MK-801-Induced Disruptions of One-Trial Inhibitory Avoidance Are Potentiated by Stress and Reversed by Naltrexone Claudio Castellano, Vincenzo Cestari, Alessandro Ciamei, and Flaminia Pavone Istituto di Psicobiologia e Psicofarmacologia del CNR, Viale Marx 15, 00137 Roma, Italy Five experiments were carried out to investigate opioid and NMDA receptor-medi- ated responses to one-trial inhibitory avoidance training in CD1 mice. In the first experiment immediate posttraining intraperitoneal administration of the noncompeti- tive N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 impaired the perfor- mance of mice. The effects of MK-801 were time-dependent (they were absent in mice injected with the drug starting 120 min after training). No effect was evident in no-foot-shock groups, showing lack of proactive influence of the treatment on perfor- mance. In the second experiment preexposure of the mice to the testing apparatus decreased the effects of MK-801. In the the third experiment naltrexone antagonized the effects of MK-801, suggesting an involvement of opioid neurons. In the fourth experiment immediate posttraining immobilization stress exerted a potentiating effect on the performance of MK-801-injected animals. In the fifth experiment the potentia- tion of the impairing effect of MK-801 induced by immobilization stress was antago- nized by naltrexone. © 1999 Academic Press Key Words: MK-801; memory consolidation; inhibitory avoidance; preexposure; im- mobilization stress; naltrexone. INTRODUCTION Recent research has demonstrated the existence of interactions between the glutamatergic and opioid systems. Studies on the pharmacology of analgesia have shown that the noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 is able to attenuate or inhibit the development of tolerance to the analgesic effect of morphine. In particular Marek, Ben Eliyahu, Gold, and Liebeskind (1991) observed that the development of tolerance to morphine in rats subjected to a hot-plate test was reduced in animals chronically treated with MK-801, which were injected intraperitoneally (ip) with the drug at the dose of 0.05 mg/kg. Similar results were obtained by Trujillo and Akil (1994) using rats subjected to a tail-flick test. These authors observed the develop- ment of a complete tolerance to the analgesic effect of morphine after 6 days of treatment, then they studied the interaction between MK-801 (0.1 mg/kg, ip) and morphine in rats after 6 days of chronic treatment with these two sub- stances. The results showed that MK-801 inhibited morphine tolerance. Sim- Address correspondence and reprint requests to Dr. Claudio Castellano, Istituto di Psicobiologia e Psicofarmacologia del CNR, Viale Marx 15, 00137 Roma, Italy. Fax: +39-6-8278735. E-mail: castella@kant.irmkant.rm.cnr.it. 215 Neurobiology of Learning and Memory 72, 215–229 (1999) Article ID nlme.1999.3908, available online at http://www.idealibrary.com on 1074-7427/99 $30.00 Copyright © 1999 by Academic Press All rights of reproduction in any form reserved.