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.
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.
Zhao
Yu
Y
Molecular and Integrative Neurosciences Department, The Scripps Research Institute, La Jolla, California 92037, USA.
Dayas
Christopher V
CV
Aujla
Harinder
H
Baptista
Marco A S
MA
Martin-Fardon
Rémi
R
Weiss
Friedbert
F
D000428:Alcohol Drinking / Q000503:physiopathology; D000437:Alcoholism / Q000235:genetics / Q000503:physiopathology* / Q000523:psychology; D000596:Amino Acids / Q000494:pharmacology; D000679:Amygdala / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001007:Anxiety / Q000503:physiopathology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D003463:Cues; D004597:Electroshock; D000431:Ethanol / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D005108:Extinction, Psychological / Q000187:drug effects* / Q000502:physiology; D016762:Genes, fos; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008032:Limbic System / Q000187:drug effects* / Q000503:physiopathology; D008297:Male; D009042:Motivation; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics; D010286:Paraventricular Hypothalamic Nucleus / Q000187:drug effects / Q000503:physiopathology; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis*; D051381:Rats; D017208:Rats, Wistar; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists* / Q000502:physiology; D012201:Reward; D055502:Secondary Prevention; D012646:Self Administration; D012686:Septal Nuclei / Q000187:drug effects / Q000503:physiopathology; D013312:Stress, Physiological / Q000235:genetics / Q000503:physiopathology* / Q000523:psychology; D009435:Synaptic Transmission / Q000187:drug effects
D000596:Amino Acids; D019086:Bridged Bicyclo Compounds, Heterocyclic; D018690:Excitatory Amino Acid Agonists; C118218:LY 379268; D009419:Nerve Tissue Proteins; D016760:Proto-Oncogene Proteins c-fos; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2; C102718:metabotropic glutamate receptor 3; D000431:Ethanol