleast80%ofbaselinefoodreinforcedresponding(i.e.,

meanresponserate±20%for3consecutivesessions)withnotrendsin

responding.Theprimarydependentmeasurewasthenumberofsessionsto

meetthesecriteria.

EXPERIMENT3:EFFECTSOFPRENATALCOCAINEEXPOSUREONDELAY

DISCOUNTING.Monkeyswerere‐exposedtotheFR30scheduleoffood

presentation,witheachpelletdeliveryfollowedbya30‐sectimeout(TO).At

thestartofthesession,onelightaboveoneresponsekeywasilluminatedto

indicateitwasactive;theorderofwhichkeywasactivevariedacross

sessions.Sessionsendedafter30reinforcerswerereceivedor60min

elapsed.Subjectsrespondedundertheseconditionsuntilrespondingonthe

rightandleftresponsekeywasreliablymaintainedandwasdeemedstable

oneachlever(i.e.,meanresponserate±20%for3consecutivesessions).

128

Theconditionswerethenchangedtoaconcurrentschedule,whichservedas

thescheduleofreinforcementforthedelaydiscountingprocedure.

Thechoicewasinitiallybetween1and3foodpelletsdelivered

immediatelyaftercompletionoftheFR30requirement.The1pellet

reinforcerwascontingentonrespondingonthekeyassociatedwiththe

highestrates,whilerespondingontheotherkeydelivered3pellets.Initially,

thedelayvalueassociatedwithbothreinforcerswas0sec.Thedelayvalue

associatedwith1pelletremainedat0secthroughouttheexperiment,while

thedelayassociatedwith3pelletreinforcervariedfrom5‐300sec.Sessions

beganwithtwoforced‐choice(i.e.,sampling)trials.Duringthesesampling

trials,onlyoneresponsekeywasactivewithilluminationofthelightand

completionoftheFR30resultedinthereinforceranddelay.Aftera30‐sec

TO,theotherresponsekeywasilluminatedandcompletionoftheFR

resultedinthereinforceranddelay.Forthedurationofthedelay,aredlight

abovetheresponsekeyflashedonandoffeachsecond.Oncebothsampling

trialswerecompletedandfollowinga30‐secTO,theschedulechangedtoa

concurrentschedulewithbothresponsekeysbeingactive.Tolimitthe

influenceofresponseperseveration,aforcedchoicewasimplemented

duringthesessionifthemonkeychosethesamelever5timesinarowand

thenreturnedtoaconcurrentschedule.Delayvalueswerekeptconstantfor

atleast5consecutivesessions,anduntilthepercentchoiceofthelarger,

delayedreinforcerwasdeemedstable(meanpercentchoice±20%for3

consecutivesessions).Sessionsterminatedafter30freechoiceswere

129

completedor60minhadelapsed.Delayvalueswerepresentedinaquasi‐

randomordertodetermineadelay‐percentchoicelargerreinforcercurve.

Basedoneachmonkey’sindividualcurve,theindifferencepoint(delayvalue

thatengendered50%choiceofthelarger,delayedreinforcerand50%choice

ofthesmaller,immediatereinforcer)wascalculated.Theprimarydependent

measureforthisexperimentwastheindifferencepoint.

DATAANALYSIS.CSFconcentrations,latencytoapproachanovelobject,

locomotoractivity,respondingduringextinction,andtheindifferencepoint

(fromdelaydiscounting)wereeachanalyzedusingatwo‐wayANOVAusing

Group(PrenatalCocaineandSaline)andSexasFactors.Post‐hoc

Bonferroni’stestswereconductedwhensignificantmaineffectswere

indicatedbytheANOVA.Forsomedependentvariables,datawereanalyzed

usingSpearman’scorrelationcoefficientforrankeddata.Inallcases,

significancewasacceptedatthe95%levelofconfidence(p<0.05).

Attheendofalltheexperiments,thedatawerecollatedandan

overallimpulsivityscorewascalculated.Todeterminethisindex,all20

monkeyswererankedfrom20(mostimpulsive)to1(leastimpulsive)on

eachdependentvariable(latencytotouchanovelobject,locomotoractivity,

numberofsessionstoreachextinctioncriteria,andindifferencepointfrom

delaydiscounting)andtheaveragerankingsacrossalltaskswascalculated.

ThesedatawereanalyzedusingaMann‐Whitneytestandcorrelatedwith

CSFconcentrationsusingSpearman’scorrelationcoefficient.

130

RESULTSEFFECTSOFPRENATALCOCAINEEXPOSUREONCSFMEASURESOF5­HIAA

ANDHVA.Atwo‐wayANOVAindicatednosignificanteffectofprenatal

condition,sexoraninteractiononCSFconcentrationsof5‐HIAAandHVA

(Table1).

EXPERIMENT1:EFFECTSOFPRENATALCOCAINEEXPOSUREON

IMPULSIVITYUSINGUNCONDITIONEDBEHAVIORS.Atwo‐wayANOVA

revealednosignificantmaineffectofprenatalcocaineexposureorsexand

nosignificantinteractiononlatencytoapproachanovelobject(Fig.1A).

Becausetherewerenodifferencesduetoprenataldrugexposure,mean

latenciesforallthemaleswerecomparedtomeanlatenciesforthefemales

andwerenotsignificantlydifferent.Locomotoractivityrangedfrom5‐316

countsoverthe30minexposureanddidnotdifferasafunctionofprenatal

exposureorsexandtherewasnosignificantinteraction(Fig.1B).

EXPERIMENT2:EFFECTSOFPRENATALCOCAINEEXPOSUREON

EXTINGUISHINGFOODREINFORCEDBEHAVIOR.Underbaselineconditions,

meanresponseratesundertheFR30scheduleoffoodpresentationwerenot

differentinmalemonkeyswithmean(±SEM)valuesof3.89(±0.68)and

2.46(±0.54)resp/secforcontrolandprenatallycocaine‐exposedmonkeys,

respectively.Similarly,femalemonkeysdidnotdifferinmeanresponserates

131

betweengroups(1.60±0.30and2.64±1.16resp/sec,forcontroland

prenatallycocaine‐exposedmonkeys,respectively).Responseextinctionwas

studiedbysubstitutingsalineforfoodpresentation.Atwo‐wayANOVA

revealedasignificantmaineffectofprenatalcocaineexposure(F(1,17)=4.78,

p=0.04)butnosignificanteffectofsexandnosignificantinteractionon

numbersessionstoreachcriteriaforresponseextinction.Prenatallycocaine‐

exposedmonkeysrequiredagreaternumberofsessionstoreachcriteriafor

extinguishingfood‐reinforcedrespondingthancontrolmonkeys(Fig.2).

EXPERIMENT3:EFFECTSOFPRENATALCOCAINEEXPOSUREONDELAY

DISCOUNTING.Undertheconcurrentschedule,whenthedelaywas0sec,

monkeyschosethelargermagnitudefoodreinforceronnearly100%ofthe

trials(seeFig.3forrepresentativecurves).Onaverage,responserateswere

higheronthekeyassociatedwiththelargermagnitudeoffood

reinforcement(1.56±0.28resps/secand1.72±0.23resps/secforthe1

pellet‐and3pellet‐associatedkeys,respectively).Responseratesdidnot

differbetweenprenatallycocaineexposedandcontrolmonkeysnorbetween

maleandfemalemonkeysandresponseratesdidnotchangesignificantly

frombaselineatanydelayvalue(Table2).Increasesinthedelayvalue

resultedintime‐dependentreductionsinthepercentoftrialsinwhichthe

largerreinforcerwaschosen(Fig.3).Indifferencepointswerecalculatedas

thedelayvalue(sec)thatengendered50%choiceofthelarger,delayed

reinforcerandthesmaller,immediatereinforcer(Fig.4).Atwo‐wayANOVA

132

revealedasignficanteffectofprenatalcocaineexposure[F(1,16)=10.56,

p=0.005]andasignificantinteractionbetweenprenatalconditionandsex

[F(1,16)=4.8,p=0.04].Post‐hocBonferronitestsindicatedthatmale

prenatallycocaine‐exposedmonkeyshadsignificantlyshorterindifference

pointsthanmalecontrolmonkeys(p=0.01),whiletherewasnodifference

betweenfemalecontrolandprenatallycocaineexposedmonkeys(Fig.4).

EFFECTSOFPRENATALCOCAINEEXPOSUREONOVERALLIMPULSIVITY.In

ordertocharacterizeeachmonkeyacrossthevariousdependentvariables,

onoverallimpulsivityscorewascalculated(seeMethods).Basedonthese

values,maleprenatallycocaine‐exposedmonkeysweremoreimpulsivethan

malecontrolmonkeys(p=0.009),whereastherewerenodifferences

observedinfemalemonkeys(Fig.5).Spearmancorrelationanalysisrevealed

thatscoresonnoneoftheimpulsivitytasks(i.e.,novelobjectreactivity,

locomotoractivity,responseextinctionanddelaydiscounting)correlated

withscoresonanyotherimpulsivitytask(datanotshown).However,there

wasasignificantnegativecorrelationbetweenCSFconcentrationofHVAand

overallimpulsivityscore(rs=‐0.45,p=0.046);nosignificantcorrelation

betweenCSF5‐HIAAconcentrationsandimpulsivityscoreswereobserved.

DISCUSSION

Thepurposeofthepresentstudieswastoextendearlierwork

characterizingadultrhesusmonkeysprenatallyexposedtococaineand

133

controlstoincludeneurochemicalcorrelatesandbehavioralendpoints

relatedtomeasuresofimpulsivity.Toaccomplishthis,CSFconcentrationsof

theDAmetaboliteHVAandthe5‐HTmetabolite5‐HIAAwereobtainedfrom

10cocaine‐exposedand10controlmonkeys.Inaddition,several

unconditionedandconditionedbehaviorsbelievedtoassessaspectsof

impulsivitywereexamined.Finally,theinteractionbetweenprenataldrug

historyandsexofthemonkeyonthesevariousmeasureswasassessed.

TherewerenodifferencesbetweengroupsorsexesinCSFconcentrationsof

monoaminemetabolitesorinresponsetonoveltyorlocomotoractivity.In

contrast,prenatallycocaine‐exposedmonkeysweremoreimpulsivethan

controlmonkeysontwoconditionedbehavioralmeasuresofimpulsivity,

responseextinctionanddelaydiscounting.Whenallthemeasureswere

combinedandeachanimalwasassignedan“impulsivityscore”,the

prenatallycocaine‐exposedmalemonkeysweresignificantlymoreimpulsive.

Thesefindingssuggestdifferentialeffectsofprenatalcocaineexposureon

measuresofimpulsivitythatareinfluencedbysex.

Thesemonkeysrepresentauniquecohortofanimals–adultmaleand

femaleOldWorldmacaqueswhohadbeenexposedtococainethroughout

the25weeksofgestation(Morrisetal.1996)andgrownupwithminimal

exposuretodrugsofabuse.UsingPETimaging,wepreviouslyreportedthat

therewerenogrouporsexdifferencesinDAD2‐likereceptoravailabilityin

theseadults(Hamiltonetal.2010).Otherpharmacologicalstudiesrevealed

nodifferencesinD1‐likereceptorfunction,butsignificantdifferencesrelated

134

toprenataldrugexposureandsensitivitytoDAD3agonisteffects.Comparing

resultsfromthatstudyandthepresentdata,thereisasignificantpositive

correlationbetweenoverallimpulsivityrankandpeakeffectsofyawning

elicitedbytheD3receptoragonistquinpiroleinmales(rs=0.61,p=0.04)but

notfemales(datanotshown).Additionally,aone‐tailedSpearman’s

correlationfoundthatinmalesubjectsimpulsivityrankingwasnegatively

correlated(rs=‐0.62,p=0.046)withD2‐likereceptoravailabilityinthe

caudatenucleus(fromHamiltonetal.2010).Thesefindingssuggestthat

long‐termneuropharmacologicaleffectsduetoprenatalcocaineexposure

canhavebehavioralconsequences,especiallyinmalesubjects.Thepresent

findingsareconsistentwithotherstudiesshowinganassociationbetween

lowstriatalD2/D3receptoravailabilityandimpulsivityinhuman

methamphetamine‐dependentsubjects(Leeetal.2009)andinrodents

(Dalleyetal.2007).ThepresentfindingsalsosupporttheideathattheD3

receptorcouldbeapromisingpharmacologicaltargetfortreating

impulsivity‐relateddisorders,includingsubstanceabuse(forreviewsseeLe

Folletal.2005;Sokoloffetal.2006;Heidbreder2008).

WefoundarelationshipbetweenimpulsivityandCSFconcentrations

oftheDAmetaboliteHVA,butnottheserotoninmetabolite5‐HIAA,in

contrasttotheextensiveliteraturedocumentinganassociationbetween

decreased5‐HIAAlevelsandincreasedimpulsivityinnonhumanprimates

(Higleyetal.1996;Westergaardetal.1999,2003;Fairbanksetal.1999,

2001,2004;Manucketal.2003).Alikelyexplanationforthediscrepancy

135

betweenfindingsistheuseofdifferentmeasuresofimpulsivity.Asdescribed

below,theconstructofimpulsivityismulti‐faceted,suchthatdifferential

contributionof5‐HTand5‐HIAAmaybedependentonthebehavioral

measure.Nonetheless,thesedatasuggestthat5‐HTisnotnecessarilyamajor

contributortobehaviorsdeemedimpulsive.Therelationshipweobserved

betweenHVAandimpulsivityisanovelfindinginnonhumanprimatesand

concurswitharecentreportthatCSFHVAisinverselycorrelatedwithaform

ofimpulsivityinhumansubjectswithpersonalitydisorder(CoccaroandLee

2010).ThisrelationshipbetweenHVAandimpulsivityprovidesfurther

evidencethatalterationsinthedopaminergicsystemmayregulate

impulsivity.

