The cellular basis of alcohol actions in the nervous system is poorly understood. Recent studies have shown that alcohols can affect the function of certain neurotransmitter receptors. However, the cellular mechanisms involved in those effects have not been established. This project studied the cellular mechanisms involved in the effects of alcohol on neurotransmitter receptor function using electrophysiological techniques. The inhibition on N-methyl-d-aspartate (NMDA) receptor-mediated responses by ethanol was investigated in mouse hippocampal neurons. In whole-cell patch-clamp experiments, ethanol decreased Emax of the agonist concentration-response curve, without affecting either the EC50 or the apparent Hill coefficient. The inhibition was voltage-independent, and did not involve the glycine, polyamine, proton, rhedox, ketamine, Mg2+ or Zn2+ regulatory sites on the receptor. In single-channel experiments, ethanol inhibition of NMDA-activated current did not involve significant changes in fast closed state kinetics, changes in open channel conductance or block of the open channel. At the IC50 for ethanol inhibition, it was estimated that the open channel lifetime was decreased by 28% and the frequency of opening was decreased by 31%. The data are consistent with ethanol being an allosteric modulator of channel gating which reduces agonist efficacy. The potentiation of gamma-aminobutyric acid type A (GABA-A) receptor-mediated responses by a series of primary alcohols was also studied in mouse hippocampal neurons. From 1-butanol to 1-undecanol, the potency of the alcohols for potentiating GABA-A-receptor-mediated ion current increased exponentially with increasing carbon chain length. However, the potency of 1-duodecanol for potentiating GABA-A responses was not significantly different from that of 1-undecanol, and alcohols with more than 12 carbon atoms (1-tridecanol and 1-tetradecanol) had no significant effect on GABA-A-activated current. This cutoff in the potency of n-alcohols for potentiation of GABA-A responses is consistent with an interaction of the alcohols with a hydrophobic pocket on the receptor protein.
