CUTOFF IN POTENCY IMPLICATES ALCOHOL INHIBITION OF N-METHYL-D-ASPARTATE RECEPTORS IN ALCOHOL-INTOXICATION

As the number of carbon atoms in an aliphatic n-alcohol is increased f rom one to five, intoxicating potency, lipid solubility, and membrane lipid disordering potency all increase in a similar exponential manner . However, the potency of aliphatic n-alcohols for producing intoxicat ion reaches a maximum at six to eight carbon atoms and then decreases. The molecular basis of this ''cutoff'' effect is not understood, as i t is not correlated with either the lipid solubility or the membrane d isordering potency of the alcohols, which continue to increase exponen tially. Since it has been suggested that inhibition of N-methyt-D-aspa rtate (NR-IDA) receptors by alcohols may play a role in alcohol intoxi cation, we investigated whether a series of aliphatic n-alcohols would exhibit a cutoff in potency for inhibition of NMDA receptors. We foun d that although potency for inhibition of NMDA receptors increased exp onentially for alcohols with one to five carbon atoms, potency for inh ibition of NMDA receptors reached a maximum at six to eight carbon ato ms and then abruptly disappeared. This cutoff for alcohol inhibition o f NMDA receptors is consistent with an interaction of the alcohols wit h a hydrophobic pocket on the receptor protein. In addition, the simil arity of the cutoffs for alcohol inhibition of NMDA receptors and alco hol intoxication suggests that the cutoff for NMDA receptor inhibition may contribute to the cutoff for alcohol intoxication, which is consi stent with an important role of NMDA receptors in alcohol intoxication .