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The motor impairment (tilt-plane test) responses to ethanol were significantly reduced on days 2, 3, 4, or 5 in rats receiving ethanol (2.3 and 1.7 g/kg) 24 and 22 h earlier, compared to the control group pretreated with saline. Administration of (+)MK-801, prior to behavioral testing with ethanol on day 1, inhibited the development of tolerance on all these days. Tolerance and the inhibitory effect of (+)MK-801 could no longer be seen if the second injection of ethanol was given on day 7, 8 or 11. Administration of (+)MK-801 on day 1 but after behavioral testing with ethanol did not block the development of rapid tolerance to ethanol on day 2. Administration of another commonly employed NMDA antagonist, i.e., ketamine, prior to ethanol on day 1, also blocked the development of rapid tolerance to ethanol. The findings suggest that NMDA antagonists block rapid tolerance by preventing some adaptation that occurs during intoxicated practice.
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