impact of alcohol and substance abuse on adolescent

8/7/2019 IMPACT OF ALCOHOL AND SUBSTANCE ABUSE ON ADOLESCENT

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Indian J Phy siol P harmacol 2010; 5 4 (3) : 2132 34

REVIEW ARTICLE

IMPACT OF ALCOHOL AND SUBSTANCE ABUSE ON ADOLESCENT

BRAIN : A PRECLINICAL PERSPECTIVE

RAKA J AIN* AND YATAN PAL SINGH BALHARA

National Drug Dependence Treatment Centre,

All India Institute of Medical Sciences,

Ansari Nagar, New Delhi 110 029

( Received on July 29, 2009 )

Abstract : Use of alcohol and addictive substances by human juveniles and

adolescents i s common. Animal models of fe r researchers unique ins ight

into the effects of alcohol and drugs on adolescents. Recent work in rat

indica tes tha t per iadolescent substance use may disrupt normal puber ta l

development and may induce stronger effects on system subserving plasticity

and cognition than in adults. Several processes may influence the adolescent

r isk of neurocogni t ive damage . The bra in goes through var ious dynamic

changes during adolescence and can seriously affect the short term growth

process . The fea tures of the adolescent bra in may in fac t predispose a

youngster to behave in ways that place him or her at particular r isk of

experimenting with alcohol or other drugs. In addition to behavioral andneurochemica l changes , a number of impor tant physiologica l a l te ra t ions

occur during adolescence, including changes in brain regions implicated in

the re inforc ing proper t ies of a lcohol and other drugs of abuse . Damage

during early stages can cause long term damage which is irreversible. The

present review discusses the neurobehaviora l , neurochemica l and

neuroendocrinal effects of alcohol and other drugs of abuse on the adolescent

bra in in ra ts .

Key words : alcohol subs t ance abuse ado lescent bra in

*Corresponding Author : Fax : 91-011-2658866 3, 26588641, Tel . No. : 91-011-265932 36, 26593595;E-mai l : rakajain200 9@gmai l .com

INTRODUCTION

Use of addictive substances and alcoholis a major problem worldwide. Studies done

in recent years suggest r is ing consumption

and progressive fall in age of initiation. Drug

abuse in adolescents ranging from 1112 to

1718 years of age i s l ike ly to s t a r t wi th

tobacco smoking, which can be followed by

mar i juana and/or a lcohol , and eventua l ly

psychostimulants as well as opiate drugs (1).

Therefore, ear ly l i fe exposure with alcoholand psychoact ive compounds appears to be

critical and may predispose an individual to

the development of alcohol and substance use

di sorder .

Before delving into the research in this


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214 Ja in and Balhara India n J Phys iol Pharma col 2010; 54 (3)

cont inues to undergo a t remendous amount

of deve lopment throughout adolescent and

into young adulthood while the overall size

of the bra in changes very l i t t l e be tween

chi ldhood and adul thood (8 , 9) . The

adolescent brain is unique and in a state of

t ransi t ion as i t undergoes both progressive

and regressive changes (2). Recent findings

indica te tha t c i rcu i t ry wi th in the bra in i s

actively being refined during adolescence and

most intriguing change occurs in the frontal

lobes (10). The frontal lobes comprise a large

region of the neocortex, evolutionary recent

t i s sue tha t b lanket s the bra in , sur rounding

older s t ruc tures . Fronta l lobe a reas p lay

vi ta l ro les in a var ie ty of impor tant

processes inc luding p lanning and dec i s ion

making , impulse cont ro l , vo luntary

movement , memory, speech product ion, and

a var ie ty of o ther func t ions . There appear

to be profound changes, both organizational

and func t iona l , in the fonta l lobes dur ingadolescence . A subs tant ia l number of

synapses a re e l imina ted or pruned, in the

cortex during adolescence (10, 11) and this

loss of synapses contributes to a decrease in

gray matter volumes in the frontal lobes as

adolescents matures to adults in both human

and ra t s (8) . Overa l l metabol i sm in the

f ronta l lobes decreases dur ing adolescence

(12) , whereas neura l ac t iv i ty dur ing the

per formance of cer ta in t asks become more

focused and efficient (13, 14, 15). It is quitelikely that this shaping of the frontal lobes

raises the possibili ty that drug abuse could

alter the normal development of the frontal

lobes during adolescence. Similar age-related

changes in bra in ac t iva t ion dur ing t ask

per formance have been observed in the

cerebe l lum, as wel l as in the super ior

col l i cu lus , tha lamus , s t r i a tum and par ie ta l

cortex (15, 16).

specific theme, i t is important to define the

stage of development that we casually refer

to as adolescence. Adolescent is not a distinct

stage. In general, adolescence is considered

a transition between childhood and adulthood

which i s assoc ia ted wi th a var ie ty of

developmental challenges. During this period

individual acquires skills necessary to enable

them to l ive independent ly . I t involves

changes at numerous levels, some of which

are defined biologically and some of which

are def ined behavioral ly. In humans, some

have suggested that adolescence encompasses

the entire second decade of l ife (i .e. 1020

years of age), while others suggest that 12

18 is more conservative range (2). In rodents,

adolescence is a difficult period to delineate

precisely. Spear and Brake (3) have defined

tha t pos tna ta l days 28 to 42 encompass a

per iadolescent per iod in the ra t ( i .e . P30-

42) . This per iod i s charac te r ized by

alterations in the behavior and neurobiologicalorganiza t ion , which a re observed in many

spec ies dur ing adolescence . Animals , l ike

the i r human counterpar t s , may show some

signs of adolescence at significantly younger

and o lder ages , wi th male ra t s t ending to

mature more s lowly than females . Indeed ,

age- typica l a l t e ra t ions charac te r i s t i c of

adolescence may begin as early as P28 and

may last in male rats unt i l P55 or so (4) .

P lay behavior in ra t s peaks be tween

postnatal days 30 to 40 (5). Rats also display

peak adrenocor t i co t ropic hormone and

cor t i sone responses to s t ress dur ing th i s

t ime (6) . In monkeys adolescence i s

recognized as occurring in the age range of

2 to 4 years (7).

Brain development

Recent ev idence sugges t s tha t , in

contrast to previous assumptions, the brain


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Indian J Physiol Pharmacol 2010; 54(3) Addiction and Adolescent Brain 215

In addition to changes that occur in the

cortex, multiple changes have been observed

in the subcort ical s t ructures . For instance,

in the rat , levels of dopamine receptors in

the nucleus accumbens increase dramatically

between days 2540, an age range that falls

roughly within the window of early adolescent

development (2, 17). Neurobiologically, the rat

periadolescent period is characterized by the

steady increase in the striatal dopamine and

serotonergic transporter levels (18), increasein the chol inerg ic innerva t ions of the

prefrontal cortex (19), and biphasic changes

in the s t r iatal dopamine receptors (17, 18,

19). Nicotinic receptors have been shown to

reach adult levels during adolescence in the

hippocampus of male rats (20) and 3 and

4 nicot inic acetylchol ine receptor subuni t

mRNAs reached adul t levels in most brain

regions during adolescence (21) . Serotonin

t ranspor te r b inding increases cont inuous ly

in to adul thood in the f ronta l cor tex butremains stable in the straitum and midbrain

af ter weaning (22) . Similar constel lat ion of

neurobiological changes has been observed

in human be ings and pr imates dur ing

adolescence (10 , 23 , 24 , 25) , making th i s

age range in the ra t a good model of

adolescence.

