A murine model is proposed for evaluating potential therapeutic agents for alcohol abuse as to their efficacy in reducing ethanol consumption and altering its interoceptive effects. The proposed experiments will utilize C57BL/6 mice, recognized for their consumption of ethanol, to assess ethanol consumption in a limited access paradigm and its interoceptive effect utilizing an operant ethanol discrimination paradigm after treatment with three antagonists; naltrexone, broad spectrum opioid receptor antagonist; naltrindole, a relatively specific delta-opioid receptor antagonist; and MDL 72222, a relatively specific 5-HT3 receptor antagonist. The following hypotheses and related specific aims will be examined. HYPOTHESIS 1 is that broad spectrum opioid, delta-opioid, and 5-HT3 antagonists will reduce ethanol consumption and its interoceptive effects. Thus, Specific Aim 1 is to determine the dose-responsive effects of naltrexone, naltrindole, and MDL 72222 on ethanol consumption and discrimination. These experiments will include time course evaluations to insure optimal intervals between antagonist injection and ethanol test, and sufficient doses to estimate ED50s for each antagonist. HYPOTHESIS 2 is that opioid and 5-HT receptor antagonists will act synergistically to reduce the consumption of ethanol and its interoceptive effect.
Thus Specific Aim 2 is to compare the effects of naltexone + MDL 7222 and naltrindole + MDL 72222 combinations on ethanol consumption and discrimination with effects of each alone. Doses in the experiments will be selected to allow isobolographic evaluation for drug additivity and potentiation. HYPOTHESIS 3 is that withdrawal from chronic ethanol consumption will alter its interoceptive effects and that the alteration will be attenuated by opioid- and 5-HT3- antagonists.
Specific Aim 3 is thus to determine if withdrawal from chronic ethanol exposure alters its discriminability and if such alterations can be counter-acted by naltrexone, naltrindole, or MDL 72222. The experiment involves training mice to discriminate ethanol and then a comparing groups of chronic- ethanol-exposed mice with controls on ethanol discrimination either in the presence or absence of antagonist. Finally, HYPOTHESIS 4 is that withdrawal from chronic exposure to opioid- and 5-HT3- antagonists will alter the interoceptive effects of ethanol.
Specific Aim 4 is to determine if ethanol discrimination will be altered during withdrawal from chronic naltrexone, naltrindole, and MDL 72222. The experiment involves training mice to discriminate ethanol and then comparing groups chronically treated with vehicle or one of the antagonists during a re-test and reacquisition of the ethanol discrimination.
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