Disrupting Reconsolidation of Drug Memories: Potential Treatment Target for

Attenuating Drug-Seeking and Relapse Elicited by Drug-Associated Stimuli

Barry Everitt and Jonathan LeeDepartment of Experimental Psychology

University of Cambridge

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

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 406 722-6)

Amnesia for fully-consolidated memories: Protein synthesis-dependent process

Fear Memory Reconsolidation

Active Inactive

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Fear CS re-exposure inducesZif268 in the amygdala(Hall et al. J. Neurosci 2001)

Zif268 ASO knockdown of Zif268in the amygdala blocks CS fear memory reconsolidation(Lee et al. Neuron 2005)

Fear context re-exposure inducesZif268 in the hippocampus(Hall et al. Nature Neurosci 2000)

Zif268 ASO knockdown of Zif268in 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)

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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 Zif268knockdown 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 Nos 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.

1. Acquisition of a new drug-seeking response2. Drug seeking under a 2nd-order schedule of cocaine reinforcement

and its reinstatement after extinction3. “Relapse” to drug taking (Shaham: no instrumental extinction)

Light-CS+

Approach locationnose poke delivers

i.v. cocaine

Pavlovian conditioningphase

CRf lever

NCRf lever

Light-CRf

X

Acquisition of a newresponse phase

Acquisition of a new responsewith conditioned reinforcement:

Effect of BLA zif268 knockdownat memory reactivation

Zif268 antisense ormissense infusioninto 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. 2005

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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 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