Thepresentfindingsalsoextendedourearlierworkbyshowing

higherlevelsofimpulsivityinthemalemonkeysexposedtococaineinutero

butnotinfemales,suggestingdifferentialeffectsofprenatalcocaine

exposureinfluencedbysex.Gender‐specificeffectshavealsobeenfoundin

animalstudieswithmalesmoresusceptibletothenegativelong‐termeffects

ofprenatalcocaineexposureon5‐HTreceptors(Johnsetal.2002)andDA

receptorbindingandreactivity(Silversetal.2006;Dow‐Edwards2010).

Additionally,recentclinicalstudiesreportedmalestobemoreadversely

affectedbyprenatalcocaineexposurethanfemales,specificallyincreasing

theirriskforproblemsofinhibitorycontrol(Delaney‐Blacketal.2004;

Benderskyetal.2006;Dennis‐Tiwaryetal.2006;Bennetetal.2007).Ithas

beensuggestedthatthemalefetusismorevulnerabletoinuterostressors

136

andneurotoxinsthanthefemalefetus(Kraemer2000)whichmayaccount

forthelargerdeficitsobservedinprenatallycocaineexposedmalesthan

females.Itisalsopossiblethatotherchangesthatoccurduringhormonal

variationsofadolescencemaymaskeffectsofprenatalcocaineexposure

untilmaturation(Cabrera‐Veraetal.2000).Ourfindingsofincreased

impulsivityinmale,butnotfemale,monkeysexposedtococainethroughout

gestationsupporttheideathatprenatalcocaineexposureoutcomesare

influencedbysex.

Thisisthefirstreporttoinvestigateawiderangeofimpulsivity

measuresinthesamecohortofnonhumanprimates.Behavioraloutcomes

fromthefourtasksusedinthisstudy(novelobjectreactivity,locomotor

activity,responseextinctionanddelaydiscounting)didnotcorrelatewith

oneanother,indicatingthatweweremeasuringdifferentfacetsofthe

constructofimpulsivity.Interestingly,differencesinimpulsivitybetween

prenatallycocaine‐exposedandcontrolmonkeyswereonlyobservedinthe

conditionedbehavioralmeasures.Thetwounconditionedbehavioral

measuresaretasksthataretypicallyusedintherodentstoassess

impulsivityandhavebeenshowntocorrelatewithdruguse(Hooksetal.

1991;Klebaretal.2001;Piazzaetal.1989,1990;reviewedinPiazzaandLe

Moal1998).Itispossiblethattheseunconditionedmeasuresarenot

sufficienttoseedifferencesinimpulsivityinnonhumanprimatesorthat

morecomplex,conditionedbehavioralmeasuresarenecessarytounmask

thesubtledifferencesinimpulsivityinprenatallycocaine‐exposedmonkeys.

137

Infuturestudies,wewillbeabletoestablishwhichimpulsivitymeasures

correlatewithstimulantself‐administrationinthissamecohortofmonkeys

todeterminewhichtaskshavethemostpredictiveability.

Ithasbeenhypothesizedthatsomenegativeeffectsofcocaine,

particularlythoseregulatedbymonoamine‐richareasofthebrain,suchas

deficitsinimpulsecontrol(Bandstraetal.2007),willultimatelyleadto

higherratesofsubstancedependence.Therefore,therelationshipbetween

addictionandimpulsivity(JentschandTaylor1999;BickelandMarsch2001;

deWit2010)suggeststhattheincreasedimpulsivityobservedinthemale

monkeysexposedtococaineinuteromaypredisposethemtodruguse.The

femaleprenatallycocaine‐exposedmonkeysdidnotdifferfromcontrolson

overallimpulsivitywhichindicatestheymaybeprotectedfromthispotential

vulnerabilitytosubstanceabuse.Sinceweobserveddeficitsinimpulsivity15

yearsafterthecocaineexposureinutero,itislikelythattheearlydeficitsin

attentionandimpulsecontrolseeninthehumancohortstudiesatages4,6,

and9yearsold(Savageetal.2005;Linaresetal.2006;Pulsiferetal.2008)

maybeassociatedwithdisturbancesininhibitorycontrolinadolescenceand

adulthoodthatcouldcontributetoanincreasedvulnerabilitytosubstance

abuse.Takentogether,thepresentresultsprovideevidenceforlong‐term

neurobehavioralconsequencesofprenatalcocaineexposureonimpulse

controlandaneurobiologicalcorrelatefortheincreaseimpulsivityobserved

inmale,butnotfemale,subjects.

138

ACKNOWLEDGEMENTS

ThisresearchwassupportedbyNationalInstituteonDrugAbusegrantsR01

DA25120,R37DA10584andK31DA024485.Theauthorsreportnoconflict

ofinterestandwouldliketoacknowledgetheexcellenttechnicalassistance

ofTonyaCalhounandWhitneyWilson.TheauthorsalsothankDr.WilliamL.

WoolvertonfortechnicalconsultationandDr.MerlePauleforproviding

informationrelatedtothehistoriesofthesemonkeys.

139

TABLE1.COMPARISONOFCSF5‐HIAAANDHVA(MEAN±SEM)BETWEEN

MALEANDFEMALEPRENATALLYCOCAINE‐EXPOSEDMONKEYSANDCONTROLS

MalePrenatallyCocaineExposed

MaleControls

FemalePrenatallyCocaineExposed

FemaleControls

5‐HIAA(nM)

148±18.1 153.5±4.9 177.1±6.4 156.0±24.4

HVA(nM)

614.7±68.5 734.2±86.8 802.7±113.1 785.1±87.1

140

TABLE2.RESPONSERATES(RESP/SEC)DURINGTHEDELAYDISCOUNTING

TASK¶.

PrenatallyCocaineExposedMonkeys

ControlMonkeys

DelayValue(sec)

Immediatereinforcerkey

Delayedreinforcer

key

Immediatereinforcerkey

Delayedreinforcer

key0 1.85±0.39 1.93±0.29 1.27±0.39 1.45±0.3310§ 1.30±0.35 1.11±0.28 1.08±0.43 1.05±0.3330 1.53±0.48 1.32±0.35 0.96±0.27 1.03±0.2260 1.84±0.43 1.61±0.40 1.19±0.29 1.36±0.23120† 1.36±0.29 1.60±0.35 1.38±0.25 1.55±0.34

¶Allpointsaremeans(±SEM)of10monkeys,exceptwherenoted

§n=10forprenatalcocainegroupandn=7forcontrols

†n=6forprenatalcocainegroupandn=9forcontrols

141

FIGURE1.A:Latencytotouchanovelobjectplacedinthemonkey’shome

cage(insec).B:Numberofgridlinecrossingsinanovelenvironmentover30

min.Valuesshownaremean±SEMforcocaine‐exposed(filledbars)and

control(openbars)maleandfemalemonkeys.

142

FIGURE2.Numberofsessionstoextinguishpreviouslyfood‐reinforced

respondinginmaleandfemalemonkeysprenatallyexposedtococaine(filled

bars)andcontrols(openbars).Eachbarrepresentsmean±SEMvalues.

*p<0.05.

143

FIGURE3.Percentageoftrialsinwhichthelarger,delayedreinforcerwas

chosenoverthesmaller,immediatereinforcerasafunctionofdelayvalue.

Dataarefromrepresentativeprenatallycocaineexposed(left)andcontrol

(right)malemonkeys.Thedelayvalueatwhichthecurveintersectswiththe

dashedline(50%choiceoflargerreinforcer)representstheindifference

point.

144

FIGURE4.Meanindifferencepointscalculatedfromdelay‐discounting

proceduresformonkeysprenatallyexposedtococaine(filledbars)and

controls(openbars).Dataareshownfrommale(left)andfemale(right)

monkeys.Eachbarrepresentsmean±SEMvalues.*p<0.05.

145

FIGURE5.Overallimpulsivityrankacross4measuresofimpulsivity

(novelobjectreactivity,locomotoractivity,responseextinctionanddelay

discounting)inmale(left)andfemale(right)prenatallycocaineexposed

(filledbars)andcontrol(openbars)monkeys.Tocalculatethescore,

monkeyswererankedfrom1(leastimpulsive)to20(mostimpulsive)and

anoverallmeanwasdeterminedforeachanimal.Higherscoresrepresent

greaterimpulsivity.Barsrepresentmean±SEMvalues.*p<0.05.

146

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CHAPTERIV

INCREASEDVULNERABILITYTOSELF­ADMINISTERCOCAINEINADULTRHESUSMONKEYSEXPOSEDTO

COCAINETHROUGHOUTGESTATION

LindseyR.Hamilton,MichaelA.Nader

ThefollowingmanuscriptisinpreparationtobesubmittedtoScienceinMay2010.Stylisticvariationsareduetotherequirementsofthejournal.LindseyR.Hamiltonperformedtheexperiments,analyzedthedata,andpreparedthemanuscript.MichaelA.Naderactedinanadvisoryandeditorialcapacity.

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ABSTRACT

RATIONALE:Prenatalcocaineexposurehasbeenassociatedwithalterations

inthedopamine(DA)systemandincreasedimpulsivityinadultmonkeys.

However,whethertheseneurobiologicalandbehavioraloutcomesof

prenatalcocaineexposureresultsinalteredsensitivitytothereinforcing

effectsofstimulantsinnonhumanprimatesisnotknown.OBJECTIVES:To

assessvulnerabilitytoacquirecocaineself‐administrationin15year‐old

rhesusmonkeysexposedtococaineorsalineinutero(n=10pergroup).

MATERIALSANDMETHODS:Monkeysweretrainedtoself‐administerfood

pellets(1g)underafixed‐ratio(FR)30scheduleofreinforcement.Salineand

ascendingdosesofintravenouscocaine(0.001‐0.3mg/kg/injection)were

substitutedforfoodpellets.Acquisitionofcocaineself‐administrationwas

operationallydefinedasthelowestdoseinwhichresponserateswere

signficantlygreaterthansaline‐contingentratesofresponding.RESULTS:

Prenatallycocaine‐exposedmonkeysacquiredcocaineself‐administrationat

lowerdosesthancontrolsandrequiredlesscocainehistorypriortofindinga

doseofdrugreinforcing.Vulnerabilitytoself‐administercocainewasfound

toberelatedtoanindividualphenotypeinvolvingincreaseddopamineD3

receptorfunctionandimpulsivity.CONCLUSIONS:Thesefindingssuggest

thatprenatalcocaineexposureresultsinincreasedvulnerabilitytostimulant

self‐adminstration.

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Keywords:Prenatalcocaine–Cocaine–Self­Administration–Predisposition–

Acquisition–Rhesusmonkey

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Althoughratesofprenatalcocaineexposurepeakedduringthelate

1980sandearly1990s,itcontinuespresentlywithapproximately50,000

additionalchildrenborneachyear(NationalPregnancyandHealthSurvey,

1996).WidespreaduseofcocaineintheUnitedStateshasresultedinmore

than1millionchildrenprenatallyexposedtococaine,manyofwhomare

nowenteringadolescenceoryoungadulthood,atimewhenmany

experimentwithdrugsofabuse.Forexample,approximately1in5

Americansbetweentheagesof21‐25havetriedcocaineatleastonceintheir

lifetime(SAMHSA,2008).Childrenandyoungadultsthatwereexposedto

cocaineinuteromaybesensitizedtothereinforcingeffectsofcocaineandbe

morevulnerabletoprogressingtodrugabuse.Currently,thehumancohort

studieshaveonlyfollowedtheprenatallycocaine‐exposedchildrenandnon‐

exposedcontrolsthrough13yearsold.Itisnotyetknownwhetherprenatal

cocaineexposureisassociatedwithincreasedriskofsubstancedependence.

Thereisaccumulatingevidencethatprenatalexposuretosubstances

predictssubsequentsubstanceuselaterinlife.Anelevatedriskoftobacco

dependenceandearlyadolescentsmokingandtobaccosmokinghasbeen

foundinoffspringofmotherswhosmokedduringtheirpregnancy(Kandelet

al.,1994;Bukaetal.,2003;Corneliusetal.,2005).Similarly,prenatal

marijuanaexposurehasbeenassociatedwithinitiationanduseofmarijuana

amongyoungadults(PorathandFried,2005).Aprospective,longitudinal

studyobservedasignificantcorrelationbetweenprenatalalcoholexposure

andsubsequentalcoholuseandalcoholproblemsat14years(Baeretal.,

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1998)andat21yearsold(Baeretal.,2003),evenaftercontrollingforfamily

historyofalcoholabuse.

