The cellular and molecular mechanisms of alcohol's actions in the nervous system have not been established. This project investigated alcohol's effects on synaptic mechanisms using the patch-clamp recording technique. Ethanol inhibits NMDA-activated ion current over a concentration range associated with intoxication (5-50 Mm). In addition, the potency of several alcohols for inhibiting NMDA current is related to their intoxicating potency, suggesting that alcohol-induced inhibition of NMDA channel function may contribute to intoxication. Analysis of mechanism indicates that ethanol inhibits NMDA current by altering gating of the channel, rather than by affecting channel conductance, ion permeance or regulatory sites on the channel. Ethanol concentrations associated with general anesthesia (50-100 Mm) inhibit kainate- and quisqualate-activated currents. The anesthetic agents, trichloroethanol, pentobarbital and volatile anesthetics, also inhibit kainate- and quisqualate-activated currents, suggesting that inhibition of these channels may contribute to the anesthetic effects of ethanol. The current associated with GABA-A channels is potentiated by ethanol (1-40 Mm) in some neurons, but is not affected in others. Since benzodiazepines selectively potentiate GABA-A current, the potentiation of this current by ethanol may contribute to the anxiolytic effects of ethanol. Behavioral studies have implicated 5-HT3 channels in the reinforcing properties of several drugs. Ethanol (25-200 Mm) potentiates 5-HT3 current; whereas, cocaine competitively inhibits serotonin activation of 5-HT3 channels (pA2=5.4; Kb=3.8 Um). Several types of ATP-gated channels can be identified; one type is inhibited by ethanol (IC50=68 Mm). Methanol is less potent, and propanol is more potent; however, 1-butanol and isopentanol are without effect on this current, suggesting that alcohols with 3 carbons or less interact a small hydrophobic pocket in the channel protein. The observation suggest that neurotransmitter-gated ion channels are molecular sites of alcohol action in the nervous system.