As d i scussed , dopamine receptor l eve l s

in the s t r i a tum a l so increase in ear ly

adolescence and then decrease s ignif icant ly

be tween adolescence and young adul thood(17) . This deve lopment in turn inf luences

cogni t ive deve lopment , i .e . a t t en t ion ,

l earn ing and in te l l ec tua l a t t a inment .

Moreover, dopamine receptors in the nucleus

accumbens p lay a major ro le in the

rewarding (euphoric) properties of drugs. As

a consequence of such changes, alcohol, and

perhaps o ther drugs , a f fec t adolescent and

adults differently (2). Furthermore, levels of

type I Gamma - amino butyric acid (GABA)A

receptors increase dramatical ly in a var iety

of subcor t i ca l s t ruc tures dur ing ear ly

adolescence between days 2836, including

the cerebe l lum and media l septa l nuc leus

(26). Maturational changes during adolescence

are a l so ev ident in o ther bra in reg ions

tha t inc lude the h ippocampus (27) and

hypotha lamus (28) . Mos t lobe func t ions

mature and very l i t t l e change i s l ike ly to

take place beyond this per iod.

In addition, as demonstrated in nonhuman

primates, the input from two key chemicals

( i .e . , neurot ransmi t t e r s ) involved in bra in

ce l l communica t ion i .e . the exc i ta tory

neurot ransmi t t e r g lu tamate and the

inhib i tory neurot ransmi t t e r gamma

aminobutyricc acid (GABA) is reduced during

adolescence, whereas the input from another

neurot ransmi t t e r , dopamine , peaks in

prefrontal cor tex during adolescence (7) .

Cur rent ly many gaps ex i s t in our

knowledge of the developmental changes that

occur in the brain during adolescence. Stil l ,

the data that are avai lable suggest that the

prominent a l t e ra t ions occur in mul t ip le

neurochemical systems during the adolescent

period not only in humans but also in other

species as well, ranging from rodents to non-

human pr imates .

Biological basis of addict ion

Over the l as t two decades , dramat ic

advances both in the neurosciences and the

behavioral sciences have revolut ionized our

understanding of drug abuse and addict ion.

Drug addiction is a complex phenomenon. It

i s a bra in d i sease (29) . The pa th to drug

addiction begins with the act of taking drugs.

Al though each drug predominant ly has a

d i s t inc t mechanism of ac t ion , v i r tua l ly a l l


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GABA sys tem

Sedative-hypnotic drugs including alcohol,

benzodiazepines and barbi turates have long

been hypothesized to modulate receptors in

GABA systems.

1.0 Alcohol and adolescent brain

The problem of adolescent a lcohol

consumpt ion cont inues to be a s igni f i cant

concern , as ear ly onse t of a lcohol use oro ther drug use i s one of the s t ronges t

predictor of later alcohol dependence (32) .

In other words, the ear l ier a person begins

drinking alcohol, the more likely he or she

i s to become dependent on a lcohol . A

poss ib le explana t ion could be tha t ear ly

exposure to a lcohol or o ther drugs dur ing

adolescence may a l t e r c r i t i ca l ongoing

processes of bra in deve lopment tha t occur

a t tha t t ime, increas ing the l ike l ihood of

problems wi th a lcohol l a te r in l i f e . An

al te rna te in te rpre ta t ion for an ear lyexposure effect is that early use of alcohol

or o ther drugs might s imply serve as a

marker, not as a precursor, for a later drug

abuse disorder (33, 34).

Animal models offer researchers unique

ins ight in to the e f fec t s of a lcohol on the

adolescent and could fur ther he lp in

determining the mechanisms underlying the

poss ib le assoc ia t ion of ear ly exposure and

later alcohol problems.

1.1 Neurobehavioral effects

It has been observed that adolescent rats

are less sensi t ive to effects of intoxicat ion

and less sens i t ive to the hangover tha t

fo l lows use . Adolescent ra t s a re more

sensitive to the social disinhibition induced

by a lcohol use . Adolescent drunk ra t s

perform worse on memory tasks than adul t

drunk ra t s .

Recent work sugges t s tha t there a re

significant long-term effects of developmental

alcohol exposure in rats (35). It was observed

that chronic intermittent exposure treatment

(5.0 g/kg ip, every 48 hrs for 20 days) during

adolescence in te r fe res wi th the normal

increase in sens i t iv i ty to a lcohol - induced

motor impai rments tha t occurs be tween

adolescence and adul thood. Under cont ro l

condi t ions ra t s were more sens i t ive to the

effects of alcohol on postnatal day 65 (youngadulthood) than they had been on postnatal

day 30 (adolescence). These results suggest

that rats become more sensitive to the motor

impairing effects of alcohol as they progress

f rom adolescence to adul thood (36) .

Surpris ingly, animals that received alcohol

during adolescence did not show the normal

pattern of increased sensitivity to alcohol as

they aged into adulthood. In these animals,

the impact of acute a lcohol on motor

coordinat ion remained unchanged before up

to 16 days a f te r chronic in te rmi t t en texposure treatment. In contrast to the effects

of chronic in te rmi t t en t exposure in

adolescent s , chronic in te rmi t t en t exposure

treatment during adulthood had li t t le impact

on the subsequent effects of alcohol on motor

coordina t ion . This sugges t s the poss ib i l i ty

that the chronic exposure during adolescence

may have locked in the adolescent

insens i t iv i ty to a lcohol s seda t ive e f fec t s ,

or a t l eas t s igni f i cant ly de layed the

normal progress ion to grea te r sens i t iv i ty

in adul thood. Us ing a s t andard t ask of

swimming to a platform in a small pool of

water , Swar tzwelder and col leagues (37)

found adolescent rats given alcohol injections

took far longer than adul ts to swim to the

des t ined t a rge t . These f indings ra i se the

possibili ty that repeated exposure to alcohol

dur ing adolescence might a l t e r the normal

brain development in long-last ing and even

permanent ways .


