N-METHYL-D-ASPARTATE ANTAGONISTS AND TOLERANCE TO PSYCHOACTIVE DRUGS

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DESCRIPTION (Adapted from the Applicant's Abstract): Excitatory amino acid (EAA) receptors, and particularly the N-methyl-D-aspartate (NMDA) receptor, have been shown to play a critical role in learning and memory and to attenuate the development of tolerance to the prototypic opioid morphine. Tolerance to the behavioral effects of morphine has been shown to be influenced by both pharmacological (non-associative) and learning (associative) processes. The proposed experiments investigate the pharmacological and behavioral influence of the prototypic competitive NMDA antagonist, CGS 19755, and the prototypic noncompetitive NMDA antagonist, dizocilpine, on the development of tolerance to the behavioral effects of morphine. The pharmacological effects of chronic administration of NMDA antagonists on the development of tolerance to the antinociceptive effects of morphine will be determined in a rat tail-withdrawal procedure. These experiments will determine pharmacological endpoints such as potency, time-course, and effectiveness of NMDA antagonists on morphine-induced antinociception and tolerance. The influence of NMDA antagonists on the development of environmentally associated (i.e., associatively learned) tolerance to morphine will also be studied using the tail-withdrawal assay. The effects of dizocilpine on the retention or extinction of associative tolerance will also be examined. Finally, the effect of acute and chronic administration of NMDA antagonists on the development of tolerance to morphine in an instrumental conditioning procedure will be investigated. Rats will be trained to discriminate 3.2 mg/kg morphine from saline under a fixed-ratio schedule of food delivery. NMDA antagonists will be administered either alone or in conjunction with morphine to determine if tolerance to the stimulus and rate-decreasing effects of morphine are altered.