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The Journal of Neuroscience, September 27, 2006, 26(39):9967-9974; doi:10.1523/JNEUROSCI.2384-06.2006

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Neurobiology of Disease
Activation of Group II Metabotropic Glutamate Receptors Attenuates Both Stress and Cue-Induced Ethanol-Seeking and Modulates c-fos Expression in the Hippocampus and Amygdala

Yu Zhao, ^* Christopher V. Dayas, ^* Harinder Aujla, Marco A. S. Baptista, Rémi Martin-Fardon, and Friedbert Weiss

Molecular and Integrative Neurosciences Department, The Scripps Research Institute, La Jolla, California 92037

Correspondence should be addressed to Dr. Christopher V. Dayas, Molecular and Integrative Neurosciences Department, The Scripps Research Institute (SP30-2120), 10550 North Torrey Pines Road, La Jolla, CA 92037. Email: cvdayas{at}scripps.edu

Major precipitating factors for relapse to drug use are stress and exposure to drug-related environmental stimuli. Group II (mGlu_2/3) metabotropic glutamate receptors (mGluRs) are densely expressed within circuitries mediating the motivating effects of stress and drug cues and, therefore, may participate in regulating drug-seeking linked to both of these risk factors. Thus, we tested the hypothesis that pharmacological activation of group II mGluRs modifies both stress- and cue-induced ethanol-seeking, using reinstatement models of relapse. In parallel, brain c-fos expression was examined to identify neural substrates for the behavioral effects of group II mGluR activation. The selective mGlu_2/3 agonist LY379268 (1R,4R,5S,6R-2-oxa-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylate) (0.3, 1.0, and 3.0 mg/kg, s.c.) dose dependently blocked the recovery of extinguished ethanol-seeking induced by either footshock stress or ethanol-associated discriminative stimuli. These effects were accompanied by modulation of c-fos expression in the hippocampus, central nucleus of the amygdala, bed nucleus of the stria terminalis, and medial parvocellular paraventricular nucleus of the hypothalamus. The results implicate group II mGluRs as a shared neuropharmacological substrate for ethanol-seeking elicited by both drug cues and stress and identify group II mGluRs as promising treatment targets for relapse prevention.

Key words: addiction; anxiolytic; glutamate; reinstatement; relapse; alcohol

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Received Nov. 20, 2005; revised Aug. 3, 2006; accepted Aug. 24, 2006.

Correspondence should be addressed to Dr. Christopher V. Dayas, Molecular and Integrative Neurosciences Department, The Scripps Research Institute (SP30-2120), 10550 North Torrey Pines Road, La Jolla, CA 92037. Email: cvdayas{at}scripps.edu

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				J. Stewart Psychological and neural mechanisms of relapse Phil Trans R Soc B, October 12, 2008; 363(1507): 3147 - 3158. [Abstract] [Full Text] [PDF]

				C. M. Gremel and C. L. Cunningham Roles of the Nucleus Accumbens and Amygdala in the Acquisition and Expression of Ethanol-Conditioned Behavior in Mice J. Neurosci., January 30, 2008; 28(5): 1076 - 1084. [Abstract] [Full Text] [PDF]

				M. E. Liechti, L. Lhuillier, K. Kaupmann, and A. Markou Metabotropic Glutamate 2/3 Receptors in the Ventral Tegmental Area and the Nucleus Accumbens Shell Are Involved in Behaviors Relating to Nicotine Dependence J. Neurosci., August 22, 2007; 27(34): 9077 - 9085. [Abstract] [Full Text] [PDF]

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