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Among the mul t i tude of behaviora l

changes produced by e thanol , perhaps the

most sa l i en t a re the e f fec t s of e thanol on

motor act ivi ty as discussed above. Ethanol

d i s rupt s the ab i l i ty to per form tasks tha t

require balance and motor coordination, such

as driving an automobile, walking, and even

s tanding s ta t ionary in an upr ight pos i t ion

(38) . In rodents , the effects of ethanol on

motor coordination often is assessed by using

the ti l t ing plane test . The ti l t ing plane testsuggests that young rats are less vulnerable

than adult ethanol induced motor impairment

(39) . In addi t ion to reac t ing d i f fe rent ly

to the acute or in i t i a l e f fec t s of e thanol ,

adolescent and adul t r a t s appear to be

af fec ted d i f fe rent ly by repea ted e thanol

exposure . For ins tance , adolescent ra t s

a re l ess vulnerable than adul t r a t s to

chemoconvulsant induced se izures a f te r

cessation of repeated ethanol exposure (40).

Fur thermore , adolescent ra t s appear todevelop chronic to le rance to the e f fec t s

of e thanol more rap id ly than adul t s .

Swar tzwelder e t a l . (41) repor ted the

development of chronic to le rance to the

impact of e thanol on body tempera ture in

adolescent and adult subjects. The degree of

hypothermia produced by ethanol on the first

day of treatment did not differ between age

groups . However , over days , adolescent

subjec t s became to le rant to the e f fec t s

of e thanol on body tempera ture a t a

s ignif icant ly faster rate than adul ts .

Long- las t ing cogni t ive def ic i t s have

a l so been observed in rodents exposed to

alcohol repeatedly during adolescence (42) .

Chronic in te rmi t t en t exposure t rea tment

in adolescent ra t s resu l t s in exacerba ted

alcohol-induced learning deficits in adulthood

(43) . Adolescent and adul t r a t s t r ea ted

wi th chronic in te rmi t t en t exposure and

then t rained on a spat ial memory task, on

subsequent examinat ion showed poor

performance for the task in subjects treated

wi th chronic in te rmi t t en t exposure dur ing

adolescence than the other groups (44) .

A s tudy compar ing dr inking be tween

adolescent rhesus monkeys ra i sed by the i r

mothers and monkeys raised only with their

peers noted tha t peer - reared monkeys

displayed more anxiety-related behaviors anddrank more a lcohol than mother - reared

animals (45). However, on being exposed to

a s ignif icant s t ress when the mother-reared

monkeys were i so la ted f rom one another ,

their levels of drinking increased until they

almost matched those of peer-reared animals.

Wi th in each group, the an imals tha t

d i sp layed more anxie ty a l so drank more

alcohol. These findings propose that anxiety

or s i tua t ions tha t produce h igh degrees of

s t ress may t r igger excess ive a lcohol

consumption (45).

Social interact ion in per iadolescent rats

has been considered as a reinforcer in place

preference condi t ioning (46) and maze-

learning (47). Social factors modulate alcohol

se l f -adminis t ra t ion in ra t s . Hous ing

condi t ions as opera t iona l ized through

comple te , par t i a l or nul l soc ia l i so la t ion

exert significant effects upon alcohol intake

(48).

Sht iegman and King, (49) , r epor tedtha t voluntary a lcohol consumpt ion dur ing

adolescence i s assoc ia ied wi th a l a te r

increase aggressive behavior significantly in

male Golden hamsters. As mentioned above,

chronic alcohol exposure in adolescent rats

induces long-lasting alterations in cognitive

func t ioning (42) and d i s rupt puber ty-

assoc ia ted increases in reproduct ive

endocrinology in both males (50) and females


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(51) . Findings in rodents showing that pre-

and post-weaning (52) alcohol exposure can

a l so increase the an imal s preference for

alcohol later in life are contrary to findings

f rom other s tudies in th i s regard showing

no increases in l a te r consumpt ion a f te r

per iods of a lcohol exposure a t t imes tha t

include adolescence (53).

Adolescent ra t s d i sp lay two to three

times higher levels of ethanol intake relativeto their body weights than do more mature

animals (54, 55), although ethanol preference

per se does not peak until well into adulthood

around 5 months of age . The e leva ted

consummatory pa t t e rns of adolescence

could cont r ibute to h igh l eve l s of e thanol

intake by these growing animals relative to

their body weight (2) . I t i s suggested that

adolescent s might be ab le to sus ta in

comparat ively large ethanol intakes due to

the i r re la t ive insens i t iv i ty to the seda t ive

and locomotor incoordina t ing e f fec t s of ethanol, which may be in part related to their

grea te r propens i ty to deve lop acute and

functional tolerance relative to more mature

o r gan i s m s .

There is considerable research that shows

tha t adolescent an imals a re more sens i t ive

to chronic a lcohol exposure , wi th more

pronounced alcohol-related memory problems

and bra in damage than adul t an imals . A

recent s tudy has found tha t adolescent

rodents are less sensi t ive to the unpleasant

consequences of an alcohol-related hangover,

as measured by anxie ty . This hangover -

associated suppression of social interactions

i s supposed to be the remini scent of the

suppression in social interactions seen during

withdrawal f rom chronic alcohol . However ,

adolescent ra t s not only d id not exhib i t a

hangover - re la ted suppress ion in soc ia l

in te rac t ions , but they ac tua l ly showed an

increase in an age-spec i f i c form of soc ia l

activity called play fighting. Thus, opposite

to what is seen in adults, adolescents became

more socially responsive during the hangover

phase. Such a lack of aversive effects could

help establish a persisting cycle of drinking

in adolescent s , l eading to fu ture a lcohol -

related problems (56) .

Recently, adolescent alcohol drinking and

i t s long- ranges consequences have been

reported by McBride et al (57). These group

of workers suggested that alcohol dr inking

during periadolescence by alcohol-preferring

ra t s produces long las t ing e f fec t s tha t

increase the acquis i t ion of e thanol se l f -

administration in adulthood, and, in addition,

increase c raving - l ike behavior and the

potent ial for alcohol relapse.

1.2 Neurochemical /Neurobiological effects

There i s now c lear ev idence tha t

adolescence represent s a unique s tage of bra in deve lopment . Changes in bra in

organization and function during adolescence

are widespread, and include intense rewiring

in the frontal lobes and other neorcort ical

reg ions , as wel l as changes in subcor t i ca l

s t ruc tures . Recent research sugges t s tha t

because of these changes in brain function,

drugs l ike a lcohol a f fec t adolescent s and

adul ts different ly.

Recent research indica tes tha t e thanol

af fec t s bra in func t ion and behavior

d i f fe rent ly in adolescent and adul t r a t s .

Depending on the effect measured, adolescent

ra t s may be more or l ess sens i t ive than

adul ts to ethanol induced impairments . For

ins tance , acute e thanol impai r s spa t i a l

l earn ing more potent ly in adolescent ra t s

than in adults (58), and ethanol inhibits the

induction of long-term potentiation (37, 59)

and NMDA receptor -media ted synapt ic


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potent ia l s more potent ly in h ippocampal

s l i ces f rom adolescent ra t s compared to

those from adults (60). These findings suggest

tha t cogni t ive func t ions , par t i cu la r ly those

re la ted to memory, may be more potent ly

attenuated by ethanol in adolescent rats than

those from adults. Conversely, the onset of

seda t ion a f te r e thanol adminis t ra t ion i s

s lower , and the magni tude of seda t ion i s

smaller in adolescent rats than in adult rats

(26, 41, 61, 62).