Whilenohumanstudieshaveexaminedtheeffectofprenatalcocaine

exposureandvulnerabilitytosubstanceabuse,studiesinrodentssuggest

thatthereinforcingefficacyofstimulantsisalteredbygestationalcocaine

exposure.Prenatalcocaineexposureenhancesthecocaine‐induced

potentiationofbrainstimulationreward(LinandKellogg,1996;Malangaet

al.,2008).Prenatallycocaineexposedratsalsoshowedsignificantlyhigher

ratesofrespondingcomparedtocontrolsforalowdoseofcocaineavailable

underanFR1scheduleofreinforcement(Kelleretal.,1996).Additionally,

Rochaetal.(2002)foundthatmiceexposedtococaineinuteroacquired

cocaineself‐administrationmorereadilythancontrolsdespiteobservingno

differencesinrateofacquisitionoffood‐reinforcedresponding.

However,thereareconflictingreportsaboutprenatallycocaine

exposedanimals’propensitytobemoresensitivetothereinforcingeffectsof

cocaine.Heyseretal.(1992)foundthatratsexposedtococainethroughout

gestationdidnotacquirecocaineconditionedplacepreferencewhich

suggestsareductionincocainereward.Furthermore,Hechtetal.(1998)

determinedthatprenatallycocaine‐exposedratswerelesssensitivetothe

reinforcingstrengthofcocainebecausetheseanimalshadsignficantlylower

breakpointsforcocaineusingaprogressive‐ratioscheduleofreinforcement.

Therefore,ithasnotbeenwellestablishedwhetherprenatalcocaine

exposurealtersvulnerabilitytococaineself‐administration.

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Inordertoevaluatetheconsequencesofinuterodrugexposurein

adulthood,thepresentstudyexaminedprenatalcocaineexposureinrhesus

moneys.Theseanimalshadbeenexposedtococaineorsalinethroughoutthe

25weeksofgestation(Morrisetal.,1996)andwerestudiedasadults(14‐15

yearsold).Werecentlyexamineddopamine(DA)receptorfunctioninthese

adultmonkeys(Hamiltonetal.,2010)usingagonist‐elicitedbehaviorsand

PETimaging.TherewerenodifferencesinDAD1andD2receptorfunction,

butprenatallycocaine‐exposedanimalsweremoresensitivetothe

behavioraleffectsoftheD3agonistquinpirolecomparedtocontrols.

Additionally,wehavepreviouslyfoundthatmale,butnotfemale,prenatally

cocaine‐exposedmonkeysaremoreimpulsivethancontrols(Hamiltonetal.,

submitted).Long‐lastingalterationsinthedopaminergicsystemand

increasedbehavioralimpulsivityareriskfactorsforincreasedvulnerability

toself‐administerstimulants,suggestingthatprenatallycocaine‐exposed

monkeysmaybemoresensitivetothereinforcingeffectsofcocaineas

adults.Inthepresentstudy,weextendedthebehavioralassessmentofthis

cohorttoexamineacquisitionofcocaineself‐administration.

METHODS

SUBJECTS.Nineteenadultrhesusmonkeys(Macacamulatta),bornbetween

1993and1995andraisedattheFDAfacilityinLittleRock,ARuntiltheir

arrivalatWakeForestUniversityin2007,servedassubjects.Tenmonkeys

(6male,4female)wereprenatallyexposedtococaineand9monkeys(5

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male,4female)servedascontrols,asdescribedpreviously(Morrisetal.,

1997).Briefly,themothersofthemonkeysusedinthisstudyreceived

intramuscularinjectionsescalatingdosesofcocainethreetimesperdayfor

theentirecourseofgestation(Morrisetal.,1996).Themeangestational

cocaineexposurewas1131.5mg/kg.Otherthantheirprenataldrug

histories,allmonkeyshadidenticalexperimentalhistories(seePauleetal.,

1996;Morrisetal.,1996).Monkeyswereindividuallyhousedinstainless‐

steelcageswithwateravailableadlibitumandhadvisualandauditory

contactwitheachother.Sincewehavepreviouslyshownthatmonoamine

functionisinfluencedbymenstrualcycle(Czotyetal.2009),wemonitored

menstrualcyclephasethroughouttheexperimentbydailyvaginalswabs.

Daysofbleedingwererecordedasindicativeofmenses.

Duringquarantine,afree‐feedingweightwasdeterminedand

monkeys’bodyweightsweremaintainedatapproximately95%ofthatvalue

throughoutthesestudies(LabDietMonkeyChowandfreshfruit).Each

monkeywasfittedwithanaluminumcollar(PrimateProducts,Redwood

City,CA)andtrainedtositcalmlyinastandardprimatechair(Primate

Products)usingaspeciallydesignedstainless‐steelpolethatattachedtothe

collar.Allmanipulationswereperformedinaccordancewiththe2003

NationalResearchCouncilGuidelinesfortheCareandUseofMammalsin

NeuroscienceandBehavioralResearchandwereapprovedbytheWake

ForestUniversityInstitutionalAnimalCareandUseCommittee.

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APPARATUS.Theapparatusconsistedofaventilated,sound‐attenuating

chamber(1.5x0.74x0.76m;MedAssociates,EastFairfield,VT)designedto

accommodateaprimatechair.Tworesponsekeys(5cmwide)werelocated

ononesideofthechamberwithahorizontalrowofthreestimuluslights14

cmaboveeachresponsekeyandafoodreceptaclewaslocatedbetweenthe

responsekeys.Thereceptaclewasconnectedwithtygontubingtoapellet

dispenser(GerbarandsCorp.,Arlington,MA)locatedonthetopofthe

chamberfordeliveryof1‐gbanana‐flavoredfoodpellets(P.K.NoyesCo.,

Lancaster,NH).Aninfusionpump(Cole‐Palmer,Inc.,Chicago,IL)waslocated

onthetopofthechamber.

SURGERY.Eachmonkeywaspreparedwithachronicindwellingvenous

catheterandsubcutaneousvascularport(AccessTechnologies,Skokie,IL)

understerilesurgicalconditions.Anesthesiawasinducedandmaintained

withketamine(15mg/kg)andbutorphanol(0.025mg/kg).Vitalsignswere

monitoredforthedurationofthesurgery.Briefly,acatheterwasinserted

intothefemoralveintothelevelofthevenacava.Thedistalendofthe

catheterwaspassedsubcutaneouslytoapointslightlyoffthemidlineofthe

back,whereanincisionwasmade.Theendofthecatheterwasthenattached

tothevascularaccessportandplacedinapocketformedbybluntdissection.

Eachportandcatheterwasfilledwithheparinizedsalinesolution(100

Units/ml)aftereveryexperimentalsessiontoprolongthepatency.Priorto

eachdrugself‐administrationsession,thebackoftheanimalwascleaned

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withbetadineand95%EtOHandtheportwasconnectedtotheinfusion

pumplocatedoutsidethechamberviaa20‐gaugeHuberPointNeedle

(AccessTechnologies).Thepumpwasoperatedforapproximately3sectofill

theportandcatheterlinewithdrugpriortostartingthesession.

ACQUISITIONOFCOCAINESELF­ADMINISTRATION.Monkeyswereinitially

trainedtorespondontheleftandrightkeysbyreinforcingeachresponse

witha1‐gbanana‐flavoredpellet;a30‐sectimeoutfollowedeachfood

presentation.Thelightabovetheresponsekeysignaledfoodavailability;

onlyonekeywasactiveduringasession.Overthecourseof2‐3weeks,the

numberofresponsesrequiredwasincreaseduntilafixed‐ratio(FR)30

scheduleoffoodpresentationwasachieved.Sessionsendedafter30

reinforcershadbeendeliveredor60minhadelapsed.Whenrespondingwas

reliablymaintained(i.e.,meanresponserate±20%for3consecutive

sessions)onbothkeysandmaximalfoodreinforcementwasobtained

consistently,intravenouscatheterswereimplanted.

Afterimplantationofthecatheter,baselinefoodreinforcement

responserateswerere‐establishedover5sessions,butonlyontheresponse

keyassociatedwiththehighestrates.Forcontrolmonkeys,4hadhigher

responseratesontheleftkeyand6ontherightkeyandforprenatalcocaine

exposedmonkeysthedistributionwas3ontheleftkeyand7ontheright

key.Salineinjectionsweresubstitutedforfoodpelletsforatleast5

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consecutivesessionsanduntilrespondingwasdeemedextinguished.The

criteriaforextinguishingfood‐reinforcedrespondingwere3consecutive

sessionsinwhichresponserateswerereducedbyatleast80%ofbaseline

foodreinforcedresponding(i.e.,meanresponserate±20%for3consecutive

sessions)withnotrendsinresponding.Theprimarydependentmeasurewas

thenumberofsessionstomeetthesecriteria.

Next,baselinefood‐maintainedratesofrespondingwerere‐

established.InjectionsofcocaineHCl(NationalInstituteonDrugAbuse,

Bethesda,MD,dissolvedinsterile0.9%saline)werethansubstitutedforthe

foodpelletsinascendingorderfrom0.001mg/kg/injectionincreasinginhalf

logunitsto0.3mg/kg/injection.Drugdoseswereavailableforatleast5

consecutivesessionsuntilanimalsreachedcriteriaforstability(response

ratemean±20%withnotrendsfor3consecutivesessions).Inbetweendrug

doses,monkeysreturnedtoafood‐reinforcedbaselineforatleast3

consecutivesessions.Thedoseatwhichcocaineself‐administrationwas

determinedtobeacquiredwasthefirstdoseatwhichresponseratewas

signficantlygreaterthantheresponseratewhensalinewasavailable(see

DataAnalysis).Forfemalesubjects,drugwasonlymadeavailableduringthe

follicularphaseofthemenstrualcycle(days2‐12whereday1isthefirstday

ofmenses).Duringthelutealphase,femalesubjectsrespondedunderanFR

30scheduleoffoodpresentation.

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DATAANALYSIS.At‐testwasusedtodetermineifresponseratesunder

eachdoseofcocainewasgreaterthansaline‐contingentresponserates.To

determineifthereweredifferencesintherateofacquisitionbetween

prenatallycocaineexposedandcontrolanimals,alogrankanalysisofKaplan‐

Meiersurvivalcurveswascomputed.Additionally,at‐testwasusedto

comparethecumulativeexposuretococainepriortoacquisitionbetweenthe

twogroups.Aftertheindividualanimalswereclassifiedintohighorlow

vulnerabilitygroups,t‐testsandMann‐Whitneytestswereusedtocompare

thetwogroupsfordifferences.Inallcases,significancewasacceptedatthe

95%levelofconfidence(p<0.05).

RESULTS

Acquisitionoffood‐maintainedrespondingonanFR30scheduledid

notdifferbetweenthetwogroups(sessionstoacquirefood‐maintainedFR

30was34.5±4.4fortheprenatallycocaineexposedanimalsand35.5±5.9

forthecontrols).MeanresponseratesundertheFR30scheduleoffood

presentationwerenotdifferentinmalemonkeyswithmean(±SEM)values

of3.89(±0.68)and2.46(±0.54)resp/secforcontrolandprenatallycocaine‐

exposedmonkeys,respectively.Similarly,femalemonkeysdidnotdifferin

meanresponseratesbetweengroups(1.60±0.30and2.64±1.16resp/sec,

forcontrolandprenatallycocaine‐exposedmonkeys,respectively).Neither

prenatallycocaine‐exposedorcontrolmonkeysdifferedinmeanresponse

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whensalinewasavailable(Males:0.03±0.01and0.04±0.02,respectively;

Females:0.02±0.01and0.02±0.01,respectively).

Aftertestingallcocainedoses(0.001‐0.3mg/kg/injection)once,80%

(8of10)ofprenatallycocaineexposedmonkeysacquiredcocaineself‐

administrationcomparedtoonly55%(5of9)ofcontrols(Fig.1).The

remaining2prenatallycocaineexposedmonkeysand3ofthe4remaining

controlmonkeyseventuallyacquiredcocaineself‐administrationoncethe

dosesweretestedasecondtime.Onefemalecontrolmonkeyneverfound

anydoseofcocainereinforcing.AlogranktestofKaplan‐Meiersurvival

curvesrevealednodifferencesbetweenprenatallycocaine‐exposedand

controlmonkeysontherateofacquisitionofcocaineself‐administration(χ2

=1.34,p=0.25).Themedianacquisitiondose(thedosebywhich50%ofthe

animalshadacquiredself‐administration)was0.01mg/kgfortheprenatally

cocaineexposedanimalsand0.3mg/kgforthecontrolanimals.At‐test

revealedgreatercumulativecocaineexposuresincebeginningthe

experimentuntilacquisitionofcocaineself‐adminstrationincontrols

comparedtoprenatallycocaine‐exposedmonkeys(p=0.04)(Fig.2).

Basedoneachanimal’sindividualcumulativeintakeofcocaineprior

toacquisition,animalsweresplitintotwogroups:highvulnerability(HV,

cumulativecocaineintakepriortoacquisition<3mg/kg,n=10)andlow

vulnerability(LV,cumulativecocaineintakepriortoacquisition>3mg/kg,n

=9)(Fig.3).At‐testshowedthatthenumberofself‐administrationsessions

toreachacquisitioncriteriawassignficantlygreaterintheLVgroup(40.8±

168

6.0sessions)comparedtotheHVgroup(15.4±2.5sessions)(p=0.0008)

(datanotshown).Usingdatageneratedfromthesemonkeysinearlier

studies(Hamiltonetal.,2010,underreview),aMann‐Whitneytestrevealed

thattheHVgroupweremoreimpulsivecomparedtotheLV(p=0.04)(Fig.4,

panelA)andat‐testrevealedtheHVgrouphadgreaterfrequencyofyawns

elicitedbyquinpirole(p=0.03)(Fig.4,panelB)comparedtotheLVgroup.

