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NMDA Antagonist Efficacy in Reducing Human Alcohol Consumption: Impact of Family History

(S. Krishnan-Sarin)

CTNA-1 described evidence that enhanced NMDA receptor function associated with alcohol dependence may increase risk for heavy drinking. This project evaluates the dose-related efficacy of memantine in reducing alcohol consumption in FHP/FHN alcohol dependent patients. It also tests whether memantine, perhaps through “normalizing” NMDA receptor function, reduces alcohol cue-induced craving. Building on previous studies, we will explore the modifying effects of familial alcoholism history. The evaluation of delay discounting, impulsivity and ventral striatal activation in these patients will enable us to explore the hypothesis that normalization of NMDA receptor function in these patients reduces risk for heavy drinking related to disturbances in motivational circuitry common to alcoholism and other substance abuse disorders. In contrast, the ability of memantine to change the subjective response to ethanol will enable CTNA-2 to explore risk factors for alcoholism that may be unique to the pharmacodynamic actions of ethanol. Our pilot data also raise the possibility that spinophilin genotype may influence both common and unique alcoholism risk mechanisms.


To evaluate the interactive effects of FH of alcoholism and the NMDA antagonist memantine on alcohol drinking in alcohol dependent heavy drinkers, using a human laboratory alcohol self-administration paradigm. The paradigm, that has been previously used in numerous projects (e.g. O’Malley et al., 2002; Anton et al., 2004; Drobes et al., 2003; Krishnan-Sarin et al, under review) involves administration of a priming drink of alcohol followed by three hour alcohol self-administration session. This double blind, placebo-controlled study will examine the effects of memantine on behavioral measures related to alcohol self-administration in alcohol dependent heavy drinkers with positive or negative family history of alcoholism (FHP and FHN). Within each family history group, subjects will be randomized to one of three doses of memantine (placebo, 20 mg/day or 40 mg/day).