Adolescent s have been shown to

di f fe rent ia l ly respond to b inge dr inking .

Binge a lcohol consumpt ion s igni f i cant ly

damaged the bra in of both the adul t s and

the adolescent s (63) . These researchers

repor ted tha t adolescent ra t s exposed to

a lcohol in a four -day b inge pa t t e rn suf fe r

extens ive bra in damage tha t inc ludes

structures that provide the hippocampus with

the informat ion tha t i t needs to form

memor ies . This damage was s igni f i cant lymore extens ive in adolescent subjec t s .

Damage to the h ippocampus fo l lowing

repea ted a lcohol exposure might s t em

from too much ac t iv i ty a t the NMDA

receptor , a par t i cu la r type of receptor for

the neurot ransmi t t e r g lu tamate , dur ing

a lcohol wi thdrawal . Too much ac t iv i ty a t

these receptors could a l low in t race l lu la r

levels of calcium (Ca2+) to become too high,

which can damage and even k i l l a ce l l .

Evidence for this remains indirect, but such

an ef fec t i s cer ta in ly feas ib le based on

research examining the impact of alcohol on

NMDA receptor ac t iv i ty in s l i ces of bra in

and cul tured neurons (64, 65) .

Cognitive impairments following repeated

a lcohol exposure and wi thdrawal in

adolescents may arise from neurotoxicity in

the h ippocampus and re la ted s t ruc tures .

Studies suggest that alcohol effects on the

hippocampus vary with age. Adolescent rats

show much grea te r vulnerabi l i ty to the

ef fec t s of a lcohol than adul t r a t s . Recent

studies in animals indicate that the l imbic

system may be particularly vulnerable to the

effects of alcohol during adolescence. This

area of the bra in p lays a major ro le in

memory formation, par t icular ly the s torage

and reca l l of fac t s , names , and events . I t

has been hypothesized that alcohol wreaks

havoc in the h ippocampus , and impai redhippocampal function appears to be directly

related to impaired memory formation (44).

Taken together, these recent studies indicate

tha t dur ing juveni le and adolescent

development in the rat the neurobehavioral

potency of ethanol varies markedly from that

observed in adul thood.

A number of repor t s sugges t tha t

repeated ethanol exposure might be expected

to produce long lasting changes in adolescent

behavior and bra in func t ion than dur ing

adul thood. Unfor tuna te ly , mos t of these

publ i shed repor t s do not inc lude an adul t

compar i son group, making i t d i f f i cu l t to

discern whether adolescent and adults differ

in their vulnerabi l i ty to the last ing effects

of e thanol . However , pre l iminary evidence

suppor t s tha t e thanol exposure dur ing

adolescence , but not adul thood, enhances

vulnerabi l i ty to e thanol - induced spa t ia l

memory impai rments l a te r in l i f e (43) .

Animal s tudies have a l so shown tha tchronic e thanol induced h ippocampal

damage cor re la tes wi th def ic i t s in spa t i a l

l earn ing and memory. Exposure to e thanol

vapor for 5 or 10 days has recent ly been

repor ted to a l t e r par ie ta l and h ippocampal

electroencephalogram act ivi ty in adolescent

ra t s (66) , whereas the oppor tuni ty to

consume a lcohol voluntar i ly dur ing

adolescence was found to increase l a te r


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aggressive behavior in male golden hamsters

(67).

Al though s tudies us ing animal models

have documented tha t adolescent s a re

resis tant to many ethanol effects , they are

converse ly more sens i t ive to cer ta in

res t r i c ted e f fec t s of e thanol - spec i f i ca l ly

ethanol- induced disrupt ions of hippocampal

p las t i c i ty and memory (37 , 68) found tha t

hippocampal slices from preadolescent (PI5-25) rats were more sensitive than adult slices

to e thanol d i s rupt ion of both N-methyl -D-

aspar ta tes (NMDA) media ted exc i ta t ion

as wel l as s t imulus- induced long- te rm

potent ia t ion .

In an imals , i t has been sugges ted tha t

a l lopregnanolone produced in response to

sys temic e thanol adminis t ra t ion could

contribute to several of the effects of ethanol

that are associated with the modulat ion of

GABA A-receptors (69) . Normal ly a lcoholenhances GABA funct ion in adul t s , bu t

adolescent rats injected with alcohol show

a decreased responsiveness to GABA, (37) .

Levels of serotonin have been found to be

assoc ia ted wi th d i f fe rences in a lcohol

preference be tween a lcohol prefer r ing (P)

and alcohol nonpreferring (NP) rats. P rats

have been found to have lower sero tonin

leve l s than NP ra t s (70) . Such var ia t ions

sugges t tha t genes tha t cont ro l se ro tonin

act ivi ty may inf luence alcohol preference.

Studies have found functional differences

in the dopamine system (as act ivated by

amphetamine) between the select ively bred

alcohol-preferring and nonpreferring lines of

rats as early as 28 days of age. Given that

the d ivergent dr inking charac te r i s t i cs of

these lines are also evident at this age, it is

possible that hyposensitivity of the dopamine

system may be a potential biological marker

for suscept ib i l i ty to a lcohol abuse . Many

of the neura l sys tems known to undergo

developmenta l changes dur ing adolescence

are ac t iva ted by s t ress which inc ludes

dopamine (DA) pro jec t ions to pref ronta l

cortex or PFC, as well as to mesolimbic brain

regions (71). These areas are thought to be

cr i t i ca l in modula t ing the p leasurable

response tha t fo l lows a lcohol use (31) .

Important receptors for the s t ress hormone

cor t i cos te rone have been ident i f i ed in ra t son DA cel l bodies in the ventral tegmental

area and substantia nigra as well as in DA

termina l reg ions , inc luding the nuc leus

accumbens and the PFC (72, 73). Increase in

cor t i cos te rone may p lay a c r i t i ca l ro le in

act ivat ing DA transmission. These f indings

suggest that s t ress- induced increases in the

s t ress hormones may in te rac t wi th

mesocorticolimbic brain regions to facili tate

alcohol-use behavior . Using the adolescent

rat as a model, adolescents have been shown

to accommodate more rapidly to the presence

of alcohol in their system (so-called acute

to le rance) than adul t r a t s do , thereby

reducing adolescent relative sensitivity to the

motor impair ing and sedat ive consequences

of alcohol (62). This insensitivity to alcohol

impairment may permit adolescents to drink

relatively large amounts when compared with

the i r more mature counterpar t s . Research

wi th rodents has shown tha t th i s exposure

has more adverse effects on hippocampal ly

re la ted memory processes in adolescent sthan in adults (58, 60).

