title: Ethanol-Associated Changes in Glutamate Reward Neurocircuitry: A Minireview of Clinical and Preclinical Genetic Findings.
abstract: Herein, we have reviewed the role of glutamate, the major excitatory neurotransmitter in the brain, in a number of neurochemical, -physiological, and -behavioral processes mediating the development of alcohol dependence. The findings discussed include results from both preclinical as well as neuroimaging and postmortem clinical studies. Expression levels for a number of glutamate-associated genes and/or proteins are modulated by alcohol abuse and dependence. These changes in expression include metabotropic receptors and ionotropic receptor subunits as well as different glutamate transporters. Moreover, these changes in gene expression parallel the pharmacologic manipulation of these same receptors and transporters. Some of these gene expression changes may have predated alcohol abuse and dependence because a number of glutamate-associated polymorphisms are related to a genetic predisposition to develop alcohol dependence. Other glutamate-associated polymorphisms are linked to age at the onset of alcohol-dependence and initial level of response/sensitivity to alcohol. Finally, findings of innate and/or ethanol-induced glutamate-associated gene expression differences/changes observed in a genetic animal model of alcoholism, the P rat, are summarized. Overall, the existing literature indicates that changes in glutamate receptors, transporters, enzymes, and scaffolding proteins are crucial for the development of alcohol dependence and there is a substantial genetic component to these effects. This indicates that continued research into the genetic underpinnings of these glutamate-associated effects will provide important novel molecular targets for treating alcohol abuse and dependence.
authors.affiliation: Department of Psychiatry, Indiana University School of Medicine, Indianapolis, Indiana, USA. Electronic address: ribell@iupui.edu.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Bell
authors.affiliation: Department of Psychiatry, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Sheketha R
authors.initials: SR
authors.lastname: Hauser
authors.affiliation: Departments of Biochemistry and Molecular Biology and Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana , USA.
authors.forename: Jeanette
authors.initials: J
authors.lastname: McClintick
authors.affiliation: Department of Pharmaceutical Sciences, South Dakota State University, Brookings, South Dakota, USA.
authors.forename: Shafiqur
authors.initials: S
authors.lastname: Rahman
authors.affiliation: Departments of Biochemistry and Molecular Biology and Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana , USA.
authors.forename: Howard J
authors.initials: HJ
authors.lastname: Edenberg
authors.affiliation: Department of Psychological and Brain Sciences, University of California Santa Barbara, Santa Barbara, California, USA.
authors.forename: Karen K
authors.initials: KK
authors.lastname: Szumlinski
authors.affiliation: Department of Psychiatry, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: William J
authors.initials: WJ
authors.lastname: McBride
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects*; D000431:Ethanol / Q000494:pharmacology*; D018698:Glutamic Acid / Q000008:administration & dosage*; D006801:Humans
chemical_list: D000431:Ethanol; D018698:Glutamic Acid
keywords: addiction; alcohol nonpreferring; alcohol preferring; alcoholism; family history; genes and environment; genetics; glutamate system; pharmacogenetics; pharmacogenomics; predisposition; selective breeding
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