Additionally,therewassignificantcorrelationbetweenquinpirole‐elicited

yawningandcumulativecocaineintakepriortoacquisition(r2=0.18,p=

0.05)(Fig.4,panelC).TherewasnodifferenceobservedbetweentheHVand

LVgroupsforanyotherphenotypicvariableexaminedincludingD2receptor

availability,D1receptor‐elicitedeye‐blinking,or5‐HIAAorHVAbasal

cerebrospinalfluidconcentration(datanotshown).

DISCUSSION

Thepurposeofthepresentstudieswastodeterminewhether

prenatallycocaineexposedadultrhesusmonkeysweremorevulnerableto

stimulantself‐administrationcomparedtocontrols.Tostudyvulnerability,

monkeysrespondedunderanFR30scheduleoffoodpresentationand,when

stable,salineandthenincreasingcocainedoseswereexamined.Between

salineorvariouscocainedoses,respondingwasagainmaintainedbyfood.In

thisway,acquisitionofcocainereinforcementcouldbeoperationallydefined

asthelowestdoseinwhichcocaine‐maintainedrespondingwassignificantly

169

higherthansaline‐contingentresponding(i.e.,thelowestdoseinwhich

cocainefunctionedasareinforcer).Prenatallycocaine‐exposedmonkeys

acquiredcocainereinforcementatlowerdosesthancontrolanimals.Thisis

notsimplyadifferenceinlearningtoacquirebecauseacquisitionoffood‐

maintainedrespondingonanFR30scheduledidnotdifferbetweenthetwo

groups.Furthermore,thecumulativecocainedosepriortoacquisition(i.e.,

theamountofcocainethathadbeenself‐administeredpriortoadose

functioningasareinforcer)wassignificantlylowerforprenatalcocaine

exposedmonkeyscomparedtocontrols.Thisisofrelevancebecausecocaine

willfunctionasareinforcerinallmonkeys;however,comparedtocontrols,

theamountofcocainehistorynecessaryfortheprenatallycocaine‐exposed

monkeysissubstantiallylessthantheamountnecessaryforcontrol

monkeys,suggestingtheyaremoresensitivetothereinforcingeffectsof

cocainethancontrols.

Aftercompletingcocainedose‐responsecurvesforallanimals,several

phenotypicvariablesthathavebeenthoughttoberelatedtococaineself‐

administrationwereexamined.Todothis,individualmonkeyswere

characterizedashighlyvulnerable(HV)orlowvulnerable(LV)tococaine

reinforcementbasedontheamountofcocaineintakepriortoacquisition

(i.e.,the10monkeyswiththelowestintakeswereconsideredHV,whilethe9

withthehighestintakeswereconsideredLV).Ofthe10HVmonkeys,70%

wereprenatallycocaineexposed.Wepreviouslyreportedthattherewereno

grouporsexdifferencesinDAD2‐likereceptorfunctionusingPETimaging

170

inthiscohort(Hamiltonetal.,2010).Otherpharmacologicalstudiesrevealed

nodifferencesinD1‐likereceptorfunction,butsignificantdifferencesrelated

toprenataldrugexposureandsensitivitytoDAD3agonisteffectsinmale

monkeys(Hamiltonetal.,2010).Comparingresultsfromthatstudyandthe

presentdata,wedeterminedthattherewerenosignificantdifferencesinD2‐

likereceptoravailabilityorD1‐elicitedeye‐blinkingbetweentheHVandLV

monkeys.However,theHVmonkeyspreviouslydisplayedincreased

frequencyofyawnselicitedbyquinpirolecomparedtoLVmonkeysand

therewasasignificantcorrelationbetweenpeakyawnsandthecumulative

cocaineintakepriortoacquisition,suggestingaroleforD3receptorfunction

incocainereinforcement.Wealsocomparedtheresultsfromthepresent

studytoimpulsivitymeasurespreviouslyexamined.Theprenatallycocaine

exposedmonkeysweremoreimpulsivecomparedtocontrols(Hamiltonet

al.,underreview).Asitrelatestoself‐administration,HVmonkeysaremore

impulsiveacrossmultiplemeasuresofimpulsivitycomparedtoLVmonkeys,

whichsuggeststhatimpulsivityisabehavioralphenotypethatpredicts

acquisitionofstimulantself‐administration.

Byusingawithinsubjectdesignandseveralbehavioraland

neuropharmacologicalmeasures,wewereabletoidentifyaspecificprofile

orphenotypethatpredictedvulnerabilitytostimulantself‐administration.

IncreasedD3receptorfunctionappearstobeaneurobiologicalriskfactor

thatpredisposesindividualstococaineself‐administration.Thepresent

findingsareconsistentwithotherstudiesshowinganassociationbetween

171

lowstriatalD2/D3receptoravailabilityandimpulsivityinhuman

methamphetamine‐dependentsubjects(Leeetal.,2009)andinrodents

(Dalleyetal.,2007).Additionally,anupregulationofD3receptorshasbeen

observedinindividualsthatdiedfromacocaineoverdose(StaleyandMash,

1996),whichindicatesperhapsD3functionplaysacriticalroleinthe

reinforcingeffectsofcocaine.Thepresentfindingsalsoprovidesupporting

evidencefortheD3receptorbeingapromisingpharmacologicaltargetfor

treatingimpulsivity‐relateddisorders,includingsubstanceabuse(for

reviewsseeLeFolletal.,2005;Sokoloffetal.,2006;Heidbreder,2008).Our

findingsthatincreasedimpulsivityappearstobeabehavioralriskfactorfor

vulnerabilitytoself‐administercocainesupporttherelationshipbetween

addictionandimpulsivitythathasbeenpreviouslyreportedintheliterature

(JentschandTaylor,1999;BickelandMarsch,2001;DeWit,2010).

Inthisstudy,only68%(13outof19)ofthesubjectsacquiredcocaine

self‐administrationinitially,whichisverylowincontrasttoourlaboratory’s

typicalacquisitionrateofapproximately100%.However,thislower

acquisitionratemayberelatedtotheexperimentaldesignandisastrength

oftheacquisitionprocedure.Typically,tohaveamonkeyacquirecocaine

self‐administration,subjectsaretrainedtorespondonanoperantschedule

withfoodreinforcementandanintermediatedoseofcocaine(0.03

mg/kg/injection)ismadeavailable,whichresultsinalmosteverysubject

acquiringself‐administrationveryquickly.Inthepresentstudy,westarted

withanextremelylowcocainedose(0.001mg/kg/injection),mademany

172

dosesavailableinanascendingorder,andrepeatedlywentbacktoafood

baselinebetweeneverydoseavailable.Thisdesignresultedinrepeated

pairingsofthecuessuchasthepumpnoiseandlightschangingassociated

withreceivinganinjectionandverylowdosesofdrugthatwerenot

reinforcing,whichistheequivalentofrepeatedlyextinguishingresponding

inthesesubjects.Ultimately95%(18of19)ofthesubjectsinthiscohort

acquiredself‐administration,althoughthemediandoseforcontrolmonkeys

wasonelog‐untihigherthanthetypical0.03cocainedoseweusefor

training.Theexperimentaldesignprovidedamoresensitivemeasureof

cocaineacquisitionandonethatallowedustodetermineindividual

differencesinvulnerabilityforcocainetofunctionasareinforcer.

Individualdifferencesinvulnerabilitytoaddictioniswellacceptedin

theclinicalliteraturebuthasnotbeenthoroughlyinvestigatedinanimalself‐

administrationstudies.Whenstudyingtheetiologyofdrugaddiction,an

importantquestioniswhycertainindividualsreportbecomingaddictedtoa

substanceaftertheirfirstdosewhereasotherindividualsareabletousea

drugformonthsorevenyearsonlysporadicallybeforebecomingaddictedto

thesubstance(O’Brienetal.,1986).Thepresentfindingssuggestthata

particularsetoftraits,increasedimpulsivityandincreasedD3receptor

function,canpredictindividualdifferencesinthedevelopmentofcocaine

self‐administrationinmonkeys.

Thedifferencesweobservedinimpulsivitymeasures,D3receptor

function,andpredispositiontoacquirestimulantself‐administrationwere15

173

yearsafterthecocaineexposureinutero.Ourdatasuggestthatprenatal

cocaineexposuremayincreasethelikelihoodofanadultbehavioraland

neurobiologicalphenotypethatpredisposesindividualstosubstanceabuse.

Thisissupportedbythehumanprospectivelongitudinalstudieswhichhave

foundearlydeficitsinattentionandimpulsecontrolinprenatallycocaine

exposedchildrenatages4,6,and9yearsold(Savageetal.,2005;Linareset

al.,2006;Pulsiferetal.,2008),indicatingthatthesechildrenmayalsobe

morevulnerabletosubstanceabuse.Takentogether,thepresentresults

providesupportingevidenceforlong‐termneurobehavioralconsequencesof

prenatalcocaineexposureonvulnerabilitytoself‐administercocaine.

ACKNOWLEDGEMENTS

ThisresearchwassupportedbyNationalInstituteonDrugAbuse

grantsR01DA25120,R37DA10584andK31DA024485.Theauthorsreport

noconflictofinterestandwouldliketoacknowledgetheexcellenttechnical

assistanceofTonyaCalhounandWhitneyWilson.TheauthorsalsothankDr.

MerlePauleforprovidinginformationrelatedtothehistoriesofthese

monkeysandDr.BethReboussinforherassistancewithstatisticalanalysis.

174

FIGURE1.Percentageofprenatallycocaineexposed(closedsymbols)and

control(opensymbols)monkeysthatreachedcriteriatoacquirecocaineself‐

administrationatvariousdosesofcocaineavailableunderanFR30schedule

ofreinforcement.

175

FIGURE2.Amountofcocaineintakepriortoreachingcriteriatoacquire

cocaineself‐administrationinprenatallycocaineexposedandcontrol

monkeys.Barsrepresentmean±SEMvalues.*p<0.05.

176

FIGURE3.Amountofcocaineintakepriortoreachingcriteriatoacquire

cocaineself‐administrationinhighvulnerableandlowvulnerablemonkeys.

Barsrepresentmean±SEMvalues.*p<0.05.

177

178

FIGURE4.a)Impulsivityscorederivedfrom4behavioralmeasuresof

impulsivity(1=leastimpulsive,20=mostimpulsive)inhighandlow

vulnerablemonkeysasdescribedinHamiltonetal.,(underreview).Squares

representprenatallycocaineexposedmonkeysandtrianglesrepresent

controlmonkeys.b)PeakyawnselicitedbytheD3receptoragonist

quinpiroleinhighandlowvulnerablemonkeys.Squaresrepresentprenatally

cocaineexposedmonkeysandtrianglesrepresentcontrolmonkeys.

Quinpirole‐elicitedyawningdataarefromHamiltonetal.(2010).c)

Relationshipbetweenpeakyawnselicitedbyquinpiroleandcumulative

cocaineintakepriortoreachingacquisitioncriteria.

179

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CHAPTERV

DISCUSSION

“Someaddictsgoformonthsoryearsusingheroinorcocaine

onlyonweekendsbeforebecomingadaily(addicted)user.

Othersreportthattheyhadsuchanintensepositiveresponse

thattheybecameaddictedwiththefirstdose…”O’Brienetal.,

1986.

Studyingacomplex,multi‐dimensionalpsychiatricdisorderlike

substanceabuseismadeevenmorechallengingbythefactthatdrugabusers

areahighlyheterogenousgroup.Determiningindividualvulnerabilitytogo

frommisuseofdrugstoaddiction,astheO’Brienandcolleaguesquote

indicates,isacriticallineofresearchinthestudyoftheetiologyofdrug

addiction.Itisbelievedthattherearemultiplefactorsthatcontributeto

vulnerability,inherentoracquired(LeMoal,2009).Quantitativetraitsthat

indicateaspecificriskfactorcanbeconceptualizedasabehavioralor

biologicalphenotype.Theresearchinthisdissertationwasdesignedto

examineseveralofthemultipledeterminantsofanaddictionphenotypeand

theirinteractions.Thesestudiesattemptedtotrytoelucidateavulnerable

phenotypeinordertoidentifycharacteristics(behavioraland

neuropharmacological)thatmaypredisposeanindividualtoaddictionby

characterizingthelong‐termeffectsofprenatalcocaineexposureinadult

183

rhesusmonkeys.Thedopaminereceptorsystem,behavioralmeasuresof

impulsivity,andacquisitionofcocaineself‐administrationwereexaminedin

acohortofadultrhesusmonkeysthatwereexposedtococainethroughout

gestation.AswillbedescribedinthisChapter,thereappearstobea

relationshipbetweenDAD3receptorfunction,impulsivity,andacquisitionof

cocaineself‐administration.Theresearchdescribedinthisdissertation

supportstheideathattherearebiologicalandbehavioralphenotypesthat

seemtopredisposeindividualstodrug‐takingbehaviorandthatprenatal

cocaineexposurecanincreasethelikelihoodofthesephenotypes.