Fetal effects

Animal models of fetal alcohol syndrome

(FAS) and alcohol- related neurodevelopmental

d i sorder (ARND) demons t ra te widespread

damage to the brain following relatively high

prena ta l exposure to a lcohol , as wel l as

significant brain changes following moderate


10/22


a lcohol exposure , l eading to ce l l loss in

several areas of the brain and affecting the

synapt ic connec t ions . In genera l , a lcohol -

exposed ra t s have smal le r and l ighter

brains. Specific brain structures affected by

prenatal exposure include the basal gangl ia

and the cerebellum, which are small in cases

of exposure. Moreover, increase in the size

of the fluid-fil led cavities in the brain (i .e.

the ventr icles) also has been observed (74,

75) . Other s tudies have reported an overal lreduct ion in the number of ce l l s in the

cerebral cortex, damage to a particular type

of ce l l ( i .e . ; pyramida l ce l l s ) in the

hippocampus , and damage to the main

pathway for the sense of smell in rats (76).

Furthermore, chronic ethanol intake during

gestation and lactation enhances natural cell

death and induces necrosis ; decreases brain

derived neurotrophic factors (BDNF) levels

and increases the rat io of the t runcated to

full length TrkB mRNA receptors during post

natal developing cerebral cortex. The ethanol

induced a l t e ra t ions in BDNF ava i lab i l i ty

and i t s receptors func t ion might impai r

intracellular signalling pathways involved in

ce l l surv iva l , g rowth and d i f fe rent ia t ion ,

causing enhanced natural cel l death during

cerebra l cor tex deve lopment .

Studies a l so indica te tha t gene t ic

differences in alcohol intake among inbred

l ines of ra t s a re present not only in

adul thood but a l so in adolescence , ra i s ing

the poss ib i l i ty tha t s imi la r gene t ic fac tors

might inf luence not only problem drinking

in adul thood, but a l so the emergence of

alcohol drinking during development (77).

Most recently, effect of alcohol on brain

neuropept ides has been repor ted in

adolescent and adul t rats (66) . The resul ts

of this study indicate that brief exposure to

a lcohol has long- te rm ef fec t s on l eve l s

of neuropept ide Y (NPY-LI) , cor t icotropin-

releasing hormone, substance P (SP-LI) and

neurokinins (NK-LI) . As these effects were

pr imar i ly the resu l t of changes in ra t s

exposed to e thanol dur ing adul thood,

however , they are unl ikely to contr ibute to

the increased susceptibility of adolescents to

the effects of chronic ethanol exposure.

Thus , the causes of the long las t ing

changes during adolescence are sti l l unclear

but might re f l ec t bra in damage in the

t radi t iona l sense . These da ta sugges t tha t

heavy, ep i sodic e thanol exposure dur ing

adolescence might a l t e r bra in deve lopment

in a lasting way.

1.3 Neuroendocrinal effects

The possibi l i ty that alcohol could al ter

neuroendocr ine deve lopment has been

suspected for years. Any effect of alcohol on

puber ty- re la ted hormones a t th i s c r i t i ca l

t ime of growth and deve lopment couldelevate the r isk for developmental def ici ts .

Research with experimental animals suggests

tha t de te rmining the e f fec t s of a lcohol on

endocr ine deve lopment war rant s se r ious

cons idera t ion .

Severa l repor t s have found tha t

adolescent a lcohol exposure reduces

testosterone levels in pubertal animals (50,

78, 79). Studies using rats have shown that

alcohol retards NMDA-tr iggered luteinizing

hormone (LH) release in adolescent femalerats (80) , and also suppresses the basel ine

secre t ions of lu te in iz ing hormone (LH) ,

growth hormone, est radiol , and insul in- l ike

growth factor (51, 81, 82). Moreover, alcohol

a l so de lays vagina l opening and lengthens

the in te rva l f rom vagina l opening to f i r s t

diestrus (83).

Neuros te ro ids have been shown to

be rewarding in rodents (84) . Therefore ,


11/22


neuros te ro ids may cont r ibute to the

anxiolytic and rewarding effects of alcohol.

Many animal s tudies have inves t iga ted

the e f fec t of a lcohol on neuros te ro id

concentrat ions (85) .

The l imi ted but s igni f i cant ly expl ic i t

l i t e ra ture on e f fec t of s t ress in l abora tory

animals shows tha t adolescent s a re more

negat ively affected by s t ressful events than

are adults. Adolescent rats have shown more

immobi l i ty under s t ress fu l s i tua t ions , such

as a forced swim test as compared to their

adult counterparts (86). It has been reported

tha t chronic soc ia l s t ress has a grea te r

impact on adolescent than on adult male mice

(87) . The h igher s t ress l eve l s resu l t in

grea te r reduct ions in food in take , body

weight ga in , and t ime spent on the open

arms of a p lus mazean indica tor of

anxie tyin adolescent s than adul t s . Also ,

adolescent s somet imes exhib i t a grea te r

overa l l hormonal response to s t ress

evidenced by the increased product ion of a

key stress-related hormone, corticosterone

compared with younger animals and a more

prolonged increase in s t ress hormones

re la t ive to adul t s (2 , 3) . In addi t ion to

s t ress fu l events , p leasurable exper iences ,

such as drinking alcohol also increase stress

hormone levels in laboratory animals (88) .

In fact, corticosterone itself has been shown

to be reinforcing and is self-administered by

rodents both in t ravenous ly and ora l ly (89 ,90) . In te res t ingly , l i t e ra ture a l so sugges t s

tha t adolescent ra t s exhib i t an a t t enua ted

cor t i cos te rone response to a lcohol as

compared to the adul t r a t s (91 , 92) .

Consider ing that increases in cor t icosterone

cont r ibute to the rewarding aspec t s of

alcohol, adolescents might need to consume

more alcohol to achieve the same effect as

compared to adul ts .

Cor t i cos te rone l eve l s in ra t s have a l so

been pos i t ive ly re la ted to ra tes of se l f -

administration of ethanol and adrenalectomy

has been assoc ia ted wi th suppress ion of

ethanol consumption (93) and stress-induced

eleva t ions in cor t i cos te rone increas ing

ethanol consumption (94). Stressors may also

enhance the ra te of to le rance deve lopment

to e thanol thereby indi rec t ly increas ing

ethanol consumption capaci ty.

2.0 Nicotine and adolescent brain

Tobacco use in adolescence represent s

one of the major cha l lenges to the fu ture

of publ ic hea l th . There i s accumula t ing

evidence tha t adolescence i s a per iod of

he ightened sens i t iv i ty to the e f fec t s of

nicotine. Adolescence appears to be a critical

per iod for the in i t i a t ion of smoking in

h u m a n s .


Despite the increasing use of tobacco by

adolescent s , f ew animal s tudies have

addressed the neurobehavioral consequences

of nicotine exposure during this period. The

acute e f fec t s of n ico t ine enhance ra t

locomotor act ivi ty in ear ly adolescent rats

and suppress it at late ages (95, 96, 97, 98).

