Determining the neurobiological basis of relapse to cocaine use is a primary mission of the Neurobiologyof Addiction Research Center (NARC), with the goal to identify novel drug targets. The Animal Core willprovide 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 nucleusaccumbens induced by extinction training or homecage abstinence after cocaine self-administration. Thethree 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 orabsence of longterm potentiation and longterm depression measured as field potential amplitude in theaccumbens after stimulating the prefrontal cortex. It is proposed that by comparing multiple modalities, acause and effect relationship will become apparent that will help other NARC projects focus on the mostimportant aspects of neuroplasticity to use as drug development targets and/or as endpoints to screen forpotential therapies. In addition to estimates of basal neuroplasticity associated with withdrawal from cocaineself-administration, cocaine-seeking will be induced by the drug context or cocaine itself, and associatedneuroadaptations quantified. Preliminary data are presented to suggest that not only are there markedneuroplastic changes in protein content, dendritic spine morphology and LTP/LTD after withdrawal fromcocaine 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 screennew drugs emerging from these projects against the profile of protein, morphological andelectrophysiological plasticity. It is proposed that neuroadaptations reversed by drugs shown behaviorallyeffective at blocking cocaine-seeking will be likely targets for future drug development. This reversetranslation from behavior to molecules is a novel aspect of the NARC and should focus our ability to identifyneuroplasticity relevant to cocaine-seeking versus other neuroadaptations related to separate aspects ofchronic cocaine administration.
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