During drug abstinence, re-exposure to cues previously associated with cocaine often trigger drug relapse. In rodent models of cocaine seeking and relapse, animals that self-administer cocaine in the presence of contingent cues often establish a strong association between cues and cocaine, such that after drug withdrawal, the presence of cues induces strong cocaine seeking. Cue-induced cocaine seeking is extremely long-lasting and intensifies progressively after withdrawal. The goal of this application is to develop new concepts and approaches through which the cue-cocaine association can be disrupted to reduce cocaine relapse. The cue-cocaine association that drives cocaine seeking shares general features of cue-conditioned memories. Similar to classic conditioning memories, cue-conditioned drug memories also undergo a destabilization and reconsolidation process after retrieval. During the brief destabilization time window, amnesic treatments are often more effective in reducing subsequent cue-induced cocaine seeking. However, the neural substrates that mediate cue-drug memory retrieval and reconsolidation remain elusive. Targeting this knowledge gap, this application focuses on cocaine-generated silent synapses and their dynamic changes within the basolateral amygdala (BLA) to nucleus accumbens (NAc) projection. We recently showed that cocaine self-administration generates silent synapses in the BLA-to-NAc projection. Silent synapses are excitatory synapses that contain NMDA receptors without stable AMPA receptors (AMPARs). Our additional results suggest that cocaine-generated silent synapses may serve as the initial hubs to establish a potentially new set of circuits. After cocaine withdrawal, BLA-to-NAc silent synapses become `un-silenced' by recruiting calcium-permeable AMPARs (CP-AMPARs), resulting in consolidation of the silent synapse-imbedded circuits. Reversing the un-silencing of BLA-to-NAc silent synapses decreases cue-induced cocaine seeking. These results suggest that the newly formed, silent synapse-embedded BLA-to-NAc projections contribute to the establishment and subsequent consolidation of cue-cocaine association. Based on extensive preliminary results, we hypothesize that after cocaine withdrawal, a brief re-exposure to cocaine-associated cues instantly induces CP-AMPAR internalization and re-silences the same set of BLA-to-NAc silent synapses that are generated by cocaine self-administration, contributing to the destabilization of cue-cocaine association. These re-silenced synapses are un-silenced again by re-recruiting CP-AMPARs hours after cue re-exposure, contributing to reconsolidation of cue-cocaine association. We will use electrophysiology, optogenetics, in vivo calcium imaging, viral-mediated gene transfer, and operant behavioral assays to test this hypothesis. By accomplishing the proposed work, we may identify a cellular and circuit basis underlying destabilization and reconsolidation of cue-cocaine association after retrieval and validate therapeutic angles to reduce cocaine relapse. Thus, objectives of this application are highly relevant to the missions of the NIDA, NIH.

Public Health Relevance

Cue-induced cocaine seeking precipitates cocaine relapse, which is partially mediated by generation and subsequent maturation of AMPA receptor-silent excitatory synapses within the amygdala-to-accumbens projection. The proposed work will test the hypothesis that upon cue re-exposure after cocaine withdrawal, matured silent synapses become re-silenced and destabilized for ~6 hours within this projection, thus providing a manipulation window to disrupt the cue-cocaine association and decrease cue-induced cocaine relapse. The expected outcomes of this proposal will provide a circuitry-based understanding of cue-induced cocaine relapse and a set of targetable substrates for clinical treatment of cocaine addiction.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Method to Extend Research in Time (MERIT) Award (R37)
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Special Emphasis Panel (ZRG1)
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Sorensen, Roger
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University of Pittsburgh
Schools of Arts and Sciences
United States
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Wright, William J; Dong, Yan (2018) Intrinsic Excitability of Cocaine-Associated Memories. Neuropsychopharmacology 43:675-676
Koya, Eisuke; Dong, Yan (2018) Sound of silent synapses from the addicted hippocampus. Neuropsychopharmacology 43:1981-1982
Cahill, Michael E; Browne, Caleb J; Wang, Junshi et al. (2018) Withdrawal from repeated morphine administration augments expression of the RhoA network in the nucleus accumbens to control synaptic structure. J Neurochem 147:84-98
Graziane, Nicholas M; Neumann, Peter A; Dong, Yan (2018) A Focus on Reward Prediction and the Lateral Habenula: Functional Alterations and the Behavioral Outcomes Induced by Drugs of Abuse. Front Synaptic Neurosci 10:12
Wang, Junshi; Ishikawa, Masago; Yang, Yue et al. (2018) Cascades of Homeostatic Dysregulation Promote Incubation of Cocaine Craving. J Neurosci 38:4316-4328
Labonté, Benoit; Engmann, Olivia; Purushothaman, Immanuel et al. (2017) Sex-specific transcriptional signatures in human depression. Nat Med 23:1102-1111
Wright, William J; Schlüter, Oliver M; Dong, Yan (2017) A Feedforward Inhibitory Circuit Mediated by CB1-Expressing Fast-Spiking Interneurons in the Nucleus Accumbens. Neuropsychopharmacology 42:1146-1156
Dong, Yan; Taylor, Jane R; Wolf, Marina E et al. (2017) Circuit and Synaptic Plasticity Mechanisms of Drug Relapse. J Neurosci 37:10867-10876
Wright, William J; Dong, Yan (2017) Tipping the Scales Toward Addiction. Biol Psychiatry 81:903-904
Liu, Yanling; Cui, Lei; Schwarz, Martin K et al. (2017) Adrenergic Gate Release for Spike Timing-Dependent Synaptic Potentiation. Neuron 93:394-408

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