Family History and Spinophilin Genotype Influence on NMDA Receptor Function and EthanolResponseIn the CTNA Overview, we hypothesize that disturbances in the interplay of glutamate and dopaminesystems contribute to the vulnerability to alcohol dependence by: 1) impairing the normal engagement ofreward/motivation circuitry and thereby increasing the relative motivational impact of alcohol-relatedrewards; and 2) by shifting the reward valence of the N-methyl-D aspartate (NMDA) glutamate receptorantagonist component of ethanol action toward reward, making ethanol a more addictive substance forthose at risk. Project 3 will explore the latter hypothesis by evaluating whether increases in NMDA receptorfunction associated with a family history of alcohol dependence are associated with changes in the 'rewardvalence' of ethanol. In this study, NMDA receptor function, assessed by evaluating the response to theNMDA receptor antagonist ketamine, and ethanol response, assessed using the ethanol 'clamp' procedure(to minimize the impact of pharmacokinetic variability), will be determined. By exploring the relationshipbetween ketamine and ethanol response, we can examine the extent to which NMDA receptor antagonismcontributes to the balance of the positive (stimulant, euphoric) and negative (sedative, dysphoric) effects ofethanol, i.e. its reward valence.A family history of alcoholism is a risk factor for the development of alcohol dependence. Acomponent of the familial risk for alcoholism appears to be expressed as a change in the reward valence toethanol effects. This study will test the hypothesis that both ketamine and alcohol response will be similarlyinfluenced by family history of alcoholism within subjects. If so, it would suggest that heritable factorsinfluencing NMDA receptor function contribute to one of the most important biomarkers for the heritable riskfor alcohol dependence. Further, this study will begin to explore the impact of variation in genes thatcontribute to alterations in NMDA receptor function associated with the familial vulnerability to alcoholdependence.
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