Yavin M. Shaham, Ph.D.Behavioral Neuroscience BranchIRP/NIDA/NIH/DHHS, Baltimore

Role of VTA Glutamate in Contextual Cue-Induced Relapse to Heroin-Seeking

Outline

• Role of VTA glutamate in context-induced relapse to heroin seeking

• Role of central amygdala ERK signaling pathway and glutamate in incubation of cocaine craving

The reinstatement model of drug relapse

Drug primingDrug cuesStressR

esp

onse

s

Self-administration training Extinction TESTING

Drug is available Drug is NOT available

Active lever

Inactive lever

Reinstatement studies(1971-2004)

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Role of VTA glutamate in context-induced relapse to heroin seeking

Systemic injections of mGluR2/3 agonists attenuate:

Opiate withdrawal symptoms (Vandergriff and Rasmussen, 1999)

Amphetamine-induced locomotor sensitization (Vezina, 2004)

Discriminative cue-induced reinstatement of cocaine seeking (Baptista et al., 2004)

Dr. Jennifer Bossert

Intra-VTA injections of ionotropic glutamate receptor antagonists attenuate:

Morphine and cocaine place preference (Harris et al. 2003; Byrne et al. 2003)

Reinstatement of cocaine seeking induced by ventral subiculum stimulation (Vorel et al. 2001) or stress (Wang et al. SFN. 2004)

Also: Over-expression of VTA GluR1 enhances morphine place preference (Carlezon et al. 1997)

From Schoepp. JPET 2001

LY379268 a selective agonist of mGluR2/3 receptors

Types of relapse-provoking drug cues in humans and laboratory animals

• Humans: Two major types of cues that provoke relapse after abstinence:

Discrete cues (e.g., drug paraphernalia) that predict drug effects

Contextual cues (e.g., street corner, bar) that predict drug availability

• Laboratory animals: Two types of cues that provoke relapse to drug seeking after extinction of the operant responding in their absence:

Discrete cues (e.g., tone, light) paired with drug injections

Discriminative cues (e.g., specific odors) that become predictors of drug availability after discrimination training

• Research question: Can we study the role of the drug context in reinstatement of drug seeking after extinction of the operant responding in the presence of the discrete cues (an animal model of the cue exposure treatment method)?

• This issue can be addressed using a “renewal” procedure, commonly used to study the role of the environmental context in the resumption of conditioned fear responses to discrete cues after extinction (Bouton & Bolles 1979)

A “renewal” procedure to study the effect of contextual drug cues on drug seeking

Crombag & Shaham. Behavioral Neuroscience, 2002

Reinstatement test

Renewal

Novel

Control (1+2)*

NovelControlRenewal

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125Extinction

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Session1

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Differences between contexts A and B:--type of grid floor --background noise --illumination level--type of odor

Control 1

Renewal

Novel

Control 2

Training (10 d)

Extinction (20 d)

Test (1 d)

Context A Context B

Context A

Context A Context B

Context A Context A

Context A

Context B

Context B

Context A

Context A

Context A

Reinstatement of heroin seeking by contextual drug cues

Control 1

Renewal

Novel

Control 2

Training (12 d)

Extinction (12-20 d)

Test (1 d)

Context A Context B

Context A

Context A Context B

Context A Context A

Context A

Context B

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Context A Context ANo Extinction

Differences between contexts A and B:--Time of day (circadian cues)--Type of grid floor (tactile)--Background noise (auditory)--Distinct chamber cues--Illumination level (visual cues)

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Effects of systemic or intra-VTA injections of an mGluR2/3 agonist on context-induced reinstatement

of heroin seekingSystemic LY379268

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1 mg/kg3 mg/kg *

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Intra-VTA LY379268

Vehicle0.3 µg

1.0 µg

Extinction(Context B)

Training(Context A)

VTA

Bossert et al. The Journal of Neuroscience, in press

Control experiments

SN

Lever presses for a 5% sucrose solution

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(mg/kg, i.p)

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Vehicle1.0 µg

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Training(Context A)

Intra-substantia nigra LY379268

Conclusions and implications

As in the case of relapse to anxiety-related disorders (Bouton 2002), the role of the environmental context in drug relapse can be studied in laboratory rats using the renewal procedure

