Pharmacology Biochemistry and Behavior, Vol. 65, No. 4, pp. 611–620, 2000 © 2000 Elsevier Science Inc. Printed in the USA. All rights reserved 0091-3057/00/$–see front matter PII S0091-3057(99)00232-4 611 Decrement in Operant Performance Produced by NMDA Receptor Antagonists in the Rat: Tolerance and Crosstolerance OLGA A. DRAVOLINA, EDWIN E. ZVARTAU AND ANTON Y. BESPALOV Laboratory of Behavioral Pharmacology, Department of Psychopharmacology, Institute of Pharmacology, Pavlov Medical University, Lev Tolstoy str., 6/8, St. Petersburg, 197089, Russia Received 7 April 1999; Revised 16 September 1999; Accepted 1 October 1999 DRAVOLINA, O. A., E. E. ZVARTAU AND A. Y. BESPALOV. Decrement in operant performance produced by NMDA receptor antagonists in the rat: Tolerance and crosstolerance. PHARMACOL BIOCHEM BEHAV 65(4) 611–620, 2000.—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 crosstolerance 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 crosstolerance to the ability of various site-selective NMDA receptor antag- onists to produce a decrement of operant responding (multiple extinction 9 s fixed-interval 1-s schedule of water reinforce- ment). 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 in- creases 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 vari- ous sites on NMDA receptor complex. © 2000 Elsevier Science Inc. Dizocilpine (MK-801) Memantine D-CPPen (SDZ EAA 494) ACEA-1021 Eliprodil Operant behavior Tolerance Rats N-METHYL-D-ASPARTATE (NMDA) receptor is a sub- type of excitatory amino acid receptors implicated in a number of physiological functions. A variety of compounds have been designed as antagonists targeting NMDA recep- tors for a wide range of possible therapeutic applications in- cluding brain ischemia, neurodegeneration, and seizure disor- ders (8,12). Although perspectives on the clinical use of NMDA recep- tor antagonists infer repeated administration schedules, ex- perimental evidence is very limited regarding the effects of repeated exposures and the possible development of toler- ance and dependence. On one hand, it was shown that phen- cyclidine (PCP)-like NMDA receptor channel blockers such as dizocilpine (MK-801) produce tolerance and dependence upon repeated administration (2,14,17,28). Repeated admin- istration of NMDA receptor antagonists may also result in sensitization to their pharmacological effects [e.g., (14,20, 36,39)]. Further, the NMDA receptor complex has multiple ligand recognition sites (2,8), and effects of repeated administration may vary significantly among site-selective antagonists. For competitive NMDA receptor antagonists, the development of tolerance was observed to locomotor decreasing [CGS 19755, (4); CGP39551, CGP37849, (21)], cataleptic [CGS 19755, (17)], and motor impairing effects [D-CPPen, (24)]. Never- theless, several studies reported no tolerance to motor im- pairing [CGS 19755, (4); CGP 37849, CGP 39551, (10)], anti- convulsant [CGS 19755, (4); CGP 37849, CGP 39551; (10); D-CPPen, (24)], neuroprotective (SDZ 220-581, (26)], anxi- olytic [CGP 37849, (13); NPC 17742, (33)] and antidepres- Requests for reprints should be addressed to Anton Yu. Bespalov, Institute of Pharmacology, Pavlov Medical University, 6/8 Lev Tolstoy St., St. Petersburg 197089, Russia.