yavin shaham neurobiology of relapse section behavioral neuroscience branch
DESCRIPTION
Relapse to food seeking: Role of CRF, PYY3-36, and hypocretin. Yavin Shaham Neurobiology of Relapse Section Behavioral Neuroscience Branch IRP/NIDA/NIH/DHHS, Baltimore Post-doctoral fellows: Sunila Nair , Udi Ghitza - PowerPoint PPT PresentationTRANSCRIPT
Yavin Shaham
Neurobiology of Relapse SectionBehavioral Neuroscience BranchIRP/NIDA/NIH/DHHS, Baltimore
Post-doctoral fellows: Sunila Nair, Udi Ghitza
Students (NIH training program): Sarah Gray, Sam Golden, Tristan Adams-Deutsch
Relapse to food seeking:Role of CRF, PYY3-36, and hypocretin
CRF = Corticotropin-releasing factor
PYY3-36 = Peptide YY3-36
Hypocretin = Orexin
Shaham laboratory
Staff scientist: Jennifer Bossert
Post-doctoral fellows: Sunila Nair, Charles Pickens
Post-baccalaureate students: Sam Golden, Kristina Wihbey, Tristan Adams-Deutsch
Hope laboratory
Staff scientist: Bruce Hope
Post-doctoral fellow: Eisuke Koya
Graduate student: Danielle Guez (Yale U)
Post-baccalaureate student: Alex Berkow
Neurobiology of Relapse Section
Ongoing research projects
1. Relapse to food seeking
2. Context-induced reinstatement of heroin seeking
3. Incubation of cocaine craving (time-dependent increases in cue-induced cocaine seeking)
4. Incubation of conditioned fear (time-dependent increases in conditioned fear)
5. Neuronal mechanisms of context-dependent cocaine sensitization (Hope lab)
Extramural collaborations:
AD Le (Toronto U): Stress-induced relapse to alcohol (NIAAA)
Geoff Schoenbaum (U of Maryland): Effect of cocaine self-administration on learning and memory (NIDA)
Abraham Zangen (Weizmann Inst., Israel): Developing a novel conflict model of drug (NIDA)
Marina Wolf and Micky Marinelli (Rosalind Franklin University): Accumbens synaptic plasticity and incubation of craving (NIDA)
Outline
• A brief description of a reinstatement model—an animal model of relapse to drug-taking behavior
• The adaptation of the reinstatement model to study:
1. Role of CRF in reinstatement of food seeking induced by:
* A pharmacological stressor (yohimbine) * Acute re-exposure to food pellets (pellet priming)
2-3. Effect of PYY3-36 and hypocretin 1 receptor antagonist on reinstatement induced by:
* Yohimbine* Pellet priming* Cue (a tone-light cue previously paired with pellet delivery)
The reinstatement model of drug relapse
Reinstatement studies
(1971-2007)
Year
0 3 4 101320
96
332
478
0
100
200
300
400
500
70 75 80 85 90 95 00 05 07
Cum
ula
tive #
of
public
ati
ons
Drug primingDrug cuesStress
X
Lever
pre
sses
Self-administration training(Drug is available)
Extinction(Drug is NOT available)
TESTING(Drug is NOT available)
Experimental day
X
Study 1
The role of CRF in reinstatement of food seeking induced by the pharmacological stressor yohimbine
Hypothalamic-pituitary-adrenal (HPA) axis
Extra-hypothalamic CRF systems
From Behan et al. 1996
The clinical problem: Excessive eating of unhealthy food is a major health problem
The preclinical situation: This issue has not been explored in preclinical laboratory studies, which have primarily focused on the effect of stress on ongoing feeding behavior
Stress can provoke relapse to unhealthy eating habits, and humans are particularly vulnerable to this effect when dieting
Stress and relapse to maladaptive eating habits
Why yohimbine?
Yohimbine (an alpha-2 adrenoceptor antagonist) increases brain noradrenaline release and induces stress-like responses in humans and laboratory animals
Yohimbine induces heroin craving in human addicts
Yohimbine reinstates drug seeking in monkeys and rats
Methamphetamine
Yohimbine dose (mg/kg, i.p.)
