NMDA-receptor antagonists block the development of rapid tolerance to ethanol in mice

Several studies have emphasized the role of learning in the development of rapid and chronic tolerances. Recently, it was shown that the NMDA antagonists MK-801(dizocilpine) and ketamine block the development of tolerance to ethanol in rats submitted to tilt-plane apparatus. The present study examines the generality of this inhibition using mice submitted to the rota-rod test. Mice were tested in the rota-rod apparatus at 5, 10 and 15 minutes after intraperitoneal ethanol injections. The first experiment evaluated the time course of acute effects of different doses of ethanol (1.0-2.25 g/kg) in the rota-rod test. In the second experiment, the most effective dose of ethanol to produce rapid tolerance (RT) was determined. Mice were injected on day 1 with ethanol or saline and tested on the rota-rod. After 24 hours, all groups were injected with the same doses of ethanol and tested. The third experiment investigated whether ketamine (1.0-5.0 mg/kg) injected before ethanol on day 1 influenced the development of RT to ethanol. The last experiment compared the actions of the (+) and (-)MK-801 isomers (0.015-0.060 mg/kg) on RT to ethanol. Maximum motor impairment was obtained 5 minutes after ethanol injections. Pretreatment of animals with ketamine (2.5 and 5 mg/kg) or with (+)MK-801 (0.030 and 0.060 mg/kg) significantly blocked the development of RT. The (-)MK-801 isomer did not affect RT, suggesting that the blockade by MK-801 is stereospecific. These results confirm and extend previous studies showing that NMDA receptor antagonists block RT to the motor impairment produced by ethanol in other animals tested in different models.