There is increasing evidence that the endogenous opiate and serotonin systems are involved in the experience of alcohol effects and in the maintenance of alcohol consumption. The opiate antagonist drug, naltrexone, and the serotonin receptor type 3 antagonist drug, ondansetron, have reported utility in reducing alcohol consumption in animals and man. Despite strong evidence of the clinical efficacy of naltrexone, not everyone benefits, and relapse is common. Similar to poly-etiologic conditions such as hypertension and cancer, it would make sense to combine drugs of different actions to enhance alcoholism treatment effectiveness. While prospective treatment trials in alcoholism are the only definitive method for evaluating the utility of medications for the treatment of this condition, these trials are costly, time consuming, and with chronic exposure, put patients at risk for adverse effects. We propose to examine the combined effects of naltrexone and ondansetron on alcohol reactivity in an acute paradigm as a first step toward understanding the potential efficacy of combining these medications in clinical trials. The proposed study will be a randomized placebo controlled comparison of the ability of naltrexone, ondansetron or their combination, to alter alcohol consumption and reactivity utilizing 1) natural observation 2) alcohol cue brain imaging 3) an acute administration of alcohol and 4) consumption of alcohol in a limited-access paradigm. Non-treatment seeking alcoholics (N=160) and social drinkers (N=16 as procedure controls) will be randomly assigned to take placebo, naltrexone, ondansetron or the combination for 8 days. A subset of individuals in each medication group will participate in an alcohol cue brain imaging (fMRI) paradigm on day seven. On the eight day all subjects will ingest a fixed dose of the beverage of their choice followed by a limited-cell alcohol consumption period. Regional brain activity changes (cue stimulation), alcohol stimulation (pharmacological), and motivated consumption (cognitive control and craving) will be assessed. Subjects will be paid for their participation and alcoholic individuals will undergo a brief motivation counseling session at the end of the protocol to educate them about the risk of heavy alcohol consumption and motivate them to reduce drinking or seek treatment.
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