ETHANOL MODIFICATION OF NEUROTRANSMITTER RECEPTOR-EFFECTOR COUPLING

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Ethanol selectively alters the function of neurotransmitter and neuromodulator receptors in the CNS, and adaptations in receptor function may be associated with ethanol tolerance and/or physical dependence. Previous work showed decreased stimulation of adenylate cyclase by various agonists and by guanine nucleotides, and decreased high-affinity binding of a beta-adrenergic agonist and forskolin in certain brain regions of mice fed ethanol chronically. These results suggested a quantitative or qualitative change in the stimulatory guanine nucleotide binding protein, Gs. Quantitation of the two (46 and 52 kDa) forms of Gs-alpha, and of Gi-- alpha, in various brain regions by Western blot analysis, however, revealed no significant change in the levels of these proteins in ethanol-fed mice, and in situ hybridization studies of Gs-alpha mRNA also showed no change. Differences in proportion of the two forms of Gs-alpha among brain regions were observed, and the 46 kDa form was found to be resistant to cholera toxin-catalyzed ADP-ribosylation. The data indicate that chronic ethanol ingestion may alter the properties rather than amount of Gs-alpha, and further characterization of the function of the two forms of the protein in ethanol-fed mice is warranted. The NMDA receptor system is also changed in ethanol-fed mice. As measured by membrane binding and autoradiographic studies of MK-801, a non-competitive antagonist at the NMDA receptor, this receptor is up-regulated in hippocampus and other brain areas of ethanol-fed mice. The time course of changes in binding parallels susceptibility to ethanol withdrawal seizures. In addition, mice bred to be prone to ethanol withdrawal seizures (WSP) have more hippocampal MK-801 binding sites than mice bred to be resistant to ethanol withdrawal seizures (WSR), both before and after chronic ethanol ingestion. These findings support a role for the NMDA receptor-gated channel in ethanol withdrawal. In preliminary studies, strychnine-insensitive glycine binding was not increased in ethanol-fed mice, suggesting a change in the function of NMDA receptor-gated channels rather than an increased number of receptor-channel complexes.