ACQUISITIONOFCOCAINESELF­ADMINISTRATION

Measuringacquisitionofdrugself‐administrationisamethodof

examiningtheetiologyofdrug‐takingbehaviorthatallowsforthe

investigationofvariablesthatmayattenuateorenhanceinitiationofdrug

use.Factorsthatimpedeacquisitionmaybetargetsfortreatment.Likewise,

variablesthatincreasetherateofacquisitionmaybeidentifiedasriskfactors

thatpredisposetodruguse.Intypicalacquisitionstudies,thedoseofthe

drugisheldcontantandthecriteriatoreachacquisitionaredefinedasaset

numberofinjectionsreceivedorsetamountofdrugtaken(mg/kg).By

definingacquisitionasreachingsetarbitrarycriteria,itcanbearguedthat

thesestudiesareassessingcriterionperformancenotacquisitionofthedrug

becomingareinforcer.Forexample,CarrollandLac(1997)investigated

acquisitionofamphetamine(0.06mg/kg/injection)self‐administrationand

184

definedacquisitionasgreaterthan50injectionspersession.Oneratthatdid

notreachthisacquisitioncriterionhadameanof44injectionspersession

overthe30daysofacquisition.Itisnotclearwhetheramphetaminewasa

reinforcerinthisparticularratbecausetherewasnocomparisontovehicle.

Itispossiblethatamphetaminewasareinforcerinthisanimalwithout

reachingthedefinedarbitrarycriteria.

InChapterIV,anacquisitionprocedurewasusedthatoperationally

definedacquisitionregardlessofdose.Weassessedmultipledosesof

cocaineinascendingorderanddefinedacquisitionasgreaterrespondingfor

cocainethanwhensalinewasavailable(Figure1).Eachanimal’sindividual

salinebaselineratesofrespondingwereusedtodeterminewhetherornot

theacquisitioncriterionhadbeenmet.Thismethodologyallowedustofocus

onindividualdifferencesinacquiringcocainereinforcement.Thismethod,

whichusedverylowdosesofdrug,alsohighlightsmorevariabilitybetween

subjectsthantrainingananimaltoacquirecocaineself‐administrationata

moderateorhighdose.Thisincreasedvariabilityallowedthegroupsof

animalstodifferentiatefromeachothermoreandenhancedourabilityto

detectvariablesthataffectedacquisitionrate.

185

FIGURE1.Representativeresponseratesforfood(opensymbols)and

drug(closedsymbols)underanFR30scheduleofreinforcementduringthe

acquisitionofcocaineself‐administrationforaprenatallycocaineexposed

monkeys.

Theloweracquisitionrateobservedinthesestudiescouldbe

explainedbylatentinhibition,whichisareductioninconditioningtoa

stimulusthatoccursasaresultofpreexposuretothatstimuluswithout

reinforcement(Weiner1990).Sincetheacquisitionprocedurerepeatedly

paireddosesofcocainethatwerenotreinforcingtotheanimalwiththecues,

themonkeysmayhavelearnedtoignorestimulithatarerepeatedly

presentedbecausetheywerenotpreviouslyfollowedbyameaningful

consequence.Itispossiblethatthelatentinhibitionprocesseswerestronger

186

incontrolanimalscomparedtoprenatallycocaine‐exposedanimalssince

theytooklongertoacquirecocaineself‐administration.Theprenatally

cocaine‐exposedmonkeysmaybelessresponsivetoPavlovianconditioning

comparedtothecontrols.

Latentinhibitionisarobustbehavioralphenomenonandcanbe

demonstratedinmanyspecies,includinginhumans,acrossavarietyof

classicalandinstrumentalconditioningprocedures,includingavoidance,

tasteaversion,anddiscriminationlearning(Lubow,1989).Itisthoughtthat

latentinhibition,sinceitisconservedacrossmanyspeciesandisobserved

acrossabroadrangeofconditions,servesanimportantadaptivefunction,

allowingformoreefficientandrapidlearning(Lubow,1989).Additionally,

latentinhibitionisconsideredtoreflectanimals’learningnottoattendtoor

toignoreirrelevantstimuliandhasalargeattentionalcomponent.

Therefore,inadditiontodisplayingincreasedsensitivitytothereinforcing

effectsoflowdosesofcocaine,prenatallycocaine‐exposedmonkeysmayalso

bedemonstratingalteredattentionalprocessescomparedtocontrol

monkeys.Sinceithasbeenhypothesizedthatactivationofthemesolimbic

dopaminergicsystemdisruptsthelatentinhibitionprocesses(Wiener,1990)

andprenatallycocaine‐exposedmonkeyshaveincreasedD3receptor

function(Hamiltonetal.,2010),itispossiblethattheprenatallycocaine‐

exposedmonkeysacquiredcocaineself‐administrationmorereadilythan

controlsduetoalterationsintheirlatentinhibitionprocesses.

187

Thisexplanationissupportedbythepreliminarydataindicatingthat

whenthecocainedose‐responsecurvesarere‐establishedafteracquisition

hasalreadyoccurred,therearenodifferencesbetweenprenatallycocaine‐

exposedmonkeysandcontrolmonkeys(Figure2).Thiswouldbeconsistent

withthehumanstudiesthathavefoundapatternofdifficultieswith

sustainedandselectiveattention(Bandstraetal.,2001;Savageetal.,2005;

Linaresetal.,2006).

FIGURE2.Dose‐responsecurvesforprenatallycocaine‐exposed(closed

symbols)andcontrol(opensymbols)monkeysunderanFR30scheduleof

reinforcementduringtheacquisition(leftpanel)andmaintenance(right

panel)ofcocaineself‐administration.

Theprenatallycocaine‐exposedmonkeyshadhigherresponserates

andthepeakoftheirdose‐responsecurvewas0.003mg/kg/injection

comparedtocontrolswhosepeakwasafulllog‐unithigher,0.03

mg/kg/injection.Thiscouldindicatetheprenatallycocaine‐exposed

188

monkeysaremoresensitivetothereinforcingeffectsofcocaine.However,

duringmaintenancesessions,thedose‐responsecurveshiftedtotherightfor

theprenatallycocaine‐exposedmonkeyssoitwasnowidenticaltothe

controlmonkeys’dose‐responsecurve.Therefore,underanFRscheduleof

reinforcement,theinitialincreasedsensitivityisnolongerpresent.Other

schedulesofreinforcement,likechoicestudiesorprogressive‐ratio(PR)

studies,shouldbeexaminedtodetermineifthereinforcingstrengthof

cocaineisthesamebetweenthetwogroups.

PRENATALCOCAINEDOSE­RESPONSEEFFECTS

Intheprenataldrugexposureliterature,thereisdebateabout

whetherthecumulativedoseovergestationorthemaximumdoseusedona

singleoccasionistheprimarydeterminantofadversiveoutcome(Franket

al.,1998).Basedonneonatalsizeatbirth,neonatalbehavior,andinfant

informationalprocessing,itappearsthatinthehumanliteraturethereisa

cocainedose‐effectrelationship(Jacobsonetal.,1996;Hurtetal.,1997;

Chiribogaetal.,1999;BatemanandChiriboga,2000).Oneoftheadvantages

ofthecohortexaminedinthisdissertationisthattheprenatallycocaine

exposedmonkeysvariedintheircumulativedoseofcocainetheywere

exposedtothroughoutgestationaswellasvariedintheirmaximaldoseused

onasingleoccasion.Therefore,wecouldexaminewhethertherewasadose

effectrelationshipthatcouldbeobservedinadulthood.InChapterII,we

189

determinedthattherewasasignificantpositivecorrelationbetweenthe

dailymaximaldoseofcocaineeachmonkeywasexposedtoinuteroandD3

receptorfunction.However,whencumulativegestationalcocaineexposure

wasusedintheanalysis,thecorrelationwasnolongersignificant.Allthe

othermeasuresdiscussedinChaptersIIIandIVwerealsoexaminedforan

inuterococainedoseeffectrelationship.Althoughtherewasatrendfora

negativecorrelationbetweensessionstoacquirecocaineself‐administration

andcumulativegestationalcocaineexposuredose,itwasnotsignificant(r2=

0.16,p=0.1;datanotshown).Noothermeasureswererevealedtohavea

relationshiptoeithercumulativegestationalcocainedoseormaximaldose

receivedonasingleoccasion.Thissuggestswhiletheremayadoseeffect

relationshippresent(asevidentbytheD3functionandacquisitionofself‐

administrationdata),itischallengingtoobserveinadulthood,yearsafterthe

prenatalcocaineexposure.

MULTIPLEASPECTSOFIMPULSIVITY

Ithasbeensaidthat,“Impulsivityiskeytounderstandingthe

phenomenologyofexternalizingdisorders,suchasaddiction”(J.D.Jentsch,

2010).Impulsivity,asitrelatestosubstanceabuse,hasbeendescribedas

difficultywithinterruptingandinhibitingautomaticresponses.Sincedrug

dependenceischaracterizedbyriskydrug‐takingbehaviorandrepeated

failuretoreducedrug‐taking,dysfunctionoftheimpulsecontrolsystems

mayplayakeyroleinaddiction.Willfulandactivesuppressionofdrug‐

190

takingbehaviorrequiresbeingabletovoluntarilymodulateimpulsive

thoughtsandactiontoinhibitimpulsivedrug‐seekinganddrug‐taking.

Traitimpulsivityisrapid,unplannedinflexibleapproachtonoveltyor

torewardsandcanbeexaminedbynovelobjectreactivity.Highnovelty‐

seekingindividualsareconsideredimpulsive(Cloninger,1987)andthis

temperamenthasbeenlinkedinthegeneralpopulationtodrugaddiction

andimpulsecontroldisorders(KimandGrant,2001).Discountingtasksare

thoughttomeasureaslightlydifferentaspectofimpulsivity,impulsive

decision‐makingorchoiceratherthanimpulsivebehavior(Jentsch,2008).

Impulsecontrolcanbeexaminedbyreversallearningorperseverationtasks.

Sinceimpulsivityisamulti‐factorialconstruct,itstandstoreasonthat

varioustaskstoassessimpulsivityrelyupononlypartiallyoverlapping

neuralcircuitry.Impulsivechoicetaskslikedelaydiscountinghavebeen

linkedtotheanteriorcingulatecortex,medialprefrontalcortex,andnucleus

accumbenscore(Cardinaletal.,2001;2004)whileimpulsecontrolof

responseadaptation(e.g.,reversallearning)dependsuponorbitofrontal

cortexanditsefferenttargetsinthemedialstriatum(Diasetal.,1996;

Schoenbaumetal.,2002;ChudasamaandRobbins,2003;FellowsandFarah,

2003;Boulougourisetal.,2007;Clarkeetal.,2008).Ifthesetasksare

neurallyindependent,thentheirindividualrelationshipstoaddictionmay

varyaswell.

Onecognitivecomponentoftheimpulsecontrolsystemistheability

tostop,withhold,orchangeresponses.Reversallearningselectively

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measurestheabilitytochangeorinhibitaconditionedresponse.Deficitsin

reversallearninghasbeenshowntobepredictiveoftheprognosisofdrug‐

dependentindividualsintreatment,withthosewiththemostdeficitsonthe

task,whoshowthemostperseverationofresponding,beinglinkedtorelapse

(Paulusetal.,2005).Inanimalstudies,Jentschandcolleagueshave

determinedthatevenshort‐term(2weeks)exposuretococainecanproduce

long‐lastingimpairmentsinreversallearning(Jentschetal.,2002;Olausson

etal.,2007).Theseimpairmentshavealsobeenobservedinratsthatself‐

administercocaine(Caluetal.,2007)andhumancocaineaddicts(Fillmore

andRush,2006;Erscheetal.,2008),indicatingthatthisisarobusteffect.

Additionally,arecentstudyrevealedthatthisdeficitininhibitionofbehavior

maybespecifictococaineasindividualswhoabusedrugsotherthancocaine

didnotshowthesameperseverativerespondinginareversallearningtask

ascocaineabusers(Erscheetal.,2008).Exposuretodrugsofabusein

adulthoodcanalsoimpairimpulsivechoice.Ratschronicallyexposedto

cocaineexhibitlessabilitytodelaygratificationthansaline‐treatedcontrols

(Paineetal.,2003;Simonetal.,2007).Cocaine‐exposedratsalsoexhibit

hypersensitivitytochangesinrewarddelayandmagnitude(Roeschetal.,

2007).Collectively,theliteratureprovidesevidencethatthedirect

pharmacologicaleffectsofdrugsofabusecanalterimpulsiverespondingand

choiceinlaboratoryanimals.Thesechangesmaymirrorsimilardeficitsin

performanceindrug‐dependentindividuals(Jentsch,2008)whichindicates

192

theselaboratorymeasuresmaybeusefulanalogousorhomologous

behavioralassessments.

InChapterIII,wedeterminedthatprenatallycocaine‐exposed

monkeysweremoreimpulsivethancontrolsacrossavarietyofmeasures.

