title: Homer2 within the nucleus accumbens core bidirectionally regulates alcohol intake by both P and Wistar rats.
abstract: In murine models of alcoholism, the glutamate receptor scaffolding protein Homer2 bidirectionally regulates alcohol intake. Although chronic alcohol drinking increases Homer2 expression within the core subregion of the nucleus accumbens (NAc) of alcohol-preferring P rats, the relevance of this neuroadaptation for alcohol intake has yet to be determined in rats. Thus, the present study employed an adeno-associated viral vector (AAV) strategy to over-express and knock down the major rodent isoform Homer2b within the NAc of both P and outbred Wistar rats to examine for changes in alcohol preference and intake (0-30% v/v) under continuous-access procedures. The generalization of AAV effects to non-drug, palatable, sweet solutions was also determined in tests of sucrose (0-5% w/v) and saccharin (0-0.125% w/v) intake/preference. No net-flux in vivo microdialysis was conducted for glutamate in the NAc to relate Homer2-dependent changes in alcohol intake to extracellular levels of glutamate. Line differences were noted for sweet solution preference and intake, but these variables were not affected by intra-NAc AAV infusion in either line. In contrast, Homer2b over-expression elevated, while Homer2b knock-down reduced, alcohol intake in both lines, and this effect was greatest at the highest concentration. Strikingly, in P rats there was a direct association between changes in Homer2b expression and NAc extracellular glutamate levels, but this effect was not seen in Wistar rats. These data indicate that NAc Homer2b expression actively regulates alcohol consumption by rats, paralleling this previous observation in mice. Overall, these findings underscore the importance of mesocorticolimbic glutamate activity in alcohol abuse/dependence and suggest that Homer2b and/or its constituents may serve as molecular targets for the treatment of these disorders.
authors.affiliation: Department of Psychological and Brain Sciences, Neuroscience Research Institute, University of California at Santa Barbara, Santa Barbara, CA 93106-9660, USA.
authors.forename: Arshad
authors.initials: A
authors.lastname: Haider
authors.affiliation: Department of Psychological and Brain Sciences, Neuroscience Research Institute, University of California at Santa Barbara, Santa Barbara, CA 93106-9660, USA.
authors.forename: Nicholas C
authors.initials: NC
authors.lastname: Woodward
authors.affiliation: Department of Psychological and Brain Sciences, Neuroscience Research Institute, University of California at Santa Barbara, Santa Barbara, CA 93106-9660, USA.
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Lominac
authors.affiliation: Department of Psychological and Brain Sciences, Neuroscience Research Institute, University of California at Santa Barbara, Santa Barbara, CA 93106-9660, USA.
authors.forename: Arianne D
authors.initials: AD
authors.lastname: Sacramento
authors.affiliation: Translational Neuroscience Facility, School of Medical Sciences, University of New South Wales, New South Wales 2052, Australia.
authors.forename: Matthias
authors.initials: M
authors.lastname: Klugmann
authors.affiliation: Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Bell
authors.affiliation: Department of Psychological and Brain Sciences, Neuroscience Research Institute, University of California at Santa Barbara, Santa Barbara, CA 93106-9660, USA. Electronic address: szumlinski@psych.ucsb.edu.
authors.forename: Karen K
authors.initials: KK
authors.lastname: Szumlinski
mesh_terms: D000428:Alcohol Drinking / Q000235:genetics / Q000378:metabolism* / Q000523:psychology; D000818:Animals; D002352:Carrier Proteins / Q000502:physiology*; D000072233:Homer Scaffolding Proteins; D008297:Male; D017551:Microdialysis / Q000379:methods; D009714:Nucleus Accumbens / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D002352:Carrier Proteins; D000072233:Homer Scaffolding Proteins; C000606625:Homer2 protein, mouse; C000606626:Homer2 protein, rat
keywords: AAV; Alcohol preference; Glutamate; Homer2; Nucleus accumbens; P rat