The discriminative stimulus properties of alcohol may contribute to its abuse and addiction potential in humans. Animal models of alcohol discrimination have indicated the involvement of serotonin (5-HT) receptors, including the G/i/o-coupled 5-HT/lB/D receptors, in mediating the discriminative stimulus properties of alcohol. The main hypothesis of the proposed pilot study is that the acquisition of ethanol discrimination in rats is associated with changes in 5-HT/l receptor activity. A technique has been developed in our laboratory, whereby receptor-coupled G-protein activity is measured by agonist-stimulated [35S]GTPgammaS autoradiography in tissue sections. This technique allows quantification of the biochemical activity of G-protein-coupled receptors with a high degree of anatomical resolution. This methodology is ideally suited to the study of the effects of the acquisition of ethanol discrimination on 5-HT1 receptor-coupled G-protein activity. Regions where changes in 5-HT1 receptor-coupled G-protein activity are observed autoradiographically will be dissected, and more quantitative biochemical and pharmacological analysis will be performed using both agonist-stimulated [35S]GTPgammaS binding and receptor binding in membranes. This approach, which combines behavioral pharmacology with neuroanatomy and signal transduction biochemistry, may elucidate the neuroadaptive role of 5-HTl receptors in the development of ethanol discrimination. This pilot project directly addresses the Center aims regarding the possible cellular mechanisms underlying ethanol's discriminative stimulus effects. It will provide import pilot data that can supplement the studies performed in Project 3 of the Center, as well as provide information for the R01 work conducted by Dr. Grant.
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