# Presentation: 477863

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

- Behavioral Neuroscience Branch
- IRP/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 priming**
**Drug cues**
**Stress**

- Responses

- Self-administration training

- Extinction

- TESTING

- Drug is available

- Drug is NOT available

- Active lever

- Inactive lever

## 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)

## 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

**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

- Context B

- Context A

- Context A

- Context A

- Context A

- No 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)

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

- Bossert et al. _The Journal of Neuroscience_, in press

## Control experiments

- SN

**Lever presses for a 5% sucrose solution**

- 0

- 25

- 50

- 75

- 100

- 0

- 1

- 3

- 6

- LY379268 dose
- (mg/kg, i.p)

- Rewards (30 min)

- *

- 0

- 15

- 30

- 45

- 60

- 75

- Responses (3 h)

- Vehicle

- 1.0 μg

- Extinction
- (Context B)

- 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

## Role of central amygdala ERK and glutamate in incubation of cocaine cravingDr. Lin LuCollaborator: Dr. Bruce Hope

**Role of central amygdala ERK and glutamate in incubation of cocaine craving**Dr. Lin LuCollaborator: Dr. Bruce Hope

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

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

- 1 day
- 2 days
- 4 days
- 7 days
- 15 days
- 29 days
- 60 days

**Training phase**

**Withdrawal **
**phase**

**Test phase**
- (drug is NOT available)

- 0

- 20

- 40

- 60

- 80

- 1

- 2

- 3

- 4

- 5

- 6

- 7

- 8

- 9

- 10

- Day

- Tone+light cue

- (n=67)

- Tone+light cue

- No T+L

- 6-8
- 60-min
- sessions

- Infusions (6 h)

- “Extinction” + Testing** (same day)**

**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

- Withdrawal period in
- home cage prior
- to extinction tests

## Experiment 1: activation of amygdala ERK by cocaine cues

**Withdrawal period: **day 1 versus day 30
**Test condition: **no cue versus cue exposure (30 min extinction test)

**Experiment 1: activation of amygdala ERK by cocaine cues**

## Behavioral data: Training and extinction test

**Behavioral data: Training and extinction test**

- Lu, Hope et al. Submitted

## Exposure to cocaine cues increases ERK phosphorylation in the central amygdala after 30 days of withdrawal

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

- NMDA
- receptor

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

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

- NMDA
- receptor

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

- ERK

- MEK

- Raf

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

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

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

- NMDA
- receptor

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

- ERK

- MEK

- Raf

**AP-5**

- NMDA
- receptor

## Food self-administration

**Food self-administration**

- 0

- 40

- 80

- 120

- 160

- 1

- 2

- 3

- 4

- 5

- 6

- hour

**Cocaine self-administration**

- Vehicle

- U0126

- 0

- 10

- 20

- 30

- 40

- hour

- Lever responses

_**Control experiment**_** ****Inhibition of ERK phosphorylation in the ****central amygdala**** ****has **_**no effect**_** on cocaine or high-fat food self-administration**

## 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)

## Animal models and FACE validity

- Courtesy of Taco de Vries

## AcknowledgementsFormer post-baccalaureate studentsShirley LiuJack DempseyPresent post-baccalaureate students Sarah GrayRobert BuschDeepti Nagarkar