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

Acknowledgements Jonathan Lee Kerrie ThomasPat Di Ciano Jeremy HallMercedes Arroyo Trevor RobbinsTony Dickinson Amy Milton Yann Pelloux Caroline ParkinsonDavid Theobald Funded by Medical Research Council

increased zif268 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 ) Amnesia for fully-consolidated memories: Protein synthesis-dependent process

Fear Memory Reconsolidation ActiveInactive 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)

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) Basal amygdala Lateral amygdala *** % change from baseline Saline Pavlovian Saline Pavlovian Unpaired **

Drug CSs, drug memories addiction Childress et al. (1999) 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?

Three methods of assessing the effect of Zif268 knockdown in the BLA on CS-cocaine memory reconsolidation 1.Focus on conditioned reinforcing effects of cocaine CSs 2.Focus on the SELF-administration of cocaine and substantial N os of cocaine-CS pairings ( ) c.f. conditioned fear or CPP studies (1-5) so as to realistically approach the problem of manipulating drug memory reconsolidation. 1.Acquisition of a new drug-seeking response 2.Drug seeking under a 2nd-order schedule of cocaine reinforcement and its reinstatement after extinction 3.“Relapse” to drug taking (Shaham: no instrumental extinction)

Light-CS+ Approach location nose poke delivers i.v. cocaine Pavlovian conditioning phase CRf lever NCRf lever Light-CRf X Acquisition of a new response phase Acquisition of a new response with conditioned reinforcement: Effect of BLA zif268 knockdown at memory reactivation Zif268 antisense or missense infusion into the BLA 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. Lee et al MSO ASO ReactivatedNon-reactivated

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

Reconsolidation blockade: a potentially powerful and novel approach to the treatment of drug addiction, especially relapse. 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 ThomasPat Di Ciano Jeremy HallMercedes Arroyo Trevor RobbinsTony Dickinson Yann PellouxAmy Milton Caroline ParkinsonDavid Theobald Funded by UK Medical Research Council