0
25
50
75
100
0 1.25 2.5
* *
Shepard et al. 2004Biol. Psychiatry
Alcohol
Le et al. 2005Psychopharmacology
0
15
30
45
60
0 1.25 2.5
* *
0 2.5
*
0
20
40
60
80
100
Yap & Shaham. 2000 (unpublished)
Lever
pre
sses
Heroin
0
40
80
120
0 0.625 1.25
Le et al. 2007(Unpublished)
*
*
Nicotine
Why CRF?
CRF injections into the ventricles and several extrahypothalamic sites (BNST, VTA, median raphe) reinstate drug seeking
Non-selective and selective CRF1 receptor antagonists attenuate stress-induced reinstatement of drug seeking
Heroin Cocaine
Intermittent footshock
No stress
0 15 30
CP-154,526 dose (mg/kg)
0
15
30
45
60
Lever
pre
sses
0 15 30
* *
* *
Shaham et al. Psychopharmacology, 1998
Alcohol
0 15 30
*
*
Gehlert et al. J Neurosci, 2007
MTIP dose (mg/kg)
*
0 15 30
CP-154,526 dose (mg/kg)
Le et al. Psychopharmacology, 1998
Pellet self-administration Three 3-h sessions/d every other day
(FR-1; 20 sec timeout)
Extinctionpellets NOT available
Tests for reinstatement pellets NOT available
Limited access to regular food: ~75% of daily intake
Limited access to regular food: ~75% of daily intake (diet condition)
Experimental procedure
Exposure to: YohimbineNon-contingent pellet (priming)45 mg pellets:
25% fat48% carbohydrate
Changes in body weight during training, extinction, and reinstatement (n=35)
Pellet self-administration Three 3-h sessions/d every other day
(FR-1; 20 sec timeout)
Extinction(pellets NOT available)
Tests for reinstatement (pellets NOT available)
Limited access to regular food: ~75% of daily intake
Limited access to regular food: ~75% of daily intake (diet condition)
Daily weight fluctuations
Training
Extinction &Reinstatement
-20
-10
0
10
20
10 20 30 40Day
Weig
ht
change
(g)
No pellets
Pellets available
Ghitza et al. Neuropsychopharmacology, 2006
Development of “compulsive” food-taking behavior during training
Pellet self-administration Three 3-h sessions/d every other day
(FR-1; 20 sec timeout)
Extinction Tests for reinstatement
Limited access to regular food: ~75% of daily intake
Limited access to regular food: ~75% % of daily intake (diet
condition)
Pellets
2 4 6 8 10 12
Training day
Resp
onse
s or
pelle
ts (
9 h
)
600
900
1200
0
300
Timeout responses
Pellet self-administration Extinction(pellets NOT available)
Tests for reinstatement (pellets NOT available)
Limited access to regular food: ~75% of daily intake
Limited access to regular food: ~75% of daily intake (diet condition)
The CRF1 receptor antagonist antalarmin decreases yohimbine-induced reinstatement of food seeking
Reinstatement
Pellet priming
**
20 mg/kg40 mg/kg
Antalarmin doseVehicle
0 2.0
Yohimbine dose (mg/kg, i.p.)
0
25
50
75
100
Lever
pre
sses
(3 h
)Extinction
0
150
300
450
600
1 2 3 4 5 6 7 8 9 10
Extinction day
Lever
pre
sses
9 h/day
3 h/day
Antalarmin was synthesized by Dr. Kenner Rice
Antalarmin decreases yohimbine-induced reinstatement of alcohol seeking
Marinelli et al. Psychopharmacology, 2007
Yohimbine-induced reinstatement
0
20
40
60
80
20100
*
Antalarmin dose (mg/kg, i.p.)
Lever
pre
sses
(1 h
)
*
VehicleYohimbine (1.25 mg/kg)
Yohimbine-induced plasma corticosterone release
0
250
500
750
0 20
VehicleYohimbine (1.25 mg/kg)
Antalarmin dose (mg/kg, i.p.)
