NMDA-RECEPTOR ANTAGONISTS BLOCK THE DEVELOPMENT OF RAPID TOLERANCE TOETHANOL IN MICE

Several studies have emphasized the role of learning in the developmen t of rapid and chronic tolerances. Recently, it was shown that the NMD A antagonists MK-801(dizocilpine) and ketamine block the development o f tolerance to ethanol in rats submitted to tilt-plane apparatus. The present study examines the generality of this inhibition using mice su bmitted to the rota-rod test. Mice were tested in the rota-rod apparat us at 5, 10 and 15 minutes after intraperitoneal ethanol injections. T he first experiment evaluated the time course of acute effects of diff erent doses of ethanol (1.0-2.25 g/kg) in the rota-rod test. In the se cond experiment, the most effective dose of ethanol to produce vapid t olerance (RT) was determined. Mice were injected on day I 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 experim ent investigated whether Ketamine (1.0-5.0 mg/kg) injected before etha nol on day I influenced the development of RT to ethanol. The last exp eriment 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 Ketamin e (2.5 and 5 mg/kg) or with (+)MK-801 (0.030 and 0.060 mg/kg) signific antly blocked the development of RT The (-)MK-801 isomer did not affec t RI; 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 o ther animals tested in different models.