AbstractWe have examined the hypothesis that phenothiazines and tricyclic antidepressans interact with the N‐methyl‐D‐aspartate (NMDA) receptor bu mimicking the action of Zn2+. Using [3H]MK801 binding to well‐washed rat brain membranes, we found a disparity between the concentrations of drug required to inhibit [3H]MK801 from its binding site. These data suggest that the Zn2+site is probably not the principle site by which tricyclic drugs inhibit NMDA receptor responses. To determine whether the effects to tricyclic drugs on the dissociation of [3H]MK801 could be explained simply by membrane stabilization, we examine dthe effect of a series of alcohols. Ethanol. isopropanol. bytanol, hexanol, and heptanol all inhibited [3H]MK801 binding. However, with the exception ot heptanol, none of the molecules altered the dissociation rate. Thus, while lipid solubility may be an important factor underlying the interactions the interactions of some drugs with the NMDA receptor, it is not sufficient to explain the effects of tricyclic antidepressants and phenothiazines in this