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.
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.
|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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