Cort
icost
ero
ne (
ng/m
l)
The CRF1 antagonist antalarmin reverses yohimbine’s effects on social and “antisocial”
behaviors
“Antisocial” behavior
Social and “antisocial” behaviors were evaluated using a social interaction test:
Social behavior: crawling together, grooming, sniffing, licking
“Antisocial” behavior: wrestling, distress vocalization, confrontation
Social behavior
20 mg/kg
0 2.0Yohimbine dose (mg/kg, i.p.)
0
10
20
30
40
Anti
soci
al bou
ts (
10 m
in)
*
0
25
50
75
100
Soci
al bouts
(10 m
in)
0 2.0 Yohimbine dose (mg/kg, i.p.)
*Vehicle
Antalarmin dose
Conclusions: Study 1
As in the case of drug relapse, the reinstatement model can be used to study mechanisms underlying relapse to maladaptive eating habits
The effect of antalarmin on yohimbine-induced reinstatement of food and alcohol seeking is likely mediated by extrahypothalamic CRF1 receptors
Project 2
Effect of PYY3-36 on yohimbine-, pellet-priming- and cue-induced reinstatement of
high-fat food seeking
The gut peptide PYY3-36 is an endogenous Y2 NPY receptor agonist that decreases home-cage feeding after systemic or arcuate nucleus injections
PYY3-36 systemic effects are reversed by systemic or arcuate injections of the Y2 receptor antagonist BIIE0246.
Background
Batterham + 9 authors (2002) Gut hormone PYY(3-36) physiologically inhibits food intake. Nature 418:650-654.
Batterham + 7 authors (2003) Inhibition of food intake in obese subjects by peptide YY3-36. N Engl J Med 349:941-948.
Pittner + 9 authors (2004) Effects of PYY(3-36) in rodent models of diabetes and obesity.
Int J Obes Relat Metab Disord 28, 963-971
But….
Tschop + 42 authors (2004) Does gut hormone PYY3-36 decrease food intake in rodents? Nature 430:1 p following 165; discussion 162 p following 165.
Boggiano + 36 authors (2005) PYY3-36 as an anti-obesity drug target. Obesity Reviews 6:307-322
* The effect of PYY(3-36) on operant food self-administration and reinstatement has not been assessed
Pellet self-administration Two 3-h sessions/d every other day
(FR-1; 20 sec timeout)
Extinctionpellets NOT available
Tests for reinstatement pellets NOT available
Limited access to regular food: ~65% of daily intake
Limited access to regular food: ~65% of daily intake (diet condition)
Experimental procedure
Exposure to:YohimbineNon-contingent pellet
45 mg pellets: 35% fat45% carbohydrate
Cue
(Tone-light cue available)(Tone-light cue NOT available)
X X
PYY3-36 has a minimal effect on high-fat pellet self-administration
Pellet self-administration two 3-h sessions/d every other day
(FR-1; 20 sec timeout)
Limited access to regular food: ~65% of daily intake
Session 1: Total intake
Food
pelle
ts (
3 h
)0
75
150
225
0 100 200
PYY3-36 dose (µg/kg, i.p.)0 100 200
Session 2: Total intake
Ghitza, Nair et al. The Journal of Neuroscience, 2007
PYY3-36 inhibits pellet-priming- and cue-induced reinstatement, but not yohimbine-induced
reinstatementCue
0
25
50
75
100
Lever
pre
sses
(3 h
)
0 100 200
PYY3-36 dose (µg/kg, i.p.)
**
No cueCue
0
25
50
75
100Le
ver
pre
sses
(3 h
)
0 100 200PYY3-36 dose (µg/kg, i.p.)
No pelletPellet
**
Pellet priming
Yohimbine
0
50
100
150
200
250
0 100 200
PYY3-36 dose (µg/kg, i.p.)
VehicleYohimbine (2.0 mg/kg)
Lever
pre
sses
(3 h
)
Conclusions: PYY3-36
Systemic PYY3-36 decreased pellet-priming-induced reinstatement at doses that had minimal effect on ongoing high-fat food self-administration
The systemic effect of PYY3-36 on reinstatement generalizes to cues- but not to yohimbine-induced reinstatement of food seeking
The systemic effect of PYY3-36 is dependent on Y2 receptors
Systemic PYY3-36 had no effect on reinstatement of heroin seeking, suggesting that its effects are specific to food relapse
Project 3
Effect of the hypocretin 1 receptor antagonist SB 334867 on high-fat food self-administration and
relapse to food-seeking in rats
Prepro-hypocretin
Hypocretin 1 Hypocretin 2
Hypocretin 1 receptor Hypocretin 2 receptor
From Sakurai, 2006 and 2007
The hypocretins (orexins)
Why hypocretin 1 receptors?
