This proposal seeks to continue studies conducted during previous funding periods that were concerned with the development of behavioral methods modeling long-lasting vulnerability to relapse in rats, and the application of these models for the testing of pharmacological agents that modify cocaine-seeking behavior. Susceptibility to relapse presents a great challenge for the treatment of cocaine addiction. Major factors implicated in the high rates of relapse associated with cocaine and other drug addictions include conditioned responses to drug-related environmental stimuli and subjective reactions to stress. A growing literature suggests that metabotropic glutamate receptors (mGluRs) play a prominent role in mediating neurobehavioral effects of cocaine and other drugs of abuse. Emerging evidence also implicates mGluRs in the regulation of anxiety and behavioral responses to stress. Based on these findings one may hypothesize that mGluR-mediated neural events play a role in conditioned drug-seeking responses elicited by drug-related environmental stimuli as well as in drug-seeking behavior induced by stress. The objective of this proposal is (1) to test this hypothesis by studying the effects of novel, selective mGluR ligands on drug-seeking and the resistance to extinction of this behavior in reinstatement models of relapse, and (2) to establish whether specific mGluR subtypes represent potential treatment targets for addictive behavior associated with the exposure to drug cues and stress. The research plan is to first systematically characterize the effect of ligands for Group I and II mGluRs on cocaine-seeking behavior induced by a drug-associated contextual stimulus or acute footshock stress, and to verify pharmacologically a role of specific mGluR subtypes in reductions of cocaine-seeking behavior. The characterization of the potential of mGluR ligands to block conditioned or stress-induced cocaine-seeking then will be extended to drug-seeking associated with other classes of drugs including heroin and nicotine. Finally, the potential of mGluR ligands to attenuate drug-seeking will be further qualified by establishing whether these agents preferentially modify behavior directed at obtaining drug reinforcers or exert general suppressant effects on motivated behavior, using stimuli conditioned to conventional reinforcers with high, but qualitatively divergent incentive value. These studies are expected to provide novel information on the role of specific mGluRs in the regulation of conditioned or stress-induced drug-seeking behavior as well as their role in incentive motivation, in general. This information will be directly relevant for the development of treatments targeting the mGluR system.
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