Early adolescence also appears to be a period

of increased sens i t iv i ty to the rewarding

effects of nicot ine (96, 98) . Adriani et a l . ,

(99) a l so provide re levant ev idence tha tn icot ine e f fec t s depend on the age of the

animal. They showed that nicotine oral self-

adminis t ra t ion dur ing ear ly adolescence

(pos tna ta l day (P) 2435) increased the

preference for the nicotine solution when the

concent ra t ion was reduced as wel l as the

locomotor response to the drug. These effects

were not observed when nicot ine was self-

administrated by either middle (P37P48) or


12/22


la te (P50P61) adolescent mice.

Other aspects of nicotine effects are also

age d i f fe rent ia ted . Faraday e t a l , (100)

reported that both gender and age interacted

to a f fec t behaviora l reac t ions to n icot ine

dosing. Some age differentiated effects of

nicot ine may actual ly reduce the l ikel ihood

of dependence. Schochet et al., (101) reported

tha t P28-42 ra t s do not exhib i t n ico t ine -

pa i red cue condi t ioning , a l though adul t sdo . Trauth e t a l . , (102) repor ted tha t

per iadolescent n icot ine (P3047.5) induces

expression of p53 genes consistent with cell

damage in severa l bra in reg ions , and

sugges ted tha t adolescence i s a t ime of

continuing susceptibility to neurotoxic effects

of n icot ine . Females were more sens i t ive

than males to this effect , and hippocampus

was a relat ively sensi t ive s t ructure. Trauth

e t a l . , (103) a l so repor ted tha t adolescent

n icot ine exposure causes upregula t ion of

nicot inic chol inergic receptors to a greater

extent than in adul t an imals , and the

upregula t ion pers i s t s for a t l eas t 1 month

af te r t e rmina t ion of drug exposure .

Dopamine and norepinephr ine were a l so

increased by per iadolescent nicot ine (104) .

These f indings re inforce the concept tha t

deve lopmenta l vulnerabi l i ty to n icot ine

extends in to adolescence , wi th pa t t e rns

of drug e f fec t s d i f fe rent f rom those in

ear l ier or later per iods. The correlat ion of

neurochemica l wi th behaviora l e f fec t s

strengths the connection between adolescent

nicot ine exposure and persis tent funct ional

changes that may influence drug habituation,

l earn ing and memory.

Other workers have conf i rmed tha t

adolescent n icot ine may have pers i s t ing

ef fec t s . Levin and co-workers (105) have

shown tha t female ra t s , aged P54, have

higher rates of nicotine intake than do older

animals. Navarro et al . (106) suggested that

adolescent n icot ine induces pers i s t ing

compromise in immune response suggest ing

that multiple signaling systems are affected

by adolescent n icot ine . Recent ly , S lo tk in

and coworkers (107) a l so rev iewed the

l i t e ra ture on adolescent n icot ine e f fec t s .

Slawecki et a l . (108) s tudied the long-term

neurobehavioral effects of alcohol or nicotine

exposure in adolescent animal models. Thiss tudy suppor ted the hypothes i s tha t

adolescents are uniquely suscept ible to the

effects of chronic alcohol and nicotine use.

Thus, i t is clear that nicotine, l ike alcohol,

can induce last ing neurobehavioral changes

when consumed dur ing the per iadolescent

per iod in animals .

2.2 Neurochemical \Neurobiological effects

Nicot ine al ters var ious neurotransmit ter

systems such as the nicotinic, dopaminergic,

and sero tonergic sys tems in adul t rodent

animal models . I t i s not fu l ly unders tood

whether the e f fec t s of n ico t ine d i f fe r on

spec i f i c neurochemica l pa thways wi th

which i t interacts in adolescents compared

wi th adul t s . Neurochemica l changes in

response to n icot ine adminis te red dur ing

periadolescence have been examined as well.

It has been reported that nicotine injections

for 10 days beginning on pos tna ta l day

34 produced an increase in n icot in ic

ace ty lchol ine receptor gene express ion 5weeks a f te r t r ea tment ended (99) . Fur ther ,

nicotinic acetylcholine receptor binding was

upregula ted a f te r cont inuous infus ion of

nicotine for 17 days beginning in adolescence

(109), and dopamine turnover was increased

at postnatal day 45 after a 17 days nicotine

infusion period that began in preadolescence

(103) . Addi t iona l ly , cont inuous ly infused

nicotine for 17 days in adolescent male rats


13/22


produced a reduction in serotonin transporter

densi t ies (110) and a decrease in serotonin

(5-HT) receptor binding (111). However, some

previous s tudies , examined neurochemica l

changes tha t occur red a t t ime poin t s pas t

the per iadolescent per iod . In s tudies

examining the effects of nicot ine exposure

on neurochemica l a l t e ra t ions wi th in the

adolescent per iod, dai ly nicot ine inject ions

for 3 days beginning on postnatal day 30,

decreased serotonin synthesis and tryptophanexpress ion 3 days l a te r (112) . Fur ther

continuous infusion or twice daily injections

of nicotine for 7 days beginning on postnatal

day 30 increased n icot in ic ace ty lchol ine

receptor binding in the midbrain immediately

after treatment ended and persisted at least

a month (113). Collins et al ., (114) studied

the neurochemica l a l t e ra t ions produced by

daily nicotine exposure in periadolescent vs.

adul t r a t s . In th i s s tudy the inves t iga tors

demonstrated the effects of a 7-day treatment

with nicotine on nicotinic, dopaminergic, and

serotonergic neurochemistry. The effect was

examined in the caudate putamen and

nucleus accumbens in per iadolescent vs .

adul t male ra t s . I t was found tha t tha t

n icot ine t rea tment increased dopamine

transporter densities and decreased serotonin

transporter densities in periadolescent

ra t s . There was no change in n icot in ic

acetylcholine receptor densities or dopamine

Dl or D2 receptor dens i t i es in n icot ine-

pre t rea ted per iadolescent ra t s . On thecont ra ry the adul t r a t s pre t rea ted wi th

nicot ine showed increase in n icot ine

ace ty lchol ine dens i t i es and no change

in dopamine t ranspor te r , dopamine Dl or

D2 receptor , or se ro tonin t ranspor te r

densities (114). These findings suggest that

per iadolescent ra t s have neurochemica l

adaptations to nicotine different from adults.

Together these da ta sugges t tha t there a re

neurochemica l a l t e ra t ions occur r ing in

response to adolescent nicotine exposure and

that these changes can last into adul thood.


Recently, great interest has been devoted

to the interaction between nicotine addiction

and the hypotha lamic -p i tu i t a ry-adrena l

(HPA) axis. Nicotine activates the HPA axis

in adul t r a t s as measured by n icot ine

induced increases in ACTH (115) and

cor t i cos te rone (116) . I t has been repor ted

tha t sys temica l ly adminis te red n icot ine

s t imula tes the hypotha lamus-pi tu i t a ry-

adrena l (HPA) axi s through a cent ra l ly

media ted cor t i co t rophin- re leas ing-hormone

(CRH) dependent mechanism (117) .

