The effects of ethanol on several neurotransmitter receptor-effector coupling systems were investigated in order to elucidate the specificity of ethanol's effects, the site(s) and mechanisms of ethanol action, and the possible role of these systems in adaptation to the chronic effects of ethanol (i.e., tolerance and/or physical dependence). In cerebral cortex of C57B1 mice, ethanol increased the activity of beta-adrenergic receptor-coupled adenylate cyclase (AC) in a dose-dependent manner. Specific sites of ethanol action were: the beta-adrenergic receptor N(s) (the guanine nucleotide-binding protein) and the catalytic unit of AC. Ethanol also promoted the interaction of guanine nucleotide-loaded N(s) with AC. Preliminary results showed that in ethanol-tolerant and -dependent mice, as well as in rats, stimulation of cortical AC by guanine nucleotides and isoproterenol (ISO) was reduced, suggesting an adaptive response at the biochemical level. Similar results (i.e., reduced sensitivity to stimulation by guanine nucleotides and ISO) were found for rat pineal gland AC, indicating a generalized effect on this receptor-effector system. In contrast, ethanol, acutely or chronically, did not alter opiate inhibition of AC in mouse striatum. The effect of ethanol seems to be relatively specific for systems using N(s), as opposed to N(i). Ethanol also affected receptor coupling to another biochemical transducer, phosphatidylinositol (PI) turnover. Ethanol inhibited this activity and, after chronic in vivo treatment of mice with ethanol, there was increased sensitivity of PI turnover to stimulation by cholinergic agonist, but not by a noradrenergic agonist. These changes paralleled previously observed alterations in ligand binding, demonstrating a functional correlate of ethanol-induced alterations in receptor number in the CNS. This change may be associated with specific symptoms of ethanol withdrawal. Overall, the studies illustrate the ethanol has specific sites of action in the CNS, and that adaptation occurs at these sites after chronic treatment of animals with ethanol, which results in tolerance and physical dependence.
