Oa. Dravolina et al., Decrement in operant performance produced by NMDA receptor antagonists in the rat: Tolerance and crosstolerance, PHARM BIO B, 65(4), 2000, pp. 611-620
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.