Due to the modest effect of current pharmacotherapies, more effective treatments must be developed to optimally treat alcohol dependent patients. Treatments combining pharmacotherapies with different mechanisms of action may better address the diverse neurobiology of alcohol and the heterogeneity of alcoholics. Aripiprazole (APZ), a partial dopamine agonist, effects dopamine and serotonin receptors without the limiting side effects seen with other atypical antipsychotics. Dopamine medicate reward based drinking and craving. Topi ram ate (TPMT), an antiepileptic, affects glutamate and GABA-A receptors and shows promise in reducing heavy drinking. Glutamate and GABA may mediate relief-based drinking and protracted withdrawal. Despite strong evidence that multiple neurotransmitters contribute to alcoholism, few studies have used two medications with such a diverse combination of actions to examine a potential synergistic effect on reducing alcohol consumption. The primary aims are to: (1) determine if APZ and TPMT are each more effective than placebo, and the combination of APZ and TPMT is more effective than either drug alone or placebo, in reducing alcohol use in non-treatment seeking alcohol dependent subjects in an alcohol selfadministration experiment (ASAE);(2) examine a hypothesized dose-response for two doses of APZ (20mg/d and 30 mg/d) and an established dose TPMT (300mg/d);(3) examine the putative mechanisms of action of APZ, TPMT alone and together on craving, subjective stimulation, candidate gene influences and other behavioral effects associated with alcohol consumption;and (4) establish the safety of giving APZ and TPMT together. We will use of a 3 X 2 drug (20mg, 30mg APZ vs. placebo) by drug (SOOmg TPMT vs. placebo) between-subjects factorial design. Nonabstinent, non-treatment seeking, alcohol dependent persons (N=216) will be recruited from the community and randomly assigned to one of 6 cells. Subjects drinking and safety is monitored over a 5-week titration to their target dose, leading to an in-laboratory alcohol self administration session, during which clinical and behavioral effects are assessed during access to alcohol. A 1 month follow-up assesses adverse events and drinking. The long term objectives of this research are to improve medications available for alcoholism treatment and inform research and theory on the mechanisms of action of such medications.
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