Ethanol, NMDA Receptor and Dopamine Interactions

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DESCRIPTION (provided by applicant): The cellular mechanisms that mediate the intoxicating and reinforcing effects of ethanol are not clearly understood. One of the many neuronal targets of ethanol is the NMDA subtype of excitatory glutamate receptors. Many studies have demonstrated that ethanol acutely inhibits NMDA receptor function. This inhibition may be involved in behavioral sensitivity to ethanol effects. In addition, inhibition of NMDA receptor function has been shown to elevate dopamine (DA) system activity. Considerable evidence supports the hypothesis that increased mesolimbic DA system activity is one of the important components of the reinforcing effects of many drugs of abuse, including ethanol. Inhibition of NMDA receptors leads to DA system activation in several brain areas. Interestingly, few studies have demonstrated that ethanol inhibition of NMDA receptors may play a central role in elevating DA levels. The overall hypothesis guiding this research is that ethanol inhibition of NMDA receptor activity may represent an important mechanism through which ethanol elevates DA in the nucleus accumbens. The main approaches to be used to test this hypothesis include microdialysis and voltammetry studies of DA function following acute and chronic administration of MK-801 and ethanol to normal (wild-type) mice and mice with a genetic deficit in NMDA receptors. These models of reduced NMDA receptor function will be used to evaluate dopamine system function in an addiction-related brain area, the nucleus accumbens. From these studies we hope to gain insights into the receptor mechanisms involved in alcohol action.