Acute and chronic effects of ethanol on receptor-mediated phosphatidylinositol 4,5-bisphosphate breakdown in mouse brain.
Phosphatidylinositol 4,5-bisphosphate (PIP2) breakdown was stimulated by agonists acting at muscarinic cholinergic and alpha 1-adrenergic receptors in mouse brain. Ethanol, in vitro, inhibited basal cerebral cortical PIP2 breakdown with a threshold concentration of 75-100 mM. Basal PIP2 breakdown in hippocampus and striatum was less sensitive to ethanol. A high concentration of ethanol (500 mM) increased the EC50 for carbachol stimulation of PIP2 breakdown in all three brain areas, but had no effect on the EC50 for norepinephrine. Following chronic ingestion of ethanol by mice, the EC50 for carbachol stimulation of PIP2 breakdown in cortex was decreased, and there was no change in striatum. These effects were consistent with previously observed increases in quinuclidinylbenzilate (QNB) binding in cortex, but not striatum, of mice fed ethanol chronically. However, in hippocampus, where chronic ethanol ingestion had also induced an increase in QNB binding, the EC50 for carbachol stimulation of PIP2 breakdown was increased. Binding studies using the specific M1 muscarinic cholinergic receptor antagonist, pirenzepine, revealed that the number of pirenzepine-binding sites was increased in cortex, but not hippocampus (or striatum) of ethanol-fed mice. These results support the hypothesis that high affinity pirenzepine-binding sites are coupled to PIP2 breakdown in mouse cortex. The changes in cerebral cortex represent one of the first demonstrations of a functional correlate of a change in receptor density in ethanol-treated animals. Increased sensitivity to cholinergic agonists in cortex may contribute to particular signs of ethanol withdrawal.
D000818:Animals; D001570:Benzodiazepinones / Q000378:metabolism; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002217:Carbachol / Q000494:pharmacology; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D000431:Ethanol / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009638:Norepinephrine / Q000494:pharmacology; D019269:Phosphatidylinositol 4,5-Diphosphate; D010716:Phosphatidylinositols / Q000378:metabolism*; D010890:Pirenzepine; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects* / Q000378:metabolism; D011976:Receptors, Muscarinic / Q000187:drug effects* / Q000378:metabolism
D001570:Benzodiazepinones; D019269:Phosphatidylinositol 4,5-Diphosphate; D010716:Phosphatidylinositols; D011942:Receptors, Adrenergic, alpha; D011976:Receptors, Muscarinic; D010890:Pirenzepine; D000431:Ethanol; D002217:Carbachol; D009638:Norepinephrine