Decrement in operant performance produced by NMDA receptor antagonists in the rat: Tolerance and crosstolerance

Current perspectives on the clinical use of NMDA receptor antagonists infer repeated administration schedules for the management of different patholog ical states. The development of tolerance and crosstolerance between differ ent NMDA receptor antagonists may be an important factor contributing to th e clinical efficacy of these drugs. The present study aimed to characterize the development of tolerance and crosstolerance to the ability of various site-selective NMDA receptor antagonists to produce a decrement of operant responding (multiple extinction 9 s fixed-interval 1-s schedule of water re inforcement). Acute administration of D-CPPen (SDZ EAA 494: 1-5.6 mg/kg), d izocilpine (MK-801; 0.03-0.3 mg/kg), memantine (0.3-17 mg/kg), ACEA-1021 (1 0-56 mg/kg), and eliprodil (1-30 mg/kg) differentially affected operant res ponding. Both increases and decreases in response rates and accuracy of res ponding were observed. Repeated preexposure to D-CPPen (5.6 mg/kg, once a d ay for 7 days) attenuated a behavioral disruption produced by an acute chal lenge with D-CPPen or ACEA-1021, but potentiated the effects of dizocilpine , memantine, and eliprodil. Based on the present results, one can suggest t hat the repeated administration of a competitive NMDA receptor antagonist d ifferentially affects the functional activity of various sites on NMDA rece ptor complex. (C) 2000 Elsevier Science Inc.