Althoughwedidnotobservedifferencesinnovelobjectreactivityor

locomotoractivityinanovelenvironment,monkeysexposedtococainein

uterodisplayedmoreresponseperseverationduringextinctionoffood‐

reinforcedbehaviorthancontrols.Thisissimilartoearlierworkwiththese

samemonkeyswhentheyweremuchyounger.Chelonisetal.(2003)showed

theprenatallycocaine‐exposedmonkeysdisplayedresponseperseveration

fortwoandhalfyearswhentheruleswerereversedonasimplevisual

discriminationtaskcomparedtocontrols,whichtheauthorsbelieved

indicatedthattheseanimalshavegreaterdifficultyadaptingtoimportant

changesintheirenvironment.InbothPauleandcolleagues’studyandinour

experiments,allthemonkeysacquiredtheoriginaltaskequallywellbutthe

prenatallycocaineexposedmonkeys(highlyimpulsive)perseveratedmuch

longerthancontrolmonkeys(lowimpulsive),indicatingdifficultyinhibiting

whathadbecomeanautomaticresponse.Additionally,maleprenatally

cocaine‐exposedmonkeysexhibitedgreaterdiscountingofadelayedfood

rewardthancontrols,indicatingimpairedimpulsivechoice.Thesedata

demonstratethattheeffectsofcocaineexposureonimpulsiveresponding

andimpulsivechoiceareincrediblylong‐lasting(14‐15yearsafterprenatal

exposure).

193

IMPULSIVITYANDCOCAINESELF­ADMINISTRATION

Ithasbeenwell‐establishedthatincreasedimpulsivitycanbeadirect

consequenceofchronicexposuretodrugsofabuse,especiallycocaine.

However,itisalsothoughtthatimpulsivityisatraitwithnaturally‐occurring

variationthatcanbearisk‐factorforsubstanceabuse.Impulsivityisatleast

inpartundergeneticcontrolwithmorethan13%ofnaturalvariationin

impulsivebehaviorattributedtovariationsindopaminesystem‐related

genes(Baileyetal.,2007;Gromanetal.,2008)andthismaybeacrucial

quantitativeindicatorofdrugabuseliability.Dalleyetal.(2007)showedthat

ratsthatexhibitedgreaterimpulsiveactiononachoicereaction‐timetask

subsequentlytookmorecocaine.Itispossiblethatthereisacausal

relationshipbetweenimpulsivityandD2‐likereceptorfunction.Theratsthat

weremostimpulsiveandmostvulnerabletococaineself‐administration

behaviorwerealsotheoneswithlowerdopamineD2‐likereceptor

availabilityintheventralstriatum(Dalleyetal.,2007).Thissame

relationshipbetweenimpulsivityandacquisitionofnicotineself‐

administrationhasbeenobservedinrodents(Diergaardeetal.,2008),

suggestingthisrelationshipmaybetrueforallstimulants.Furthermore,

blockadeofD2‐likereceptorfunctionincreasesperseverativebehaviorona

reversallearningtaskinmonkeys(Leeetal.,2007).

Vulnerabilitytoself‐administerdrugsofabuseinrodentshasbeen

relatedtonaturallyoccurringimpulsivity.Forexample,ratsthatexhibitthe

194

steepestdelaydiscountingeffectsself‐administermoreethanolandcocaine

thanratscharacterizedaslessimpulsive(Poulosetal.,1995;Perryetal.,

2005).Inratsself‐administeringnicotine,impulsivedelaydiscounting

performancepredictsresistancetoextinctionandsusceptibilityto

conditionedcuereinstatement(Diergaardeetal.,2008).Furthermore,naïve

animalsthatarecharacterizedashighlyimpulsivearemorelikelycompared

withlowimpulsiveanimalstotransitionsoonertoinflexiblecocaine‐taking

thatisresistanttopunishment(Belinetal.,2008).

InChapterIV,wedeterminedthatprenatallycocaineexposed

monkeys,whowerepreviouslycharacterizedasmoreimpulsivethan

controls,weremorevulnerabletoacquiringcocaineself‐administration.

Additionally,themostimpulsivemonkeys,regardlessofprenatalcondition,

acquiredcocaineself‐administrationmorereadilythanthelessimpulsive

monkeys.Thestudiesweusedtomeasureaspectsofimpulsivitywereuseful

indefiningacocaineabuse“vulnerable”phenotype.Furthermore,wewere

abletoestablishthatthebiologicalbasisofthispredispositiontoself‐

administercocainemaybeD3receptorfunction,asanimalsthatdisplayed

thelargestbehavioralresponsetoaD3agonistwerealsomoreimpulsiveand

moresusceptibletococainefunctioningasareinforcerthananimalswithout

asrobustD3receptorfunction.

Althoughallfourbehavioralassaysdeemedtomeasureimpulsivity

wereusedinthecalculationoftheimpulsivityscore,certaintasksmayhave

morepredictivevalidityinNHPforwhichindividualsmaybemost

195

vulnerabletoself‐administration.Thetwoconditionedbehavioralmeasures,

delaydiscountingandperseverativerespondingwhileextinguishingfood‐

reinforcedbehavior,revealedsignificantdifferencesbetweenprenatally

cocaineexposedandcontrolmonkeysbythemselveswhilethetwo

unconditionedbehavioralmeasures,novelobjectreactivityandlocomotor

activity,onlyrevealedtrendstowardsadifferencebetweenthetwogroups.

InNHP,morechallenging,complextasksliketheconditionedbehavioral

measuresmaybemoreusefulforparsingoutdifferencesinimpulsivitythan

unconditionedbehavioralmeasures,whichhavetraditionallybeenusedin

rodentstudies.Althoughnooneimpulsivitymeasurecorrelatedwith

acquisitionofself‐administrationmeasures,inChapterIV,weshowedthat

monkeysclassifiedashighlyvulnerableweremoreimpulsiveoverallthan

monkeysclassifiedaslessvulnerable.Althoughtheconditionedbehavioral

measuresmightbebettersuitedfordetectingsubtledifferencesin

impulsivity,allmeasuresusedcontributetowardspredictingpredisposition

toself‐administrationbehavior.Therefore,thereisstillgreatvalueinusing

multipleassaystoinvestigateandtocreateacleareroverallpictureof

impulsivity.

Impulsivebehaviorhasbeenshowntoplayakeyroleinourcurrent

conceptsofdrugabuse.Sinceanimalmodelscontinuetodemonstratethe

natureoftheserelationships(i.e.,chronicdrugexposurecausesincreasesin

impulsivitybutalsothatimpulsivityisariskfactorforsubstanceabuse),new

pharmacologicaltreatmentsshouldbeselectedfortheirabilitytoenhance

196

impulsecontrolintheseanimalmodelsinordertoideallyreducedrug‐

seekinganddrug‐takingbehaviorinaddicts.

D2­LIKERECEPTORFUNCTION

D2‐likeagonistshaveabiphasiceffectonyawning,withlow‐doses

producingadose‐dependentincreaseinyawningandhigherdosesinhibiting

yawningandinducinghypothermia(Collinsetal.,2005;2007).Theseeffects

havebeenattributedtotheD3andD2receptors,respectively.Collinsand

colleagues(2005;2007;2008;2009)haveprovidedsupportforthese

subtypespecificrolesbyantagonistinteractionstudiesinwhichD3‐selective

antagonistshavebeenshowntoproducedose‐dependentandselective

rightwardshiftsoftheascendinglimb,whereasD2‐preferringantagonists

havebeenshowntoproduceaselectiverightwardshiftofthedescending

limbofthedose‐responsecurveforD2‐likeagonist‐inducedyawningat

dosesthatalsoinhibittheinductionofhypothermia.Thesedifferentialroles

oftheD3(induction)andD2(inhibition)receptorsinthemediationof

yawning,allowsforthedeterminationofchangesinthesetworeceptor

subtypesafterexposuretococainesinceincreasesinD3receptordensity

shouldresultinleftwardshiftsoftheascendinglimboftheyawningdose‐

responsecurvewhiledecreasesinD2receptordensityshouldresultin

rightwardshiftsofthedescendinglimboftheyawningdose‐responsecurve.

Collinsetal(inpreparation)foundthatratstreatedwith15mg/kg

cocainei.p.onceperdayforsevendays,adosethatresultsinlocomotor

197

sensitization,displayedaprogressiveandpersistantleftwardandupward

shiftoftheascendinglimbofthepramipexole‐elicitedyawningdose‐

responsecurvebeginningasearlyas72hoursafterthefirstinjection.This

effectonthedose‐responsecurvewasapparenteven6weeksafterthe

cocaineadministrationhadceasedwhilethehypothermicresponseto

pramipexolewasunaffectedbycocainetreatment.Furthermore,itwas

determinedthattherewereincreasesinD3receptorbindingusinginvitro

[3H]7‐OH‐DPATbindingassaysonmembranespreparedfromtheventral

striatumtissuecollectedat6weekspost‐cocainetreatmentsuggestingthe

increasedsensitivityinpramipexole‐elicitedyawningwasduetoan

upregulationofD3receptors.Thisworksupportspreviousresearchthat

foundincreasesinD3receptorbindinginthenucleusaccumbenscoreand

ventralcaudate‐putameninratsthatself‐administeredcocaine(0.75

mg/kg/injection)onavariable‐ratio(VR)5scheduleofreinforcementfor2

weeksafter32days(butnot2or8days)aftertheirlastself‐administration

session(Neisewanderetal.,2004).

InChapterII,weusedD1‐likeandD2‐likeagonist‐inducedbehavioral

effectsinconjunctionwithPETmeasuresofD2‐likereceptoravailabilityto

determineifprenatalcocaine‐exposureaffectedthefunctionofD1‐likeor

D2‐likereceptorsinadultrhesusmonkeys.Interestingly,althoughthe

prenatallycocaineexposedmonkeysdidnotdifferfromcontrolswith

respecttoPETmeasuresofD2‐likereceptoravailabilityorD1‐likeagonist‐

inducedeyeblinking,asignificantincreaseinquinpirole‐elicitedyawning

198

wasobservedinmonkeysthatwereexposedtococaineinuteroascompared

tocontrols(Hamiltonetal.,2010).Notonlywasthiseffectpositively

correlatedwiththemaximaldailydoseofcocainereceivedthroughout

gestation,buttheseincreasesinquinpirole‐elicitedyawningwereobserved

13yearsafterinuteroexposure.Thissuggeststhatcocaineexposuremay

resultinlong‐lasting,ifnotpermanent,enhancementofthefunctionand/or

sensitivityofD3receptors,whichwouldsupportthefindingofupregulation

ofD3receptorsinthenucleusaccumbensofhumancocaineoverdose

fatalities(StaleyandMash,1996;Segaletal.,1997).

TheuseofD2‐likePETligands(e.g.,[11C]raclopride,[18F]FCP,and

[18F]fallypride)hasimprovedtheabilitytoconductlongitudinal,within

subjectstudiesoftherelationshipbetweenstriatalD2‐likereceptor

availabilityandbehaviorinhumans,monkeys,andrats(Volkowetal.,1999;

Morganetal.,2002;Martinezetal.,2004;Naderetal.,2006;Dalleyetal.,

2007).However,itisdifficulttoparsethecontributionsofchangesinD3

receptoravailabilityand/orchangesintheD2orD3receptoraffinityasthese

radioligandsdonotdiscriminatebetweenD2andD3receptorsandare

insensitivetochangesinthefunctionalstateofD2‐likereceptors.Therefore,

anotherexplanationforthelackofdifferencesinD2‐likereceptoravailability

asexaminedwithPETisthatifthereweredifferencesinD3andD2receptor

density(upregulatedD3,downregulatedD2)intheprenatallycocaine

exposedmonkeyscomparedtocontrolsitcouldhavebeenmaskedbybasal

dopaminebindingtoreceptorsdifferentially.

199

Dopaminehasa70‐foldgreateraffinityfortheD3receptorcompared

totheD2receptor(Sokoloffetal.,1992).Bindingconstantsforthedopamine

receptorforcompetitionwithdopamineinclonedhumandopamine

receptorsinvitro[Ki(nM)]areD3=30,D5=230,D4=450,D2=2000,D1=

2300(Sokoloffetal.,1992).Therefore,atarestingdopamineconcentration

of5nM,theserelativeaffinitieswouldpredictthatD3receptorswouldbe

14%occupiedwhileoccupancyofD2receptorswouldbeabout0.2%.Ifthe

dopamineconcentrationwasincreasedbytheblockadeoftheDATbya

stimulantdruglikecocaineto250nM,D3receptoroccupancywouldbe90%

whileD2receptorswouldbeabout10%occupied.Thesemarkeddifferences

inreceptoroccupancycouldresultindifferencesinFCPbinding.Iftherewas

anupregulationofD3receptordensity,moredopaminewouldbeboundto

theD3receptors,allowingFCPtobindmoreatD2receptorsintheprenatally

cocaineexposedmonkeys.IfthesemonkeysalsohadadecreaseinD2

receptordensity,itcouldstillappearthesameusingFCPascontrolanimals

wheremoreD2receptorsareboundwithdopamine(seeFigure3).

200

D3receptorD2receptorDopamineFCP

D3receptorD2receptorDopamineFCP

PRENATALLYCOCAINEEXPOSED

CONTROLS

201

FIGURE3:DespitepotentialalterationsinD3andD2receptorsinprenatally

cocaineexposedmonkeys,D2‐likereceptoravailabilityasmeasuredby

[18F]FCPcouldstillhavebeensimilartocontrolsduetodifferencesin

dopamine’saffinityforthereceptorsubtypes.

