Antagonists of the N-methyl-D-aspartate subtype of glutamate receptor have been reported to block the development of tolerance to various effects of ethanol and opiates, using paradigms in which tolerance is believed to be governed by learning. There is considerable evidence to implicate the N-methyl-D-aspartate receptor in learning processes, and therefore the ability of the antagonists to block tolerance has been attributed to their effects on learning. To evaluate this hypothesis, we compared, in C57BL/6 mice, the effect of the uncompetitive N-methyl-D-aspartate receptor antagonist, dizocilpine, on environment-dependent (associative) tolerance to ethanol, which is governed by learning, and on environment-independent (nonassociative) ethanol tolerance, in which learning plays a minimal role. Environment-dependent tolerance was induced by repeated ethanol injections, and dizocilpine blocked the development of this type of tolerance to the hypothermic and incoordinating effects of ethanol. In contrast, when environment-independent ethanol tolerance was induced by feeding the mice an ethanol-containing liquid diet, dizocilpine treatment had no effect on the development of tolerance to the hypothermic, incoordinating or hypnotic effects of ethanol. The results support the hypothesis that the effect of N-methyl-D-aspartate receptor antagonists on ethanol tolerance reflects the more general role of this receptor in processes involving learning and memory.