EFFECT OF NMDA ANTAGONISTS ON ACUTE OPIOID DEPENDENCE

Virginia Commonwealth University, Richmond VA

Investigators

Abstract

DESCRIPTION: (Applicant's Abstract) This project will investigate the interaction between the NMDA and opioid neurotransmitter systems by evaluating the ability of NMDA receptor antagonists to alter the development of acute opioid dependence. Protracted use of opioid compounds for licit or illicit purposes can result in the development of tolerance to their pharmacological effects as well as physical dependence. These neuroadaptations have been implicated in the formation of drug abuse disorders by escalating opioid use and contributing to relapse. Animal and human studies have shown that administration of a single dose of an opioid agonist some hours prior to opioid antagonist administration will enhance the potency of the antagonist in eliciting signs typically associated with opioid withdrawal. This sensitization to the physiological and behavioral effects of opioid antagonists has also been termed "acute dependence" and has been suggested to represent the initial neuroadaptive changes in the development of opioid dependence. Studies have shown that NMDA receptor antagonists are able to prevent the development of tolerance and dependence in animal models utilizing chronic opioid administration. The proposed study will further characterize the NMDA/opioid interaction by evaluating the effects of NMDA antagonists in a model of acute dependence. Production and/or attenuation of acute opioid antagonist sensitization (AOAS) under various experimental conditions will be determined by comparing the potency of naltrexone to disrupt operant behavior under a FIR schedule of responding for food reinforcers in rats. AOAS is manifest as a leftward shift in the naltrexone dose-effect curve. The role of NMDA neurotransmission in this model will be evaluated by 1) testing the efficacy of the potent NMDA antagonist dizocilpine for attenuating AOAS and 2) evaluating the efficacy of different site-selective NMDA antagonists, many of which have better side-effect profiles than MK-801 and other PCP-like antagonists, in attenuating the development of AOAS. Characterization of the involvement of NMDA neurotransmission in this model of acute dependence will provide evidence of similarities and differences with chronic administration models of opioid dependence; help delineate the role of NMDA neurotransmission in this neuroadaptive process and potentially provide a rapid screening model for evaluating NMDA; and other glutamate receptor modulators as potential pharmacotherapies for opioid abuse.