N-methyl-D-aspartate receptor neurotransmission in learning and memory: Pharmacological assessment in pigeons.

Abstract

Several types of procedures used to assess learning have demonstrated that blocking NMDA receptor neurotransmission impairs processes involved in acquisition of novel behavior. Such impairments produced by competitive and PCP-like NMDA antagonists have been repeatedly observed using these procedures. Glycine site NMDA antagonists also produce impairments in procedures used to assess learning; yet, these reports are only recently emerging. Therefore, initial experiments were designed to examine the effects of a glycine site NMDA antagonist ((+)-HA-966) in comparison with a competitive (i.e., CGS-19755) and PCP-like (i.e., MK-801) NMDA antagonist on the acquisition of response chains in pigeons. Results from these experiments revealed that similar reductions in accuracy of responding could be produced by each type of NMDA antagonist investigated in the repeated acquisition procedure. Subsequent experiments explored the mechanism by which glycine site antagonism may produce a similar reduction in accuracy of responding to non-glycine site NMDA antagonists in this procedure. Therefore, the effects of co-administration of the glycine site agonist D-serine with the glycine site antagonists, (+)-HA-966 and L-701,324 were examined in analogous experiments. D-serine antagonized the behavioral effects of both glycine site antagonists. To investigate the pharmacological site selectivity of the actions of D-serine with the uncompetitive antagonists, PCP and MK-801, and the competitive antagonist CGS-19755 were also examined. In contrast to its effects with glycine site antagonists, D-serine had little effect against impairments produced by the competitive or uncompetitive NMDA antagonists. Since nitric oxide synthase (NOS) activation is a major consequence of NMDA receptor neurotransmission, suppressed nitric oxide production may result from NMDA antagonism. Thus, augmenting NOS activity may attenuate NMDA antagonist-induced impairments. Thus, behavioral effects of i.m. co-administration of the endogenous NOS substrate, L-arginine, with PCP and CGS-19755 were examined in the repeated acquisition and schedule-controlled response rate procedures. L-arginine had no effect in the latter procedure, but modestly reversed the rate-decreasing effects of each NMDA antagonist in the former.