Effect of NMDA antagonists on development of rapid tolerance to various barbiturates.

We recently reported that the noncompetitive antagonists, (+)-MK-801 and ketamine, block the development of rapid tolerance to ethanol. We now show that pretreatment with these NMDA antagonists also blocks rapid tolerance to the various barbiturates (pentobarbital, barbital, and phenobarbital) examined. Tolerance to pentobarbital occurred under three difference conditions: (a) in groups of rats that were tested at repeated times on day 1 (intoxicated practice or testing group), (b) in groups of rats that were not tested on the apparatus but handled at the same times on day 1 (dummy testing or associative learning group), and (c) in groups of rats that were not subjected to testing at all on day 1 (nontesting). However, NMDA antagonists blocked intoxicated practice and associative tolerance, but not tolerance produced in the nontesting group. In the last experiment NMDA antagonist failed to block tolerance (unlearned) when animals were treated in the animal quarters and tested in a different room (i.e., in the laboratory). These findings suggest that NMDA antagonists affect barbiturate tolerance in a manner similar to their effect on ethanol tolerance.