Cor t i cos te rone modula t ion of behaviora l

responses to n icot ine appears to be qui te

complex (118) . There is also evidence that

cort icosterone par t icipates in neuroadpat ive

changes underlying conditioned tolerance tonicotine (118). Few studies investigated the

involvement of glucocort icoids on repeated

nicot ine e f fec t on locomotor ac t iv i ty and

sensitization. Shoaib and Shippenberg (119)

have demons t ra ted tha t adrena lec tomy did

not affect the depressant effect of repeated

nicotine but blocked the stimulation induced

by this drug. In addition, Johnson et al. (120)

showed tha t adrena lec tomy di s rupted the

development , but not the express ion of

nicot ine induced locomotor sensi t izat ion.

Despi te the relevance of the interact ion

between drugs and the HPA axis, the effect

of acute or chronic nicotine on the activation

of HPA axis in adolescent s has not been

inves t iga ted . Recent ly , Cruz e t a l . , (121)

repor ted the d i f fe rent ia l behaviora l and

endocr ine e f fec t s of repea ted n icot ine in

adolescent and adult rats. The results of this

s tudy provide evidence that adolescent rats


14/22


exposed to repeated display behavioral and

neuroendocr ine adapta t ions d i s t inc t f rom

tha t observed in adul t an imals . Also these

resul ts fur ther suggest that cor t icosterone -

activating effect of nicotine did not develop

to le rance in adolescent ra t s as compared

to adul t s . The l ack of to le rance to the

corticosterone-activating effect of nicotine in

adolescent ra t s could be re la ted to the

absence of behaviora l sens i t i za t ion , s ince

in these an imals the h igh l eve l s of cor t i cos te rone fo l lowing repea ted n icot ine

could main ta in the n icot ine chol inerg ic

receptors in the desensitized state. However,

the e f fec t of cor t i cos te rone on n icot ines

action appears to be very complex and thus

the actions of the glucocorticoids may vary

for different nicotinic receptor subtypes and

/or brain regions, as i t has been suggested

for n icot ines ac t ion on i t s own receptors

(109, 122) . Fur ther , s ince cor t i cos te rone

seems to have re inforc ing proper t i es (90) ,the lack of tolerance to the cor t icosterone-

ac t iva t ing e f fec t of n ico t ine in adolescent

rats may increase the reinforcing effect of

n ico t ine and the vulnerabi l i ty to tobacco

addict ion during adolescence. Furthermore,

invest igat ion on the role of glucocort icoids

on the e f fec t s of n ico t ine may provide

re levant knowledge to the deve lopment of

therapeut ic agents for the t rea tment of

nicot ine addict ion.

During late chi ldhood and adolescence,neurobiological systems are sti l l undergoing

impor tant deve lopmenta l rear rangements .

Thus, several mechanisms could account for

age differences in nicotines behavioral and

neuroendocrine actions. Understanding these

di f fe rences in n icot ine e f fec t s be tween

adolescent s and adul t s may lead to age

spec i f i c s t ra teg ies of prevent ion and

treatment . Therefore, i t wi l l be interest ing

in fu ture s tudies to de te rmine which

neurochemica l and molecular mechanisms

may contribute to the differential effects of

nicot ine in adul ts and adolescents .

3 .0 Substance abuse and adole scent bra in

As ment ioned above, drug abuse among

humans of ten begins during adolescence, a

per iod of ontogeny in which indiv idua l s

exhibit age-specific behavioral characteristics,

such as r i sk t ak ing and novel ty seeking ,

which could d i spose them to in i t i a te drug

use (2).


The per iadolescent per iod in the ra t i s

character ized by changes in the behavioral

respons iveness to many drugs of abuse .

These a l t e ra t ions may be predic t ive of

al terat ions in the reward value of drugs of

abuse . Campbel l e t a l . , (123) s tudied the

coca ine and morphine - induced p lacecondi t ioning in adolescent and adul t r a t s .

These workers suggested that adolescent and

adult rats exhibited similar sensitivity to the

rewarding effects of morphine and cocaine.

No differences was found between adolescent

and adul t s in the magni tude of p lace

condi t ioning expressed for morphine or

cocaine.

Persis tent effects of adolescent cocaine

have been reported in a few recent studies.

Smith et al ., (124) reported that 10 mg/kg/day adolescent cocaine modified the pattern

of cocaine stimulated upon field activity in

adul t s and a l so resu l ted in improved

per formance in DLR 20-s t ask . Pepin and

Smi th (125) found tha t 20 mg/kg/day

adolescent cocaine reduced adult consumption

of a cocaine solution in a schedule induced

polydipsia task. Smith et al . , (126) showed

tha t 5 or 20 mg/kg/day coca ine dur ing


15/22


adolescent or preadolescent dosing with one

drug can induce changes in reac t ion to

another drug la te r in l i f e . I t i s now c lear

tha t poss ib le cont r ibut ions of b io logica l

factors to adolescent drug progression needs

fur ther s tudy.

3.3 Neurochetnical \Neurobiological effects

Very few published reports are available

on the neurochemica l and neurobio logica l

effects of abusable drugs in adolescent rats.

Recent work on animals have indicated that

adolescent subs tance abuse may have long

las t ing consequences , inc luding bra in

damage , changes in cogni t ive capabi l i t i es ,

changes in electrophysiology, and hormonal

ef fec t s tha t may a l t e r sexual matura t ion .

Riddle et al . (135) have reported that four

10 mg/kg in jec t ions of methamphetamine ,

which induced reduct ions in DA persis t ing

for a t l eas t 7 days in adul t r a t s , induced

only short-term effects in 40-day-old rats. Foramphetamines , Lavio la e t a l . , (136) have

recent ly repor ted tha t adolescent mice

exhib i t d i f fe rent reac t ions than do adul t

mice . The s tudy showed tha t e f fec t s of

adolescent dosing include enhanced s t r iatal

DA response amphetamine cha l lenge , but

adul t dos ing does not produce the same

ef fec t . Other e f fec t s inc lude a marked

sens i t i za t ion of explora tory behavior in

response to amphetamine challenge in adults

but not adolescent s . To unders tand ef fec t sof abusable substances on adolescents, i t is

necessary to s tudy adolescent s . This

conclusion is supported by work of Kosofsky

et a l . , (137) . These workers found tha t

cocaine administration at each of four ages

(P8, PI5 , P28, and adul t ) r esu l ted in

dis t inct ively different pat terns of induct ion

of immedia te ear ly genes a t each age . At

the gene express ion l eve l , adminis t ra t ion

adolescent a l t e red per formance in a

coca ine condi t ioned p lace preference t ask .

Interestingly, 5 mg/kg/day cocaine increased

place conditioning only when the conditioning

chamber had hor izonta l b lack and whi te

s t r ipes whi le 20 mg/kg/day increased

condi t ioning only in a ver t i ca l ly s t r ipped

chamber . This f inding i s sugges t ive of

modi f ica t ion of some aspec t s of v i sua l

functioning by adolescent cocaine. Morin et

al., (127) reported the binge regimen affects

adul t cocaine condi t ioned place preference.

