MK-801 potentiates ethanol's effects on locomotor activity in mice

FAST vs. SLOW selected mouse lines and C57BL/6J (B6) vs. DBA/2J (D2) inbred strains differ in their sensitivities to ethanol's locomotor stimulant effects, and provide two unique sets of genetic animal models to study neurophysiological substrates of this behavior. To determine whether NMDA receptor function mediates sensitivity to ethanol's stimulant effects, we assessed the effects of the noncompetitive NMDA antagonist, MK-801, on locomotor activity of naive and ethanol-treated FAST, SLOW, B6, and D2 mice. MK-801 (0.01-0.5 mg/kg, I.P.) had biphasic effects in all genotypes, with stimulation at moderate doses and decreased activation at the highest dose. FAST mice were more activated by MK-801 than SLOW mice, suggesting that selection differentially altered NMDA receptor function between the lines. B6 and D2 mice did not differ in locomotor responses following MK-801 administration. Stimulant doses of MK-801 decreased or blocked ethanol-stimulated locomotor activity in FAST and D2 mice, and potentiated the locomotor depressant actions of ethanol in SLOW and B6 mice. Potentiation of ethanol's activating properties was observed in one treatment group in D2 mice. These data suggest that NMDA receptors modulate ethanol's stimulant properties, by a more significant involvement in expression of ethanol's locomotor depressant properties.