title: Rescue of infralimbic mGluR2 deficit restores control over drug-seeking behavior in alcohol dependence.
abstract: A key deficit in alcohol dependence is disrupted prefrontal function leading to excessive alcohol seeking, but the molecular events underlying the emergence of addictive responses remain unknown. Here we show by convergent transcriptome analysis that the pyramidal neurons of the infralimbic cortex are particularly vulnerable for the long-term effects of chronic intermittent ethanol intoxication. These neurons exhibit a pronounced deficit in metabotropic glutamate receptor subtype 2 (mGluR(2)). Also, alcohol-dependent rats do not respond to mGluR(2/3) agonist treatment with reducing extracellular glutamate levels in the nucleus accumbens. Together these data imply a loss of autoreceptor feedback control. Alcohol-dependent rats show escalation of ethanol seeking, which was abolished by restoring mGluR(2) expression in the infralimbic cortex via viral-mediated gene transfer. Human anterior cingulate cortex from alcoholic patients shows a significant reduction in mGluR(2) transcripts compared to control subjects, suggesting that mGluR(2) loss in the rodent and human corticoaccumbal neurocircuitry may be a major consequence of alcohol dependence and a key pathophysiological mechanism mediating increased propensity to relapse. Normalization of mGluR(2) function within this brain circuit may be of therapeutic value.
authors: Institute of Psychopharmacology at Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, 68159 Mannheim, Germany.
authors: Marcus W
authors: MW
authors: Meinhardt
authors: Anita C
authors: AC
authors: Hansson
authors: Stephanie
authors: S
authors: Perreau-Lenz
authors: Christina
authors: C
authors: Bauder-Wenz
authors: Oliver
authors: O
authors: Stählin
authors: Markus
authors: M
authors: Heilig
authors: Clive
authors: C
authors: Harper
authors: Karla U
authors: KU
authors: Drescher
authors: Rainer
authors: R
authors: Spanagel
authors: Wolfgang H
authors: WH
authors: Sommer
mesh_terms: D000437:Alcoholism / Q000235:genetics / Q000503:physiopathology / Q000523:psychology*; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D001921:Brain / Q000473:pathology; D002492:Central Nervous System Depressants / Q000494:pharmacology; D039721:Diagnostic and Statistical Manual of Mental Disorders; D015536:Down-Regulation / Q000502:physiology; D058999:Drug-Seeking Behavior / Q000502:physiology*; D000431:Ethanol / Q000494:pharmacology; D015870:Gene Expression; D005822:Genetic Vectors; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D016086:Lentivirus / Q000235:genetics; D008032:Limbic System / Q000502:physiology*; D008297:Male; D046228:Microarray Analysis; D012313:RNA / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction; D018094:Receptors, Metabotropic Glutamate / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D013375:Substance Withdrawal Syndrome / Q000523:psychology
chemical_list: D002492:Central Nervous System Depressants; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2; D000431:Ethanol; D012313:RNA