Ethanol-induced hypnotic tolerance is absent in N-methyl-D-aspartate receptor epsilon 1 subunit knockout mice.

Recent pharmacological studies suggest that N-methyl-D-aspartate (NMDA) receptors play an important role in neuroadaptive processes in the development of tolerance to addictive drugs, such as opioids, amphetamine, and cocaine. In the present study, we investigated the contribution of the NMDA receptor to ethanol-induced hypnotic tolerance using NMDA receptor epsilon1 subunit knockout mice. Hypnotic sensitivity to a single injection of 3, 3.5, and 4 g/kg ethanol was not significantly different between wild-type mice and NMDA receptor epsilon1 subunit knockout mice. In contrast, although wild-type mice displayed hypnotic tolerance after repeated administration of 4 g/kg ethanol for 4 consecutive days, no change in the duration of hypnosis was observed in knockout mice. No significant differences were observed in blood ethanol clearance between wild-type and knockout mice on day 4. Our results indicate epsilon1 subunit containing the NMDA receptor might be involved in the development of ethanol-induced hypnotic tolerance.