Cutoff in potency implicates alcohol inhibition of N-methyl-D-aspartate receptors in alcohol intoxication.

Abstract

As the number of carbon atoms in an aliphatic n-alcohol is increased from 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 intoxication reaches a maximum at six to eight carbon atoms and then decreases. The molecular basis of this "cutoff" effect is not understood, as it is not correlated with either the lipid solubility or the membrane disordering potency of the alcohols, which continue to increase exponentially. Since it has been suggested that inhibition of N-methyl-D-aspartate (NMDA) receptors by alcohols may play a role in alcohol intoxication, we investigated whether a series of aliphatic n-alcohols would exhibit a cutoff in potency for inhibition of NMDA receptors. We found that although potency for inhibition of NMDA receptors increased exponentially for alcohols with one to five carbon atoms, potency for inhibition of NMDA receptors reached a maximum at six to eight carbon atoms and then abruptly disappeared. This cutoff for alcohol inhibition of NMDA receptors is consistent with an interaction of the alcohols with a hydrophobic pocket on the receptor protein. In addition, the similarity of the cutoffs for alcohol inhibition of NMDA receptors and alcohol intoxication suggests that the cutoff for NMDA receptor inhibition may contribute to the cutoff for alcohol intoxication, which is consistent with an important role of NMDA receptors in alcohol intoxication.The molecular basis of alcohol's behavioral effects is poorly understood. Since the turn of the century, it has been widely accepted that alcohols produce their central nervous system effects by acting on the lipids of neuronal membranes (1-8). According to this "lipid theory," the effects of alcohols on the function of membrane proteins, such as receptors and ion channels, are secondary to their perturbation of membrane lipids. Consistent with this hypothesis, the intoxicating potency of aliphatic n-alcohols with up to five carbon atoms is correlated with both their lipid solubility (membrane/buffer partition coefficient) and their membrane lipid disordering potency (9, 10). However, as the number of carbon atoms is increased from six to eight, the intoxicating potency of aliphatic nalcohols reaches a plateau and then decreases (9, 10). This cutoff effect for intoxication is difficult to reconcile with the lipid theory of alcohol action, because it is not correlated with either membrane/buffer partition coefficient or potency for disordering membrane lipids, which both continue to increase exponentially with increasing carbon chain length (9-12).Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system. N-Methyl-D-aspartate (NMDA) receptors are a subtype of glutamate receptors that appear to be involved in a variety of neural phenomena including nervous system excitability, cognitive function, and motor coordination (13-15). Since NMDA receptor function is inhibit...

A Site of Alcohol Action in the Fourth Membrane-associated Domain of the N-Methyl-D-aspartate Receptor

“…In addition, in this study we observed that ethanol sensitivity of the mutants, with the exception of tryptophan, was related to the hydrophilicity at this position. A number of previous studies have demonstrated that the action of alcohols on NMDA receptors largely depends upon hydrophobic interactions (1,(32)(33)(34)(35). The observation of a relation between ethanol sensitivity and hydrophilicity of the substituent at NR2A(Met 823 ) in this study suggests that ethanol interacts with this site in a manner that involves hydrophobic binding.…”

Role of Altered Structure and Function of NMDA Receptors in Development of Alcohol Dependence

“…Earlier it was thought that ethanol binds to a hydrophobic pocket distinct from other modulatory binding sites of the NMDARs [166,167]. Recently it was suggested that this pocket is associated with the third transmembrane domain (TM3) of the NR1 subunit [181].…”

Signaling Cascades Regulating NMDA Receptor Sensitivity to Ethanol

“…Indeed, early studies implied that ethanol attenuates the activity of the NMDAR channel by reducing the potency of the coagonist glycine (Hoffman and others 1989;Rabe and Tabakoff 1990). Other studies in heterologous systems, such as transfected HEK293 cells and Xenopus oocytes, suggest other sites of direct interactions of ethanol with NMDAR subunits (Peoples and Weight 1995;Peoples and Stewart 2000;Ronald and others 2001;Ren and others 2003). In addition, indirect mechanisms strongly influence the short-and long-term effects of ethanol on the NMDAR.…”