This application seeks to continue an established research program concerned with understanding the compulsive nature of ethanol-seeking behavior at the neuropharmacological and neurochemical level. Efforts during the previous funding period were dedicated to developing animal models of relapse and implementation of these models for investigations of the neuropharmacological and neurochemical mechanisms responsible for the resumption of ethanol seeking following abstinence. In this work, several promising leads emerged on novel neural systems that participate in the regulation of ethanol-seeking and relapse. Among these is modulation of glutamatergic neurotransmission by the Group II family of metabotropic glutamate receptors (mGluRs). These findings, along with an emerging literature implicating Group II mGluRs in several neurobehavioral effects of ethanol, strongly suggest that mGluR-mediated neural events participate in the control of ethanol-seeking elicited by exposure to drug-related environmental stimuli and stress. The purpose of this proposal is to test this hypothesis at the behavioral, neurocircuitry, and neurochemical level. The research plan is to first establish, via pharmacological manipulations, the significance of Group II mGluRs in ethanol-seeking associated with alcohol cue exposure and stress using operant response-reinstatement models of relapse (SPECIFIC AIM 1). These studies will be followed by investigation of the role of Group II mGluRs in susceptibility to relapse in ethanol-dependent rats. This question will be approached from two perspectives. The first will focus on the consequences of a history of repeated ethanol withdrawal on Group II mGluR receptor function and the regulation of ethanol-seeking by these receptors (SPECIFIC AIM 2). The second approach will be to examine whether Group II mGluRs play a specific role in enhanced susceptibility relapse that develops as a result of experience with ethanol during withdrawal - an event that introduces learning about a previously latent incentive dimension of ethanol's rewarding potential, namely its capacity to alleviate physically or emotionally aversive states (SPECIFIC AIM 3). These studies of the behavioral pharmacology of Group II mGluRs as it relates to ethanol-seeking and relapse will be complemented by experiments designed to elucidate the neurocircuitry details and neurochemical mechanisms by which Group II mGluR-regulated glutamate signaling attenuates cue and stress-induced reinstatement of ethanol-seeking behavior (SPECIFIC AIM 4). The proposed research will generate original information on a novel neural mechanism relevant for understanding the neurobiological basis of long-lasting vulnerability to relapse in alcoholics. As well, the results will provide information directly relevant for evaluating the potential of Group II mGluRs to serve as treatment drug targets for relapse prevention.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Research Project (R01)
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Neurotoxicology and Alcohol Study Section (NAL)
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Egli, Mark
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Scripps Research Institute
La Jolla
United States
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Martin-Fardon, Rémi; Weiss, Friedbert (2017) Perseveration of craving: effects of stimuli conditioned to drugs of abuse versus conventional reinforcers differing in demand. Addict Biol 22:923-932
Martin-Fardon, Rémi; Weiss, Friedbert (2013) Modeling relapse in animals. Curr Top Behav Neurosci 13:403-32
Kufahl, Peter R; Martin-Fardon, Rémi; Weiss, Friedbert (2011) Enhanced sensitivity to attenuation of conditioned reinstatement by the mGluR 2/3 agonist LY379268 and increased functional activity of mGluR 2/3 in rats with a history of ethanol dependence. Neuropsychopharmacology 36:2762-73
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Sidhpura, Nimish; Weiss, Friedbert; Martin-Fardon, Rémi (2010) Effects of the mGlu2/3 agonist LY379268 and the mGlu5 antagonist MTEP on ethanol seeking and reinforcement are differentially altered in rats with a history of ethanol dependence. Biol Psychiatry 67:804-11
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