N-METHYL-D-ASPARTATE RECEPTORS, NITRIC-OXIDE, AND ETHANOL TOLERANCE

Several experimental models have been used to study tolerance to ethan ol. The development of tolerance to the motor incoordinating effect of a single administration of ethanol occurs within 8-24 h after the eff ect of the first dose has disappeared. This form of tolerance is desig nated rapid tolerance and seems to involve functional rather than phar macokinetic mechanisms. Like chronic tolerance, rapid tolerance has be en shown to be influenced by processes related to learning and memory. It is known that N-methyl-D-aspartate (NMDA) receptor systems are inv olved in the expression and maintenance of one form of long-term poten tiation (LTP), a synaptic adaptive process which has been suggested to be the cellular basis of memory or associative memory. Considering th e similarities between learning and tolerance, the effects of NMDA ago nists and antagonists on tolerance to ethanol were investigated. Our s tudies demonstrated that NMDA antagonists that impair learning, such a s dizocilpine or ketamine, inhibit tolerance, while NMDA agonists that improve learning, such as D-cycloserine, increase tolerance. Moreover , the nitric oxide synthase inhibitor L-nitroarginine blocks tolerance to the effects of ethanol. Taken together, these data confirm the inv olvement of the NMDA system in ethanol tolerance and emphasize the par ticipation of learning in phenomenon.