title: Decrement in operant performance produced by NMDA receptor antagonists in the rat: tolerance and cross-tolerance.
abstract: Current perspectives on the clinical use of NMDA receptor antagonists infer repeated administration schedules for the management of different pathological states. The development of tolerance and cross-tolerance between different NMDA receptor antagonists may be an important factor contributing to the clinical efficacy of these drugs. The present study aimed to characterize the development of tolerance and cross-tolerance 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 reinforcement). Acute administration of D-CPPen (SDZ EAA 494; 1-5.6 mg/kg), dizocilpine (MK-801; 0.03-0.3 mg/kg), memantine (0.3-17 mg/kg), ACEA-1021 (10-56 mg/kg), and eliprodil (1-30 mg/kg) differentially affected operant responding. Both increases and decreases in response rates and accuracy of responding were observed. Repeated preexposure to D-CPPen (5.6 mg/kg, once a day for 7 days) attenuated a behavioral disruption produced by an acute challenge with D-CPPen or ACEA-1021, but potentiated the effects of dizocilpine, memantine, and eliprodil. Based on the present results, one can suggest that the repeated administration of a competitive NMDA receptor antagonist differentially affects the functional activity of various sites on NMDA receptor complex.
authors.affiliation: Laboratory of Behavioral Pharmacology, Department of Psychopharmacology, Institute of Pharmacology, Pavlov Medical University, Lev Tolstoy str., 6/8, St. Petersburg, Russia.
authors.forename: O A
authors.initials: OA
authors.lastname: Dravolina
authors.forename: E E
authors.initials: EE
authors.lastname: Zvartau
authors.forename: A Y
authors.initials: AY
authors.lastname: Bespalov
mesh_terms: D000818:Animals; D003216:Conditioning, Operant / Q000187:drug effects*; D003864:Depression, Chemical; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D008297:Male; D008559:Memantine / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011597:Psychomotor Performance / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D018009:Receptors, Glycine / Q000187:drug effects; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D012055:Reinforcement Schedule; D014867:Water
chemical_list: D018691:Excitatory Amino Acid Antagonists; D010880:Piperidines; D018009:Receptors, Glycine; D016194:Receptors, N-Methyl-D-Aspartate; D014867:Water; D016291:Dizocilpine Maleate; D008559:Memantine; C058083:eliprodil