While a relationship between dopamine and ethanol is widely accepted, this interaction remains relatively undocumented in primates, including humans. The proposed research is critical to the understanding of factors influencing the association between ethanol reinforcement and midbrain dopamine response. Background studies suggest that one mechanism by which ethanol can affect dopaminergic function if through modulation of GABAergic tone in the central nervous system. It is known that the endogenous neurosteroid allopregnanolone acts as a positive modulator of GABAA/benzodiazepine receptors and shares significant overlap with ethanol in producing similar discriminative stimulus effects. There is also evidence that there may be a sex difference in sensitivity to the ethanol-like stimulus effects of allopreganolone. Based on our current knowledge of the interactions between ethanol, dopamine and neurosteroids we hypothesize that we can use positron emission tomography (PET) to document ethanol's increase synaptic dopamine under acute exposure and that these effects of ethanol will be mimicked by allopregnanolone. Further, we hypothesize that chronic ethanol self-administration of ethanol will result in a neuroadaptation of dopaminergic response, reflected in a functional down-regulation of D2 receptor availability. Finally, we hypothesize that the neuroadaptation to ethanol will be slowly reversed by abstinence from ethanol self-administration. With this model and the proposed PET methodology, we can explore neuroadaptation of midbrain dopamine neurons to chronic ethanol self-administration in a longitudinal study. Thus, this research provides a critical step in the understanding the mechanisms underlying the association between dopamine and ethanol reinforcement.
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