ETHANOL MODIFICATION OF NEUROTRANSMITTER RECEPTOR

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Ethanol selectively alters the function of neurotransmitter and neuromodulator receptors in the CNS. These changes may contribute to the acute, intoxicating effects of ethanol, and adaptations in receptor function may be associated with ethanol tolerance and/or physical dependence. The imidazobenzodiazepine, Ro15-4513, a putative ethanol antagonist, was used to assess the role of the GABA/benzodiazepine receptor in the acute effects of ethanol. Ro15-4513 reduced the incoordinating, but not the hypothermic effect of ethanol in mice, indicating the certain of ethanol's actions may involve the GABA receptor complex. Biochemical and behavioral methods were used to determine the role of receptor-coupled adenylate cyclase (AC) systems in ethanol's effects. In mouse cerebral cortex, low concentrations of ethanol in vitro stimulated isoproterenol- sensitive AC activity and altered high-affinity agonist binding. The data suggested that ethanol affected Gs, the guanine nucleotide binding protein. In ethanol tolerant/dependent animals, high-affinity agonist binding was undetectable, and stimulation of AC activity by isoproterenol and other agonists was reduced, reminiscent of changes that occur during heterologous desensitization, and that may involve a change in G-protein function. Analysis of cortical G-proteins in these animals by cholera toxin and pertussis toxin-induced 32P-ADP ribosylation and SDS-PAGE revealed a selective decrease in the amount of Gs. The potential importance of adenylate cyclase activity in neuroadaptation to ethanol was suggested by the finding that administration of forskolin, which stimulates brain AC activity, overcame the blockade of tolerance development produced by norepinephrine depletion. Chronic ethanol ingestion produced different changes in beta-adrenergic receptor characteristics in cerebellum (primarily beta-2 receptors) than in cortex and hippocampus (primarily beta-1), suggesting that ethanol affects the coupling of these receptor subtypes, and/or regional G-protein characteristics, in a selective manner. Chronic ethanol ingestion also selectively reduced the number of mu opiate receptors in cerebral cortex.