Competitive and noncompetitive NMDA antagonist effects in rats trained to discriminate lever-press counts

The glutamate activated N-methyl-D-aspartate (NMDA) receptor may play a rol e in short-term memory processing. Among the evidence for this is that NMDA antagonists can impair accuracy in fixed consecutive number (FCN) tasks. T his study was designed to further characterize this effect by examining NMD A antagonists differing in their cellular mechanisms of action. Rats were t rained to respond under an FCN operant schedule, which required eight press es on one lever (counting lever) before one press at an alternate lever (re inforcement lever) would produce food reinforcement. The effects of three n oncompetitive [MK-801 (0.01-0.56 mg/kg); phencyclidine (0.3-3.0 mg/kg); mem antine (1-10 mg/kg)] and two competitive [SDZ EAA 494 (0.3-3.0 mg/kg) and N PC 17742 (2.0-16 mg/kg)] NMDA antagonists were analyzed. MK-801 and phencyc lidine decreased accuracy at doses not reducing response rates. Memantine, and both of the competitive antagonists, also reduced accuracy, but did so only at doses that markedly reduced response rates. These results suggest t hat both the affinity and the site bound on the NMDA glutamate receptor by antagonists can determine their effects on FCN performance. Subsequent stud ies investigated whether SCH 23390, a dopamine D1 receptor antagonist, and NMDA could modulate the effects by phencyclidine and SDZ EAA 494, respectiv ely, on FCN performance. (C) 2001 Elsevier Science Inc. All rights reserved .