Alcoholism is a substantial medical and social problem in the U.S. and relapse represents a majorchallenge to treatment efforts. Currently, there is no therapeutic intervention that is fully satisfactory inpreventing relapse and sustaining abstinence. While dependence is known to contribute to the problem ofrelapse, this issue has not been thoroughly studied. The focus and overall objective of this proposal is toutilize a mouse model of EtOH dependence and relapse to evaluate the ability of pharmacotherapies toreduce voluntary EtOH drinking, as well as neurochemical alterations that may underlie motivation todrink in dependent compared to non-dependent animals. A contemporary view of alcohol and drugaddiction indicates that activation of different neurochemical systems within the brain reward ('motive')circuitry play a critical role in establishing the initial reinforcing effects of EtOH, as well as shapingmotivational forces that perpetuate EtOH use/abuse during later stages in addiction. The mesolimbicdopamine pathway, with the nucleus accumbens being a key target structure, is a prominent componentof this circuitry. Among several neurotransmitter systems that impinge on this dopamine pathway,glutamate transmission has emerged as a key player in contributing to the motivational effects of EtOH. Aguiding principle of this proposal is that activation of the mesolimbic dopamine pathway plays an importantrole in establishing the acute reinforcing properties of EtOH, while adaptive changes in dopamine andglutamate transmission contribute to conditions that promote relapse and engender excessive EtOHdrinking behavior characteristic of dependence. The research plan entails use of in vivo microdialysisprocedures to characterize changes in extracellular levels of dopamine and glutamate in nucleusaccumbens associated with voluntary EtOH drinking, as well as evaluation of various pharmacologicalagents for their ability to influence concomitant measures of behavior (drinking) and associatedneurochemical changes in the model of dependence and relapse. The overall goal of the proposal is toprovide new information about neural substrates underlying EtOH drinking in dependent compared to nondependentsubjects, as well as evaluate the ability of potential pharmacotherapeutics to impact bothneurochemical and behavioral (drinking) changes related to dependence and relapse.
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