Glutamate transmission in the VTA plays an important role in context-induced relapse to heroin seeking

The present data and those from previous studies (see Baptista et al. 2004) suggest that mGluR2/3 agonists and other drugs that target metabotropic glutamate receptors (see Kenny & Markou 2004) should be considered in the treatment of drug relapse

A key regulator of synaptic plasticity and learning and memory (Sweatt 2001)

Amygdala ERK is involved in conditioned fear responses (Schaffe et al. 2000)

Mesolimbic ERK is activated by cocaine (Licata and Pierce 2003; Valjent et al. 2000)

ERK

MEK

Raf

U0126

NMDA receptor

NMDA/AP-5

From Thomas and Huganir. Nature Neuroscience, 2004

ERK (extracellular signal-regulated

kinase)

Role of central amygdala ERK and glutamate in incubation of cocaine

craving

Dr. Lin Lu

Collaborator: Dr. Bruce Hope

Grimm et al. Incubation of cocaine craving after withdrawal. Nature, 2001

1 day2 days4 days7 days15 days29 days60 days

Training phase Withdrawal phase

Test phase(drug is NOT available)

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Tone+light cue(n=67)

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“Extinction” + Testing (same day)

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Cue-induced reinstatement

Cue available

Last extinctionsession (no T+L)

Time-dependent changes in extinction responding and cue-induced reinstatement of cocaine seeking after

withdrawal

Incubation of reward craving after withdrawal from

drug and non-drug reinforcers

Alcohol Bienkowski et al. (2004) Withdrawal period in

home cage prior to extinction tests

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Heroin Shalev et al. 2001

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Cocaine (4)Lu et al. 2004

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Cocaine (1)Tran-Nguyen et al. (1998)

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Sucrose Lu et al. 2004

MethamphetamineShepard et al. 2004

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Training condition: saline versus cocaine

Withdrawal period: day 1 versus day 30

Test condition: no cue versus cue exposure (30 min extinction test)

Cocaine/saline SA training (10 Days)

Withdrawal period (1 or 30 Days)

Extinction testDay 1

Extinction test Day 30

4 groups

Cocaine/saline SA training (10 Days)

Withdrawal period (1 or 30 Days)

No test Day 1

No test Day 30

4 groups

Experiment 1: activation of amygdala ERK by cocaine cues

Withdrawal day

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Behavioral data: Training and extinction test

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Cocaine-trained rats

Saline-trained ratsLu, Hope et al. Submitted

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Exposure to cocaine cues increases ERK phosphorylation in the central amygdala after 30

days of withdrawal

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Inhibition of ERK phosphorylation in the central amygdala attenuates cocaine seeking after 30 days of

withdrawal

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Inhibition of ERK phosphorylation in the basolateral amygdala has no effect on cocaine seeking after 30

days of withdrawal

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Induction of ERK phosphorylation in the central amygdala restores cocaine seeking after 1 day of

withdrawal

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Inhibition of ERK phosphorylation in the central amygdala reverses the effect of NMDA on cocaine seeking after 1 day

of withdrawal

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Blockade of NMDA receptors in the central amygdala attenuates cocaine seeking after 30

days of withdrawal

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Control experiment Inhibition of ERK phosphorylation in the central amygdala

has no effect on cocaine or high-fat food self-administration

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Conclusions and implications• The phenomenon of incubation of reward craving has important implications for the treatment of relapse to a range of

addictive disorders (drug addiction, excessive eating, gambling?)

• Our results suggest that time-dependent increases in the responsiveness of central amygdala ERK signaling pathway to cocaine cues mediate the incubation of cocaine craving

• Our results also suggest a novel function of activation of the ERK pathway in the amygdala in associative learning: enhancement of the motivational impact of learned reward cues

Lu L, Grimm JW, Hope BT, Shaham Y (2004) Incubation of cocaine craving after withdrawal: a review of preclinical data. Neuropharmacology 47S1: 214-227 (NIDA special issue)

Courtesy of Taco de Vries

Animal models and FACE validity

Acknowledgements

Former post-baccalaureate studentsShirley LiuJack Dempsey

Present post-baccalaureate students

Sarah GrayRobert BuschDeepti Nagarkar