The proposed experiments utilize a C57BL/6 murine model to determine the influence of potential therapeutic agents for alcohol abuse on the rewarding effect of ethanol and ethanol conditioned stimuli as well as accompanying changes in mesoaccumbens dopamine (DA). Experiments will test the general hypothesis that drugs which influence mesolimbic DA system function will 1) reduce the reinforcing effects of ethanol conditioned stimuli; and 2) attenuate the changes in mesoaccumbens DA function involved with mediating these effects. The drugs to be evaluated initially include SCH 39166, a dopamine D1 receptor antagonist, and drugs which indirectly influence mesolimbic system transmission via their action via their action on other neural systems. Indirect acting agents include: Nalmefene, which has specifically of the mu-opioid receptor; Ondansetron which has high specificity for the 5-HT3 receptor; Vigabatrin, a gamma-aminobutyric acid transaminase inhibitor, and Topiramate, an AMPA glutamate antagonist.. The compounds are used clinically, alter dopaminergic transmission, and preliminary data indicate they can reduce self administration of ethanol and other abused substances in rodents. Behavioral measures, all used during the initial grant period to evaluate naltrexone effects on ethanol reward, include: 1) lever responding for 12% ethanol and 2) voluntary ethanol consumption in a free access paradigm as measures of ethanol reward; and 3) ethanol place conditioning as a measure of ethanol conditioned stimuli effects. Possible adverse effects of the agents will be determined by examining their effects on food and water reward, on food and water ingestion, and whether or not they produce conditioned place aversion at doses which reduce ethanol reward. Proposed microdialysis experiments will assess changes in mesolimbic DA function associated with the rewarding effects of ethanol and ethanol conditioned stimuli, as well as their modulation by potential therapeutic agents. The proposed research contributes to the development of pharmacotherapy for alcohol abuse by examining the effect of compounds acting upon different transmitter systems on neurochemical and behavioral parameters associated with the regarding effects of ethanol and ethanol conditioned stimuli, and sets the stage for future studies.
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