Role of major NMDA or AMPA receptor subunits in MK-801 potentiation of ethanol intoxication

Background: The glutamate system plays a major role in mediating EtOH’s effects on brain and behavior, and is implicated in the pathophysiology of alcohol‐related disorders. N‐methyl‐D‐aspartate receptor (NMDAR) antagonists such as MK‐801 (dizocilpine) interact with EtOH at the behavioral level, but the molecular basis of this interaction is unclear. Methods: We first characterized the effects of MK‐801 treatment on responses to the ataxic (accelerating rotarod), hypothermic and sedative/hypnotic effects of acute EtOH administration in C57BL/6J and 129/SvImJ inbred mice. Effects of another NMDAR antagonist, phencyclidine, on EtOH‐induced sedation/hypnosis were also assessed. Gene knockout of the NMDAR subunit NR2A or l ‐alpha‐amino‐3‐hydroxy‐5‐methylisoxazole‐4‐propionate GluR1 or pharmacological antagonism of the NMDAR subunit NR2B (via Ro 25‐6981) was employed to examine whether inactivating any one of these glutamate signaling molecules modified MK‐801’s effect on EtOH‐related behaviors. Results: MK‐801 markedly potentiated the ataxic effects of 1.75 g/kg EtOH and the sedative/hypnotic effects of 3.0 g/kg EtOH, but not the hypothermic effects of 3.0 g/kg EtOH, in C57BL/6J and 129/SvImJ mice. Phencyclidine potentiated EtOH‐induced sedation/hypnosis in both inbred strains. Neither NR2A nor GluR1 KO significantly altered basal EtOH‐induced ataxia, hypothermia, or sedation/hypnosis. Ro 25‐6981 modestly increased EtOH‐induced sedation/hypnosis. The ability of MK‐801 to potentiate EtOH‐induced ataxia and sedation/hypnosis was unaffected by GluR1 KO or NR2B antagonism. NR2A KO partially reduced MK‐801 + EtOH‐induced sedation/hypnosis, but not ataxia or hypothermia. Conclusions: Data confirm a robust and response‐specific potentiating effect of MK‐801 on sensitivity to EtOH’s intoxicating effects. Inactivation of three major components of glutamate signaling had no or only partial impact on the ability of MK‐801 to potentiate behavioral sensitivity to EtOH. Further work to elucidate the mechanisms underlying NMDAR × EtOH interactions could ultimately provide novel insight into the role of NMDARs in alcoholism and its treatment.