Historically, development of successful treatments for various psychiatric conditions has been based on anunderstanding of the mechanisms mediating the condition. Similar principles have been applied to thetreatment of substance use disorders including alcohol drinking; a prime example is the elegant preclinicalclinicaldevelopmental profile of the use of naltrexone for reducing alcohol drinking. Evidence from ourongoing project in CTNA1 significantly adds to this literature and suggests that the efficacy of naltrexone ismoderated by the presence of a family history of alcoholism.The current proposal is based on initial evidence from our group suggesting that alcohol craving is alteredby the glutamatergic agent memantine. This follows preclinical evidence in the literature and clinicalevidence from other members of our group indicating that glutamatergic antagonists have alcohol-like effectsand that the presence of a family history of alcoholism alters the dysphoric effects of these agents.Therefore, we are now proposing to evaluate the efficacy of memantine in reducing alcohol drinking in alaboratory model of alcohol self-administration. This model has been developed and validated usingnaltrexone (O'Malley et al., 2002) and is currently used by our and other groups to screen medications. Inthe current proposal we will evaluate the effects of memantine on alcohol drinking behavior, alcohol cravingand stimulation/sedation in non-treatment seeking, alcohol-dependent heavy drinkers with either a positive ornegative family history of alcoholism. We will test the following specific aims:
Specific Aim 1 : To evaluatethe efficacy of seven days of pretreatment with one of three doses of memantine (placebo, 20 mg and 40mg/day) using a laboratory model consisting of exposure to a priming drink of alcohol and subsequent freechoicedrinking during a three-hour drinking period.
Specific Aim 2 : To evaluate the influence of familyhistory of alcoholism on the efficacy of memantine. Exploratory aims will also evaluate the presence of apolymorphism of the spinophillin gene as well impulsivity and delayed discounting measures as correlates ofalcohol responses, drinking behavior and memantine efficacy. Thus, the results of this proposal will providean initial signal regarding the potential clinical utility of memantine to reduce alcohol drinking in alcoholdependent individuals.
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