Sensitization to cocaine has been reported

to develop in periadolescent much as it does

in adults (128, 129). Some studies have also

repor ted tha t sens i t i za t ion to coca ine

develops differently in preadolescent animals

than in adults. Synder et al . (130) reported

tha t sens i t i za t ion in preweanl ing ra t s was

especially long- lasting, suggesting that there

may be ontogenetic changes in the substances

for sensitization. Zavala et al. (131) showed

that sensitization to the locomotor effects of

coca ine pers i s ted for a longer per iod in

preadolescent ra t s than in adul t an imals ,

implying that the substrate for sensitization

are somehow di f fe rent depending upon the

age of the subject . Col l ins and Izenwasser

(132) , on the o ther hand, found tha t

per iadolescent ra t s were not sens i t i zed to

cocaine over a 7-day regimen from P 28-35,

while adults were sensitized. More recently,

Melnick and Dow-Edward (133) found thatprepuber ta l coca ine (P-20) reduced the

development of amphetamine sensitization in

older (>6 months) rats. Brandon et al., (134)

repor ted tha t adolescent dos ing wi th

methylphenida te increased responding

for in t ravenous coca ine on a progress ive

ra t io schedule in adul t s . Thus , there a re

now repor t s for four drugs (a lcohol ,

nicotine, cocaine, and methylphenidate) that


16/22


Groups of prepubescent male ra t s (2527

days of age) were implanted with morphine-

or p lacebo-pe l le t s . When the acute and

chronic effects of morphine on reproductive

endocr ine parameters had d i ss ipa ted and

the i r fe r t i l i ty and the deve lopment of the

male and female progeny was character ized

the resul ts showed that morphine exposure

dur ing adolescence l ed to a pronounced

inhibition of a number of indices of sexual

matura t ion (e .g . se rum tes tos te rone and

lu te in iz ing hormone leve l s and reduced

weights of the testes and seminal vesicles).

Breeding morphine- and p lacebo- implanted

male rats with drug-naive females resul ted

in smal le r l i t t e r s der ived f rom morphine-

t reated fathers when compared to controls ,

but in a l l o ther respec t s the deve lopment

of the of f spr ing in the two groups were

equiva lent . However , upon reaching

adul thood, a number of select ive endocrine

di f fe rences were de tec ted in morphine-derived offspring when compared to controls

(50). Byrnes et al., (141) studied the effects

of chronic morphine exposure during puberty

on pos tpar tum behavior and pro lac t in

secret ion in female rats (141) . The s tudied

showed that per ipubertal morphine delayed

vaginal opening and significantly attenuated

later lactat ion in female rats . The lactat ion

def ic i t s were accompanied by def ic ien t

suckling-induced prolactin release. They also

reported that the offspring of mothers dosed

per ipuber ta l ly wi th morphine were de layed

in vagina l opening , presumably resu l t ing

f rom a l t e ra t ions in materna l hormones .

Adolescent coca ine use (20 mg/kg/day)

reduces es t rous cyc l ing both dur ing and

fol lowing dos ing (Raap e t a l . , 2000) . In

female mice, cocaine can delay the puberty-

acce le ra t ing e f fec t s of exposure to male

pheromones (83) .

of cocaine to early adolescent rats (P28) is

biologically different than adult administration,

and it should not be surprising if other effects

of such administration also differ.

More recently, concerns about subtle long

las t ing neurobio logica l changes tha t might

be t r iggered by exposure to cannabis

exposure derivatives, especially in a crit ical

phase of brain maturat ion, such as puberty

has been ra i sed (138) . The mesol imbicdopamine (DA) sys tem, involved in the

processing of drug induced reward, is a locus

of action of cannabinoid and endocannabinoids

(139). These investigators suggested that an

enduring form of neuronal adaptation occurs

in DA neurons after sub chronic cannabinoid

intake at a young age, affecting subsequent

responses to drug of abuse.

There i s insuf f ic ien t da ta to draw rea l

conclusions. It is speculated that effects of

abusable substances on adolescents and their

behavior with respect to these drugs could

be on account of combinat ion of cont inued

plasticity of the CNS during late maturation.

Moreover , some spec i f i c adolescent adul t

differences in reactions to drugs may perhaps

due to ontogenet ic or exper ience- induced

differences in receptor expression or other

aspects of neurotransmit ter system or other

behavior cont ro l sys tems such as l a te

maturation of frontal lobes etc. (140). More

work i s needed to fu l ly unders tand theneurochemical and neurobiological substrates

of this par t icular age group.


The ef fec t s of adolescent morphine

exposure on the sexual maturat ion of male

ra t s , the i r reproduct ive capac i ty and the

development of the i r progeny have been

examined by var ious groups of au thors .


17/22


amount of ev idence tha t adolescent

consumpt ion of severa l drugs by animals

subjec t s may resul t in res idua l e f fec t s on

neurobehaviora l func t ioning . In some

s tudies , d i rec t compar i sons wi th adul t s

indicated that the adolescent brain is more

sens i t ive to l as t ing e f fec t s of a lcohol and

abusable drugs than i s the adul t s CNS. In

many o ther s tudies , there a re no adul t

comparision groups. However, at this point,

there a re suf f i c ien t da ta to sugges t tha t

consumpt ion of a lcohol , n ico t ine and

abusable drugs by adolescents poses a real

r i sk of l as t ing CNS changes , as re f l ec ted

in par t by cogni t ive changes . Moreover ,

these f indings have he lped in the be t t e r

understanding of the issue and have provided

subs t ra te for the c l in ica l appl ica t ion . But

stil l a lot remains to be answered regarding

impact of a lcohol and subs tance abuse on

adolescent brain. Future s tudies wil l prove

useful to understand the biological substratesof subs tance abuse by th i s par t i cu la r age

group.

Thus, i t is clear that periadolescent use

of abusable substances may alter aspects of

neuroendocr ine cont ro l and assoc ia ted

indices of sexual matura t ion . Fur ther ,

functional consequences for adult reproductive

func t ioning , and poss ib le cont r ibut ions of

a l t e red endocr ine s ta tus to per iadolescent

CNS development , remain to be def ined.

C o n c l u s i o n

The adolescent bra in i s not mere ly a

miniature adult brain rather it is structurally

and developmentally different from its adult

counterpar t . This difference is seen in the

s t ruc tures involved in the use of a lcohol ,

n icot ine and o ther abusable drugs i .e .

stressor-sensitive, mesocorticolimbic dopamine

project ions that are cr i t ical for modulat ing

the perceived value of reinforcing s t imuli .

Moreover, since it is still developing it means

tha t the impact i t suf fe r s would have

consequences for adul t l i f e func t ioning aswel l . Al though signif icant quest ions remain

to be answered, there is now a considerable

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