# Presentation: 666936

## Disrupting Reconsolidation of Drug Memories: Potential Treatment Target for Attenuating Drug-Seeking and Relapse Elicited by Drug-Associated StimuliBarry Everitt and Jonathan LeeDepartment of Experimental PsychologyUniversity of Cambridge

- Frontiers in Addiction Research
- NIDA Mini-Convention, 2005

## Acknowledgements

**Jonathan Lee**
**	****Kerrie Thomas****	****Pat Di Ciano**
**	****Jeremy Hall****	****Mercedes Arroyo**
**	****Trevor Robbins****	****Tony Dickinson**
**	****Amy Milton ****	****Yann Pelloux**
**	****Caroline Parkinson****	****David Theobald**
**	****Funded by Medical Research Council**
**	**

## Fear Memory Reconsolidation Retrieval-dependent amnesia (Nader et al. 2000, Nature 406 722-6)Amnesia for fully-consolidated memories: Protein synthesis-dependent process

***increased zif*****268 expression on retrieval of cued and contextual fear**** **

**Hall et al., J. Neurosci (2001)**

**Fear Memory Reconsolidation**** ****Retrieval-dependent amnesia (**Nader et al. 2000, *Nature* **406** 722-6**)****Amnesia for fully-consolidated memories: Protein synthesis-dependent process**

## Fear Memory Reconsolidation

**Fear CS re-exposure induces**
***Zif268 ***** in the amygdala**
- (Hall et al. J. Neurosci 2001)
***Zif268 *****ASO knockdown of Zif268**
**in the amygdala blocks CS fear **
**memory reconsolidation**
- (Lee et al. Neuron 2005)

**Fear context re-exposure induces**
***Zif268 ***** in the hippocampus**
- (Hall et al. Nature Neurosci 2000)
***Zif268 *****ASO knockdown of Zif268**
**in the hippocampus (CA1) and blocks **
**context fear memory reconsolidation**
- (Lee et al. Science, 2004)

**Notes:**
History
BLA!
PR-STM vs. PR-LTM

## Zif268 is also upregulated in the amygdala following exposure to cocaine-associated CSs 

**Is *****Zif268***** in the BLA required for the reconsolidation of drug CS memories?**
**Will blockade of *****Zif268***** expression in the BLA reduce the impact of drug conditioned cues on drug seeking and relapse?**

- Thomas et al (2003)

** **

*******

**% change from baseline**

**Saline**

**Pavlovian**

**Saline**

**Pavlovian**

**Unpaired**

**Unpaired**

******

## Drug CSs, drug memories addiction

**Drug-associated stimuli in humans:**
**Induce memories of prior drug experiences, craving and relapse**
**Drug-associated stimuli in animals & humans :**
**reinforce the acquisition of new drug seeking repertoires**
**maintain drug seeking**
**induce relapse to drug seeking**

**But extinction of drug cues has not been **
**a successful treatment strategy.**
**Can the original association be disrupted **
**by blocking drug memory reconsolidation?**

**Notes:**
Mention ANR & responding in absence of drug

## Three methods of assessing the effect of Zif268

**knockdown in the BLA on CS-cocaine memory **
**reconsolidation **

**Focus on conditioned reinforcing effects of cocaine CSs **
**Focus on the SELF-administration of cocaine and substantial N****os**** of **
**	****cocaine-CS pairings (200-600) c.f. conditioned fear or CPP studies (1-5) so as **
**	****to realistically approach the problem of manipulating drug memory reconsolidation.**

**Acquisition of a new drug-seeking response**
**Drug seeking under a 2nd-order schedule of cocaine reinforcement **
**	****and its reinstatement after extinction**
**3.****	****“Relapse” to drug taking (Shaham: no instrumental extinction)**

## Acquisition of a new response

**Acquisition of a new response**
**with conditioned reinforcement:**
**Effect of BLA zif268 knockdown**
**at memory reactivation**

## Zif268 knockdown in the BLA during drug memory reconsolidation prevents the acquisition of a new drug seeking response with conditioned reinforcement 

**Intra-BLA Zif268 antisense disrupts the reconsolidation of a   CS-cocaine association.**
**Blockade of drug memory reconsolidation reduces the conditioned reinforcing properties of a cocaine-associated CS, and abolishes its ability to support new learning.**

**Notes:**
Mention lack of effect on nps – no reconsolidation of instrumental learning

## Cocaine-seeking behaviour:

**Cocaine-seeking behaviour:**
**Second-order schedule of cocaine reinforcement**

## Summary and Conclusions

**  ****Drug memories elicited by presentation of a cocaine-associated CS reconsolidate**
**  ****Drug memory reconsolidation requires Zif268 expression in the amygdala**
**  ****Molecular commonality in fear and drug memory reconsolidation.**

**Blocking drug memory reconsolidation:**
**  ****Prevents the acquisition of new drug seeking responses**
**  ****Impairs the maintenance of cocaine seeking**
**  ****Reduces relapse to drug seeking**
**Each of which depends upon the conditioned reinforcing **
**properties of a cocaine-associated conditioned reinforcer**

## Summary and Conclusions

**But need to understand:**** **
**Limits and limitations of memory reconsolidation as a therapeutic target.**
**Possible reconsolidation of other memories at other sites within limbic cortical-ventral striatopallidal systems**
**Underlying molecular and neurochemical mechanisms**

**Summary and Conclusions**

## Acknowledgements

**Jonathan Lee**
**	****Kerrie Thomas****	****Pat Di Ciano**
**	****Jeremy Hall****	****Mercedes Arroyo**
**	****Trevor Robbins****	****Tony Dickinson**
**	****Yann Pelloux****	****Amy Milton**
**	****Caroline Parkinson****	****David Theobald**
**	****Funded by UK Medical Research Council**
**	**