Pharmacology Biochemistry and Behavior, Vol. 63, No. 4, pp. 613–619, 1999 © 1999 Elsevier Science Inc. Printed in the USA. All rights reserved 0091-3057/99/$–see front matter PII S0091-3057(99)00028-3 613 Morphine Tolerance and Dependence in Mice with History of Repeated Exposures to NMDA Receptor Channel Blockers OLGA A. DRAVOLINA, IRINA V. BELOZERTSEVA, IRINA A. SUKHOTINA 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 4 November 1998; Revised 27 January 1999; Accepted 25 January 1999 DRAVOLINA, O. A., I. V. BELOZERTSEVA, I. A. SUKHOTINA AND A. Y. BESPALOV. Morphine tolerance and dependence in mice with history of repeated exposures to NMDA receptor channel blockers. PHARMACOL BIOCHEM BEHAV 63(4) 613–619, 1999.—Mice were subjected to two successive treatment protocols: first with NMDA receptor chan- nel blockers (14 days, once a day) and second with morphine (5 mg/kg, 8 days, once a day). Treatment with the higher doses of dizocilpine (1 mg/kg), memantine (30 mg/kg), and MRZ 2/576 (30 mg/kg) upon discontinuation revealed only minor be- havioral abnormalities attributable to the state of withdrawal. Following repeated administration of low-dose morphine, tol- erance to morphine analgesia developed in mice preexposed to dizocilpine (1 mg/kg but not 0.3 mg/kg) but not memantine (10 and 30 mg/kg), MRZ 2/579 (10 and 30 mg/kg), or saline. There were no signs of morphine dependence in any treatment group. Overall, the present study found only minor effects of the subchronic administration of high doses of NMDA receptor channel blockers, suggesting that clinical use of NMDA receptor channel blockers such as memantine will not be accompa- nied by increased propensity to induction of morphine tolerance and dependence. © 1999 Elsevier Science Inc. Dizocilpine Memantine MRZ 2/579 Morphine Tolerance Dependence Analgesia Social interaction test Mice IT is widely accepted that learning and memory involve N-methyl-D-aspartate (NMDA) receptor-dependent mecha- nisms. Beside the prominent role of NMDA receptor in syn- aptic plasticity (7), vast experimental evidence implicates NMDA receptors in the development of drug tolerance and dependence (13,33). On the other hand, there is little doubt that repeated administration of NMDA receptor ligands themselves may result in altered sensitivity to their pharmaco- logical effects [e.g., sensitization to locomotor stimulant ef- fects; (39,41)]. Considering current perspectives on clinical use of NMDA receptor antagonists (14), one should note that knowledge of the functional consequences of chronic NMDA receptor blockade is limited. Review of molecular data indicates that studies with re- peated exposures to NMDA receptor antagonists yield quite controversial results. The outcome of the experiments (i.e., receptor upregulation, downregulation, or no effect) signifi- cantly depends on the type of antagonist used (noncompeti- tive vs. competitive), duration of exposure to the antagonist (3–28 days), dosing, and schedule of administration (intermit- tent vs. continuous) (2,16,20,21,22,29,32,36,38). Analysis of the reports relevant to the experimental design used in the present study reveals that repeated dizocilpine (MK-801) ex- posures increased both NMDAR1 mRNA (21,32) and [ 3 H]di- zocilpine binding [(23,38); for memantine, see (16)]. Expres- sion of non-NMDA subtypes of glutamate receptors is either unaffected (38) or affected in more complex ways (21). In ad- dition, there is some evidence that NMDA receptor channel blockers may produce selective changes in binding to NMDA receptors, but not to other glutamate binding sites [i.e., AMPA; (9)]. Similarly, behavioral data also point to facilitated NMDA receptor function following repeated administration of NMDA receptor blockers. For instance, treatment with PCP (6), Requests for reprints should be addressed to Anton Y. Bespalov, Institute of Pharmacology, Pavlov Medical University, 6/8 Lev Tolstoy St., St. Petersburg 197089, Russia.