Effect of NMDA antagonists on rapid tolerance to ethanol under two different testing paradigms.

We have recently reported that pretreatment with NMDA receptor antagonists [(+)MK-801 and ketamine] inhibited the development of rapid tolerance to ethanol hypothermia and motor-impairment on day 2 in animals receiving ethanol on day 1, compared to the control group pretreated with saline. In these studies rats were tested at 30, 60, 90 and 120 min after ethanol on both day 1 and 2. In the present report we compared the development of rapid tolerance under 2 different conditions: (1) in groups of rats that were tested on the tilt-plane at all test times (Testing or Intoxicated Practice group), (2) in groups of rats that were not tested on the tilt-plane but were handled at all test times on day 1 (dummy testing). Rats were pretreated with ethanol or saline on day 1 and tested with ethanol on day 2 in all the above studies. Both testing (intoxicated practice) and dummy testing of animals on day 1 after pretreatment with ethanol produced rapid tolerance to ethanol on day 2. However, (+)MK-801 or ketamine pretreatment, which blocked rapid tolerance in the intoxicated practice testing paradigm, failed to block rapid tolerance in the dummy testing paradigm. Similar results were obtained for rapid tolerance and for the effect of ketamine in the hypothermia experiment. These findings suggest that NMDA antagonists block rapid tolerance in the intoxicated testing paradigm but not in the dummy testing paradigm. However, whether the two types of rapid tolerance tested in the present experiments are indeed different or interrelated remains to be further investigated.