Todeterminemoredefinitivelywhethertherewasanupregulationof

D3receptorsand/oradownregulationofD2receptors,completivebinding

studiescouldbedone.AdministeringaselectiveD2receptorantagonistprior

toinjectionofFCPwouldallowresearcherstoexaminejusttheD3receptor

availability.Likewise,administrationofaselectiveD3receptorantagonist

thatwouldcompetewithdopaminetobindtheD3receptorspriortoFCP

injectionwouldallowforexaminationofjustD2receptoravailability.

Anotherimportantpointisthateventhoughtherewerenochangesdetected

inD2‐likereceptoravailabilitywithPET(ChapterII),oncetheanimalshave

self‐administeredcocainechronically,therecouldbedifferencesinthe

reductionofD2‐likereceptoravailabilityobservedbetweenthetwogroups.

Forexample,whenthesystemisstressedbythechroniccocaineexposurein

adulthood,theprenatallycocaineexposedmonkeysmayshowmore

dramaticdecreasesinD2‐receptoravailabilitycomparedtocontrols.

D3RECEPTORFUNCTIONANDSELF­ADMINISTRATION

D3receptorsmayplayacrucialroleinthereinforcingeffectsof

stimulants.TheearliestindicatorwasthatD3receptorshaveaunique

202

anatomicaldistributionwithhighestconcentrationsfoundinmesolimbic

systemsthathavebeenimplicatedindrugabuse(Levesqueetal.,1992).D3‐

preferringagonistscanmodulatecocaineself‐administration(Caineand

Koob,1993;1995;NaderandMach,1996;Parsonsetal.,1996).Moreover,it

hasbeenshownthattherelativepotenciesofD2‐likereceptoragoniststo

altercocaineself‐administrationishighlycorrelatedwiththeirrelative

potenciesforincreasingmitogenesisinvitroincelllinesexpressingD3but

notD2receptors(Caineetal.,1997).TheD3‐preferringagonist7‐OH‐DPAT

functionsasareinforcerinmonkeyswithacocaineself‐administration

historybutfailstosupportself‐administrationindrug‐naïvemonkeys

(NaderandMach,1996).ThissuggeststhatsomealterationinD3receptor

sensitivityand/ordensityoccursfollowingcocaineexposure.

AlthoughD3‐selectiveantagonistshavegenerallybeenfoundtobe

ineffectiveatdecreasingself‐administrationwhencocaineisavailableunder

alowFR(i.e.,FR1orFR2)schedulesofreinforcement(GalandGyertyan,

2003;Xietal.,2005;Xietal.,2006),thereisgrowingevidencesuggesting

thattheD3receptorplaysanimportantroleindrugabuse‐relatedbehaviors,

likereactivityoflaboratoryanimalstodrug‐pairedstimulianddrug‐seeking

behaviors.D3‐preferringagonistslikequinpirolehavebeenshowntoinduce

respondingforstimulithathadbeenpreviouslypairedwithcocaine

reinforcement(CollinsandWoods,2009).Additionally,avarietyofD3‐

selectiveantagonistsandpartialagonistshavealsobeenshowntoinhibitthe

capacityofcuestoreinstaterespondingaftersomeperiodofabstinencefrom

203

stimulantself‐administration(Voreletal.,2002;Gilbertetal.,2005;Galand

Gyertyan,2006;Cervoetal.,2007;Khaledetal.,2009).Furthermore,in

ChapterIV,wedeterminedthatmonkeysthatweremostvulnerableto

acquisitionofcocaineself‐administrationhadgreatersensitivitytoD3

agonist‐elicitedyawningthanmonkeysthatwerelessvulnerabletococaine

self‐administration.Therefore,itappearsthatincreasedD3receptor

sensitivityand/ordensitymaybeabiologicalriskfactorforprogressingto

stimulantaddictionandthatthereisincreaseinD3receptordensitythat

occursfollowingcocaineexposurethatmaybelinkedtothereinforcing

effectsofcocaineandthedevelopmentofcocainedependence.

IMPULSIVITYANDD3RECEPTORFUNCTION

Recently,ithasbeenobservedthatpatientswithParkinson’sDisease

beingtreatedwithDAagonistsmaydevelopimpulsecontroldisorders,such

aspathologicalgambling,compulsiveshopping,andhypersexuality(Pontone

etal.,2006;Szarkmanetal.,2006;Weintraubetal.,2006;Voonetal.,2007).

AreviewoftheFoodandDrugAdministrationadverseeventsdatabase

revealedthattreatmentwithDAagonistswasamajorcorrelateof

pathologicalgamblingandthemostfrequentlyidentifiedmedicationwas

pramipexole,theD3receptorpreferringagonist(Szarfmanetal.,2006).In

fact,pramipexolewasidentifiedin58%ofthe67pathologicalgambling

reportsinthedatabase(whichwasnotconfinedtoParkinson’sDisease

patients)(Szarfmanetal.,2006).Amorerecentreviewofallpublishedcases

204

ofParkinson’sdiseasepatientsthatdevelopedanimpulsecontroldisorder,

174outof177patientswerebeingtreatedwithaDAagonist(Gallagheret

al.,2007).Thisreviewalsoconcludedthatincidenceofpathological

gamblingwasashighas8%inParkinson’sDiseasepatientstreatedwithDA

agonistscomparedtolessthan1%inthegeneralpopulation(Gallagheretal.,

2007).

Althoughtherehavebeenquestionsregardingacausalrelationship

betweenDAagonistslikepramipexoleandpathologicalgambling,evidence

forsuchacausativeroleisgrowing.Rigorousclinicalevaluationshave

shownthatpatientstreatedwithlevodopaalonedidnotdevelopimpulse

controldisorderswhiletreatmentwithpramipexolewaspredictiveof

developinganimpulsecontroldisorder(Pontoneetal.,2006;Weintraubet

al.,2006).Thisindicatesthatthedevelopmentofimpulsecontroldisorders

maynotbesimplyduetoanincreaseinDAsignal,butperhapsrelatedtoD3

receptorstimulation.Inafollow‐upstudywith12Parkinson’sDisease

patientsthathaddevelopedanimpulsecontroldisorder,reducingthedose

oftheDAagonistandincreasinglevodopadosetoachievethesamebenefitin

relievingmotorsymptomsresultedinresolutionoftheimpulsecontrol

disordersymptomsinallpatients(Mamikonyanetal.,2008).Also,an

associationhasbeenshownbetweenavariantoftheD3receptorgeneDRD3,

butnottheD2receptorgeneDRD2,anddevelopmentofimpulsecontrol

disordersinParkinson’spatients(Leeetal.,2009).

205

Itappearsthatthisincreasedriskofimpulsecontroldisorders

associatedwithDAagonistsisnotuniquetoParkinson’sDiseasepatients.

Reportsareemergingofpathologicalgamblingasasideeffectinpatients

withrestlesslegssyndromebeingtreatedwithpramipexole(Tippmann‐

Peikertetal.,2007;Driver‐Dunckleyetal.,2007;OndoandLai,2008,

Corneliusetal.,2010).OndoandLai(2008)foundthatalmost20%of

patientsinterviewedindicatedincreasedimpulsivitywiththeuseofDA

agonists,specificallypramipexole.Furthermore,astatisticallysignificant

correlationforpramipexoledoseandimpulsecontroldisordershasbeen

observedinrestlesslegssyndromepatients(OndoandLai,2008;Cornelius

etal.,2010).Takentogether,itappearsthattheadministrationofDA

agonists,inparticulartheD3preferringagonistpramipexole,canbeatrigger

fordevelopmentofpathologicalgamblingandotherimpulsecontrol

disorders,suggestingacausalroleforincreasedD3receptorstimulationand

impulsivity.ThisconclusionissupportedbythedatainChaptersIIandIII

thatfoundprenatallycocaineexposedmonkeysweremoreimpulsivethan

controlsandthatincreasedD3receptorfunctionmaybetheneurobiological

correlateforthatbehavioralchange.

SEXDIFFERENCES

OtherthanDAagonisttreatment,oneofthemainriskfactorsforthe

developmentofimpulsecontroldisordersinpatientswithparkinsonian‐

relateddiseasesismalesex(Voonetal.,2007).Thisisinterestingtonote

206

consideringthesexdifferenceobservedinChaptersIII.Theincreasein

overallimpulsivitywasobservedinmale,butnotfemale,prenatallycocaine‐

exposedmonkeys.Despitethefactthatdifferenceswereobservedin

impulsivity,inChapterIVwedidnotfindanysexdifferencesinacquisition

ofcocaineself‐administration(Figure4),suggestingthatincreasedD3

receptorfunctionmaybealargerriskfactorforvulnerabilitytostimulant

self‐administrationthanincreasedimpulsivity,atleastinfemales.

FIGURE4.Percentageofmale(closedsymbols)andfemale(open

symbols)monkeysthatreachedcriteriatoacquirecocaineself‐

administrationatvariousdosesofcocaineavailableunderanFR30schedule

ofreinforcement.

207

Furthermore,therelationshipwefoundinindividualanimals

betweenimpulsivityandD3receptorfunctionandtotalcumulativecocaine

intakepriortoreachingacquisitioncriteriawasfoundinbothmaleand

femalesubjects.However,wehadfairlylowpowertodetectdifferencesin

thesurvivalanalysisofacquisitionofcocaineself‐administrationduetosuch

alowacquisitionrateacrossallgroupsresultingincensoreddata.Therefore,

itispossiblethatwithalargercohort,subtlesexdifferencesinacquisitionof

cocaineself‐adminstrationmaybeobservable.

Alternatively,othermechanismsmayplayalargerrolein

vulnerabilitytostimulantself‐administrationbehaviorinfemalesubjects

thanimpulsivityandD3receptorfunction.Forexample,ithasbeenshown

thatestrogencanaltertheresponsetococaineinrats(Selletal.,2000).

EstrogencanalsomodulateDAneuronfiringactivityinVTAneurons

inducedbyacocaineinjection(Zhangetal.,2008),andregulatemRNA

expressionforspecificDAand5‐HTreceptors(Zhouetal.,2002).Studiesin

NHPhaveshownovariansteroidcanaffectfunctionalpropertiesofthe5‐HT

neuralsystem(Betheaetal.,1998;Pecins‐Thompsonetal.,1998;Pecins‐

ThompsonandBethea,1999).Sincethereisevidenceforamodulatoryrole

of5‐HTinthebehavioraleffectsofcocaine(CunninghamandCallahan,1994;

Sateletal.,1995),ovarianhormoneshavethepotentialtoalterboth5‐HT

andDAneurotransmissionresultinginmodificationoftheresponseto

stimulants.Itispossiblethatthemodulatoryroleof5‐HTonresponseto

cocainemaybemorecriticalinfemalesthaninmalesforacquisitionofself‐

208

administration.Itisalsopossiblethatifwehadexaminedcocaineself‐

administrationinthelutealphasewhenestrogenlevelsarelowerthaninthe

follicularphaseorifwehadexaminedself‐administrationduring

adolescence,wemayhaveobservedsexdifferencesintheacquisitionofself‐

administration.

Nevertheless,thefindingsinthisdissertationthatmalesexposedto

cocainethroughoutgestationaremoreimpulsivecomparedtocontrols

concurswiththehumanliterature.Thebehavioralissuesnotedinchildren

exposedtococaineinuteroappeartobeexaggeratedinmales,withthe

prenatallycocaine‐exposedboysoftendemonstratingincreasedaggression,

hyperactivity,anddisruptivebehaviorthannon‐exposedboys,whereasgirls

donotshowthesedifference(Benderskyetal.,2006;Bennettetal.,2007;

Delaney‐Blacketal.,2004).Sincethesepatternsofbehavioralissuesare

associatedwithdevelopmentofsubstanceusedisorders,itsuggeststhat

thesemalechildrenmaybemorevulnerabletostimulantdrugtaking.

CONCLUSION

Theresearchpresentedinthisdissertationfurtherextendsour

understandingoftheneurobiologicalandneurobehavioralunderpinningsof

individualphenotypesrelatedtovulnerabilityofdrug‐takingbehavior.The

researchinthisdissertationalsoprovidestotherationaleforthe

developmentofD3receptorcompoundsaspharmacologicaltargetsfor

209

treatingimpulsecontroldisruptions.Beyondpharmacologicaltreatment,

behavioralinterventionscouldbeimplementedwiththishighrisk

populationofchildren.Forexample,cognitive‐behavioraltherapyhasshown

modestsuccessindecreasingimpulsivebehaviorinadultswithimpulse

controldisorders(Drysdaleetal.,2009;FilomenskyandTavares,2009;

Okudaetal.,2009)andcouldbeadaptedforyoungerchildren.Thedatain

thisdissertationsuggestthatpredispositiontoacquirecocaineself‐

administrationisassociatedwithincreasedimpulsivityandincreasedD3

receptorfunction.Sinceitappearsthatprenatalcocaineexposureincreases

thetendencyofanindividualhavingthisvulnerablephenotypeinadulthood,

prenatallycocaineexposedchildrenmaybeatriskforincreasedlikelihoodof

stimulantuse.

