Determining the neurobiological basis of relapse to cocaine use is a primary mission of the Neurobiology of Addiction Research Center (NARC), with the goal to identify novel drug targets. The Animal Core will provide animals to all projects that have been trained and extinguished or are abstinent from cocaine selfadministration. The goal of Project 1 is to evaluate neuroplasticity in subcompartments of the nucleus accumbens induced by extinction training or homecage abstinence after cocaine self-administration. The three primary measures of neuroplasticity include, 1) levels of proteins related to glutamate homeostasis, actin cycling and postsynaptic glutamate signaling, 2) density of dendritic spines, and 3) presence or absence of longterm potentiation and longterm depression measured as field potential amplitude in the accumbens after stimulating the prefrontal cortex. It is proposed that by comparing multiple modalities, a cause and effect relationship will become apparent that will help other NARC projects focus on the most important aspects of neuroplasticity to use as drug development targets and/or as endpoints to screen for potential therapies. In addition to estimates of basal neuroplasticity associated with withdrawal from cocaine self-administration, cocaine-seeking will be induced by the drug context or cocaine itself, and associated neuroadaptations quantified. Preliminary data are presented to suggest that not only are there marked neuroplastic changes in protein content, dendritic spine morphology and LTP/LTD after withdrawal from cocaine self-administration, but rapid neuroplastic changes are also induced during cocaine-seeking. Another important goal is to integrate Project 1 with the other projects of the NARC by serving to screen new drugs emerging from these projects against the profile of protein, morphological and electrophysiological plasticity. It is proposed that neuroadaptations reversed by drugs shown behaviorally effective at blocking cocaine-seeking will be likely targets for future drug development. This reverse translation from behavior to molecules is a novel aspect of the NARC and should focus our ability to identify neuroplasticity relevant to cocaine-seeking versus other neuroadaptations related to separate aspects of chronic cocaine administration.
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