Systemic injections of SB 334,867 decrease home-cage food intake and reverse hypocretin 1-induced increases in food intake (Rodgers et al. 2002)
Systemic injections of SB 334,867 decrease:
Reinstatement of morphine conditioned place preference induced stimulation of lateral hypothalamus hypocretin neurons (Harris et al. 2005)
Footshock stress-induced reinstatement of cocaine seeking (Boutrel et al. 2005)
Cue-induced reinstatement of alcohol seeking (Lawrence et al. 2006)
SB 334,867 decreases high-fat pellet self-administration
Nair et al. British Journal of Pharmacology, 2008
Pellet intake
0
100
200
300
400
0 10 20
SB 334867 dose (mg/kg, i.p.)
Pelle
ts (
3 h
)
*
*
SB 334867 dose (mg/kg i.p.)
Timeout lever presses per pellet
0
2
4
6
0 10 20
Tim
eou
t re
spon
ses/
pelle
t
Pelle
ts
Time course
Vehicle10 mg/kg20 mg/kg
Session minutes
0
10
20
30
40
50
30 60 90 120 150 180
Training
0
500
1000
1500
1 2 3 4 5 6 7 8 9Training session
Pelle
ts o
r le
ver
pre
sses
Timeout responsesPellets
SB 334,867 has no effect on hypocretin 1-induced reinstatement of food seeking
Hypocretin 1-induced reinstatement
0
25
50
75
100
0 3.0 6.0
Lever
pre
sses
(3 h
)
*
Hypocretin 1 dose (µg, icv)
Vehicle
10 mg/kg
20 mg/kg
Effect of SB 334,867
0
25
50
75
100
0 6.0Hypocretin 1 dose (µg, icv)
Lever
pre
sses
(3 h
)
SB 334,867 has no effect on pellet-priming-, pellet-cue- or yohimbine-induced reinstatement of food seeking
Pellet priming
0
25
50
75
100
No pellet Pellet
Lever
pre
sses
(3 h
)
Vehicle
20 mg/kg
Cue
No cue Cue
Vehicle
20 mg/kg
Yohimbine
0 2.0
Yohimbine (mg/kg, i.p.)
Vehicle
20 mg/kg
The hypocretin 1 receptor plays a role in the self-administration of high-fat pellets
The hypocretin 1 receptor likely plays a minimal role in reinstatement induced acute re-exposure to hypocretin 1, food priming, cues and stress
Conclusions: hypocretin 1 receptor
From Shalev et al. Neurobiology of relapse to heroin and cocaine seeking: a review. Pharmacol Rev, 2002
“Taken together, it appears that multiple and dissociable brain systems are involved in relapse to heroin and cocaine seeking induced by drug priming, conditioned cues and stress. Somewhat surprisingly, it also appears that the neuronal events that mediate heroin- or cocaine-induced reinstatement are to some degree different from those involved in their reinforcing effects.”
Implications of the findings
Our data suggest:
1. A dissociation between the neuronal mechanisms mediating stress-induced relapse to food seeking versus food priming- or cue-induced relapse
2. A potential dissociation between the neuronal mechanisms mediating food self-administration versus food priming- or cue-induced relapse
Clinical implications
CRF1 receptor antagonists (currently in clinical development for the treatment of anxiety, depression and drug abuse) should be considered as pharmacological adjuncts in dietary treatments of maladaptive or excessive eating habits
PYY3-36 (currently in clinical development for the treatment of obesity) may be a more effective treatment for relapse prevention than for decreasing ongoing high-fat food intake
Hypocretin 1 receptor antagonists may be a more effective treatment for decreasing ongoing high-fat food intake than for relapse prevention
“The best material model for a cat is another, or preferably the same cat”Norbert Wiener, 1945
Acknowledgments
Dr. Jennifer BossertJamie UejimaKristina WihbeyDr. Kenner Rice