210

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219

SCHOLASTICVITAE

LINDSEYREBECCAHAMILTON EDUCATION:2001‐2004 BatesCollege Lewiston,Maine B.S.Neuroscience;MagnaCumLaude

Thesis:Medialseptallesionsenhancecocaine‐inducedsuppressionofsaccharinintakeinrats.

Advisor:JohnE.Kelsey,Ph.D.2005‐2010 WakeForestUniversitySchoolofMedicine Winston‐Salem,NorthCarolina Ph.D.Neuroscience

Dissertation:Neurobiologicalandneurobehavioralphenotypesassociatedwithvulnerabilitytococaineself‐administrationinadultrhesusmonkeysexposedtococainethroughoutgestation.Advisor:MichaelA.Nader,Ph.D.

EXPERIENCE:RESEARCHEXPERIENCEJune2006–May2010 GraduateResearch MichaelA.Nader,Ph.D. WakeForestUniversitySchoolofMedicineJan.2006–May2006 GraduateResearchRotation AnthonyLiguori,Ph.D. WakeForestUniversitySchoolofMedicineAug.2005–Dec.2005 GraduateResearchRotation PaulW.Czoty,Ph.D. WakeForestUniversitySchoolofMedicineJan.2005–July2005 Post‐BaccalaureateResearchAssistant RoyA.Wise,Ph.D. NationalInstituteonDrugAbuse

220

EXPERIENCE:(CONTINUED)May2003–Dec.2004 UndergraduateResearchAssistant JohnE.Kelsey,Ph.D. BatesCollegeSCHOLASTICEXPERIENCE2008–2009 Winston‐SalemStateUniversity LifeScienceDepartment LecturerandLaboratoryInstructor BIO1301:PrinciplesofBiology,5hours/week2007‐2008 WakeForestUniversitySchoolofMedicine GraduateSchool DiscussionFacilitator EthicsinScience,1hour/week2007 WakeForestUniversity DepartmentofCounseling GuestLecturer PsychiatricPharmacology,3hours

2005‐2010 Winston‐SalemPublicSchoolSystem BrainAwarenessCouncilPresentations DrugAddiction,3hours/month2003‐2004 BatesCollege DepartmentofNeuroscience LaboratoryInstructor PhysiologicalPsychology,3hours/weekINSTITUTIONALAPPOINTMENTSANDSERVICE:Women’sHealthCenterofExcellenceStudentRepresentative,2008‐2010PrograminNeuroscienceRecruitmentCommitteeStudentRepresentative,2007‐2009GraduateSchoolProfessionalDevelopmentCo‐Director,2006‐2007

221

PROFESSIONALMEMBERSHIPS:2009–Present SocietyfortheStimulusPropertiesofDrugs2006–Present AmericanSocietyforPharmacologyand

ExperimentalTherapeutics2005–Present WesternNorthCarolinaSocietyforNeuroscience

Chapter2005–Present SocietyforNeuroscience2004–Present SigmaXiHONORSANDAWARDS:2010 GraduateStudentTravelAward

AmericanSocietyforPharmacologyandExperimentalTherapeutics

2010 GraduateStudentBestAbstractAward2ndPlace BehavioralPharmacologyDivision

AmericanSocietyforPharmacologyandExperimentalTherapeutics

2010 BestIntegrativeSciencePosterAward

WakeForestUniversityGraduateStudentResearchDay

2009 MaryA.BellAwardforBestPosterand

Presentation BehavioralNeuroscienceDivision WesternNorthCarolinaSocietyforNeuroscience

ResearchDay2009 BestSeminarAward PrograminNeuroscienceTutorialSeries2009 BestPosterAward FourthAnnualWomen’sHealthResearchDay

222

HONORSANDAWARDS:(CONTINUED)2007 BestGraduateStudentPosterAward Women’sHealthCenterofExcellence WesternNorthCarolinaSocietyforNeuroscience

ResearchDay 2006 BestFirst‐YearStudentTutorialPresentation PrograminNeuroscienceTutorialSeries2005–2006 GraduateStudentFellowship GraduateSchoolofArtsandSciences WakeForestUniversity2004–2005 Post‐BaccalaureateIntramuralResearch

TrainingAward NationalInstituteonDrugAbuse2005 PhiBetaKappa

GRANTS:ACTIVENationalInstituteonDrugAbuseF31DA024485,6/2008–6/2010“VulnerabilitytoAddictioninAdultRhesusMonkeysExposedtoCocaineInUtero”PASTHughesStudent‐FacultyResearchGrant,5/2003‐8/2003“TheEffectsofLesionsoftheN.AccumbensCoreorShellonContext‐SpecificLocomotorSensitizationtoNicotine”

PUBLICATIONS:

HamiltonLR,NaderMA.Increasedvulnerabilitytoself‐administercocaineinadultrhesusmonkeysexposedtococainethroughoutgestation.TobesubmittedMay2010toScience.

223

PUBLICATIONS:(CONTINUED)

HamiltonLR,CzotyPW,NaderMA.Increasedimpulsivityinmale,butnotfemale,adultrhesusmonkeysexposedtococainethroughoutgestation.SubmittedApril2010toPsychopharmacology.HamiltonLR,CzotyPW,GageHD,NaderMA(2010)Characterizationofthedopaminereceptorsysteminadultrhesusmonkeysexposedtococainethroughoutgestation.Psychopharmacology,210(4):481‐488.ElmerGI,PieperJO,HamiltonLR,WiseRA(2010)QualitativedifferencesbetweenC57/BL/6JandDBA/2Jmiceinmorphinepotentiationofbrainstimulationrewardandintravenousself‐adminstration.Psychopharmacology,208(2):309‐21.

ABSTRACTS:

HamiltonLR,WilsonWD,NaderMA(2010)Increasedvulnerabilitytococaineself‐administrationinadultrhesusmonkeysexposedtococainethroughoutgestation.FASEBJ24:765.5.HamiltonLR,CzotyPW,NaderMA(2010)Impulsivityandvulnerabilitytococaineself‐administrationinadultrhesusmonkeysexposedtococainethroughoutgestation.WakeForestUniversityGraduateSchoolStudentResearchDay,ProgramNo.12.HamiltonLR,CzotyPW,NaderMA(2009)Impulsivityandvulnerabilitytococaineself‐administrationinadultrhesusmonkeysexposedtococaineinutero.ProgramNo.842.14,NeuroscienceMeetingPlanner.HamiltonLR,CzotyPW,CalhounTL,NaderMA(2009)Impulsivityandvulnerabilitytococaineself‐administrationinadultrhesusmonkeysexposedtococaineinutero.FASEBJ23:588.9.HamiltonLR,CalhounTL,NaderMA(2009)Increasedimpulsivityinmale,butnotfemale,adultrhesusmonkeysexposedtococaineinutero.FourthAnnualWomen’sHealthResearchDay,ProgramNo.3.HamiltonLR,CalhounTL,NaderMA(2008)Increasedimpulsivityinmale,butnotfemale,adultrhesusmonkeysexposedtococaineinutero.WesternNorthCarolinaChapteroftheSocietyforNeurosciencePosterCompetition,ProgramNo.5.

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ABSTRACTS:(CONTINUTED)

HamiltonLR,GageHD,CalhounTL,NaderMA(2008)CharacterizationoftheD1,D2,andD3receptorsystemsinadultrhesusmonkeysexposedtococaineinutero.JohnsHopkinsBloombergSchoolofPublicHealthSecondAnnualConferencefortheDisseminationofResearchonAddiction,InfectiousDisease,andPublicHealth,ProgramNo.6.

HamiltonLR,GageHD,CalhounTL,NaderMA(2008)CharacterizationoftheD1,D2,andD3receptorsystemsinadultrhesusmonkeysexposedtococaineinutero.FASEBJ22:904.2.HamiltonLR,GageHD,CalhounTL,NaderMA(2008)CharacterizationoftheD1,D2,andD3receptorsystemsinadultrhesusmonkeysexposedtococaineinutero.WakeForestUniversityGraduateStudentResearchDay,ProgramNo.9.HamiltonLR,GageHD,CalhounTL,NaderMA(2008)CharacterizationoftheD1,D2,andD3receptorsystemsinadultrhesusmonkeysexposedtococaineinutero.WakeForestUniversityWomen’sHealthResearchDay,ProgramNo5.HamiltonLR,GageHD,CalhounTL,NaderMA(2007)CharacterizationoftheD1,D2,andD3receptorsystemsinadultrhesusmonkeysexposedtococaineinutero.WesternNorthCarolinaChapteroftheSocietyforNeurosciencePosterCompetition,ProgramNo.12.HamiltonLR,GageHD,NaderMA(2007)AlteredD2receptoravailabilityinadultrhesusmonkeysexposedtococaineinutero.FASEBJ21:885.13.CzotyPW,NaderSH,ReboussinBA,CalhounTL,HamiltonLR,NaderMA(2006)Long‐termcocaineself‐administrationunderbingeconditionsorasecond‐orderscheduleinmonkeys:influenceofself‐administration.ProgramNo.123.2,NeuroscienceMeetingPlanner.ElmerGI,PieperJO,HamiltonLR,WiseRA,BeckerJB,ArnoldAP(2005)Sex‐chromosomegenesinfluenceamphetaminepotentiationofbrainstimulationrewardindependentlyofgonadalsecretionsinmice.ProgramNo.541.5,NeuroscienceMeetingPlanner.

225

ABSTRACTS:(CONTINUTED)

HamiltonLR,ElmerGI,PieperJO,WiseRA,BeckerJB,ArnoldAP(2005)Sex‐chromosomegenesinfluenceamphetaminepotentiationofbrainstimulationrewardindependentlyofgonadalsecretionsinmice.WesternNorthCarolinaChapteroftheSocietyforNeurosciencePosterCompetition,ProgramNo.16.

SEMINARSANDPRESENTATIONS:

HamiltonLR,(2010)Effectsofprenatalcocaineexposureonlong‐termneurobiologicalandneurobehavioralphenotypesassociatedwithaddiction.UnitedStatesArmyMedicalResearchInstituteofChemicalDefense,InvitedSpeaker.HamiltonLR(2010)Long‐termneurobiologicalandneurobehavioralphenotypesassociatedwithaddictioninrhesusmonkeysexposedtococaineinutero.YaleUniversity,DepartmentofPsychiatry,InvitedSpeaker.HamiltonLR(2010)Impulsivityandvulnerabilitytoaddictioninadultrhesusmonkeysexposedtococaineinutero.31stAnnualMeetingoftheSocietyfortheStimulusPropertiesofDrugs,KeynoteSpeaker.NaderMA,CzotyPW,NaderSH,HamiltonLR,MartelleSE,IcenhowerM,RiddickNV(2010)Whatisimpliedbypotencydifferencesinacquisitionandmaintenanceofcocaineself‐administration?53rdAnnualBehavioralPharmacologySocietyMeeting.HamiltonLR(2009)Long‐termeffectsofprenatalcocaineexposureinrhesusmonkeys.JohnsHopkinsUniversity,DepartmentofPsychiatry,BehavioralPharmacologyResearchUnit,InvitedSpeaker.HamiltonLR(2009)Long‐termneurobiologicalandneurobehavioralphenotypesassociatedwithaddictioninrhesusmonkeysexposedtococaineinutero.WakeForestUniversitySchoolofMedicine,PhysiologyandPharmacologyDepartmentalSeminar.HamiltonLR(2009)Increasedimpulsivityinadultrhesusmonkeysexposedtococaineinutero.WakeForestUniversity–EmoryUniversityBehavioralPharmacologySymposium.

226

SEMINARSANDPRESENTATIONS:(CONTINUED)

HamiltonLR(2009)Sexdifferencesinthelong‐termeffectsofprenatalcocaineexposureinrhesusmonkeys.WakeForestUniversityPrograminNeuroscienceTutorialSeries.HamiltonLR(2008)Characterizationofthedopaminergicreceptorsysteminadultrhesusmonkeysexposedtococaineinutero.WakeForestUniversitySchoolofMedicine,PhysiologyandPharmacologyDepartmentalSeminar.

HamiltonLR(2008)Characterizingthedopaminergicreceptorsysteminadultrhesusmonkeys.WakeForestUniversity–EmoryUniversityBehavioralPharmacologySymposium.HamiltonLR(2008)Characterizationofthedopaminergicreceptorsysteminadultrhesusmonkeys.WakeForestUniversityPrograminNeuroscienceTutorialSeries.HamiltonLR(2007)Prenatalcocaineexposureandvulnerabilitytoaddictioninadultrhesusmonkey.WakeForestUniversitySchoolofMedicine,PhysiologyandPharmacologyDepartmentalSeminar.HamiltonLR(2007)Prenatalcocaineexposureandvulnerabilitytoaddictioninadultrhesusmonkeys.WakeForestUniversity–EmoryUniversityBehavioralPharmacologySymposium.HamiltonLR(2006)Effectsofprenatalcocaineexposureinrhesusmonkeys.WakeForestUniversity–EmoryUniversityBehavioralPharmacologySymposium.HamiltonLR(2006)Comparisonofmarijuanaandtobaccowithdrawalduringatwoweekabstinenceperiod.WakeForestUniversityPrograminNeuroscienceTutorialSeries.