Effects of post-ethanol administration of NMDA and non-NMDA receptor antagonists on the development of ethanol tolerance in C57B1 mice.

The effect of post-ethanol administration of NMDA and non-NMDA receptor antagonists on the development of environment-dependent ethanol tolerance was studied in C57B1 mice. Ethanol tolerance was produced by daily injections of ethanol (3.5 g/kg, IP) in the same experimental environment and measured as ethanol-produced "sleep-time" during 5 consecutive days. The non-competitive NMDA receptor antagonist, dizocilpine (MK-801; 0.1 mg/kg, IP), and the competitive NMDA receptor antagonist, CGP 39551 (5 mg/kg, IP), both given 120 min after the administration of ethanol, inhibited the development of tolerance to the hypnotic actions of ethanol. In contrast, the development of ethanol tolerance was not altered by administration of the specific AMPA/KA receptor blocking agents, NBQX (10 mg/kg, IP), and LY326325 (2.5 mg/kg, IP), respectively. Modulation of NMDA receptor activity by drugs like NMDA, d-cycloserine, and milacemide, which are known to enhance learning and memory in rodents, had no significant effect on the development of ethanol tolerance. Our present data confirm and extend previous findings which indicate that NMDA, but not non-NMDA, glutamate receptors may play an important role in the neuroadaptive processes associated with the development of ethanol tolerance.