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Binge drinking upregulates accumbens mGluR5-Homer2-PI3K signaling: functional implications for alcoholism.

The glutamate receptor-associated protein Homer2 regulates alcohol-induced neuroplasticity within the nucleus accumbens (NAC), but the precise intracellular signaling cascades involved are not known. This study examined the role for NAC metabotropic glutamate receptor (mGluR)-Homer2-phosphatidylinositol 3-kinase (PI3K) signaling in regulating excessive alcohol consumption within the context of the scheduled high alcohol consumption (SHAC) model of binge alcohol drinking. Repeated bouts of binge drinking ( approximately 1.5 g/kg per 30 min) elevated NAC Homer2a/b expression and increased PI3K activity in this region. Virus-mediated knockdown of NAC Homer2b expression attenuated alcohol intake, as did an intra-NAC infusion of the mGluR5 antagonist MPEP [2-methyl-6-(phenylethynyl)pyridine hydrochloride] (0.1-1 microg/side) and the PI3K antagonist wortmannin (50 ng/side), supporting necessary roles for mGluR5/Homer2/PI3K in binge alcohol drinking. Moreover, when compared with wild-type littermates, transgenic mice with an F1128R point mutation in mGluR5 that markedly reduces Homer binding exhibited a 50% reduction in binge alcohol drinking, which was related to reduced NAC basal PI3K activity. Consistent with the hypothesis that mGluR5-Homer-PI3K signaling may be a mechanism governing excessive alcohol intake, the "anti-binge" effects of MPEP and wortmannin were not additive, nor were they observed in the mGluR5(F1128R) transgenic mice. Finally, mice genetically selected for a high versus low SHAC phenotype differed in NAC mGluR, Homer2, and PI3K activity, consistent with the hypothesis that augmented NAC mGluR5-Homer2-PI3K signaling predisposes a high binge alcohol-drinking phenotype. Together, these data point to an important role for NAC mGluR5-Homer2-PI3K signaling in regulating binge-like alcohol consumption that has relevance for our understanding of the neurobiology of alcoholism and its pharmacotherapy.

Pubmed ID: 19587272

Authors

  • Cozzoli DK
  • Goulding SP
  • Zhang PW
  • Xiao B
  • Hu JH
  • Ary AW
  • Obara I
  • Rahn A
  • Abou-Ziab H
  • Tyrrel B
  • Marini C
  • Yoneyama N
  • Metten P
  • Snelling C
  • Dehoff MH
  • Crabbe JC
  • Finn DA
  • Klugmann M
  • Worley PF
  • Szumlinski KK

Journal

The Journal of neuroscience : the official journal of the Society for Neuroscience

Publication Data

July 8, 2009

Associated Grants

  • Agency: NIAAA NIH HHS, Id: AA013478
  • Agency: NIAAA NIH HHS, Id: AA015351
  • Agency: NIAAA NIH HHS, Id: AA016650
  • Agency: NIAAA NIH HHS, Id: AA10760
  • Agency: NIAAA NIH HHS, Id: AA13519
  • Agency: NIDA NIH HHS, Id: DA00266
  • Agency: NIDA NIH HHS, Id: DA011742
  • Agency: NIAAA NIH HHS, Id: P50 AA010760
  • Agency: NIAAA NIH HHS, Id: P50 AA010760-020001
  • Agency: NIAAA NIH HHS, Id: P50 AA010760-030001
  • Agency: NIDA NIH HHS, Id: P50 DA000266
  • Agency: NIDA NIH HHS, Id: P50 DA000266-310015
  • Agency: NIDA NIH HHS, Id: P50 DA000266-360017
  • Agency: NIDA NIH HHS, Id: P50 DA000266-370017
  • Agency: NIDA NIH HHS, Id: P50 DA000266-380017
  • Agency: NIAAA NIH HHS, Id: R01 AA016981
  • Agency: NIAAA NIH HHS, Id: R01 AA016981-01A1
  • Agency: NIAAA NIH HHS, Id: R01 AA016981-02
  • Agency: NIDA NIH HHS, Id: R01 DA011742
  • Agency: NIDA NIH HHS, Id: R01 DA011742-02
  • Agency: NIDA NIH HHS, Id: R01 DA011742-03
  • Agency: NIDA NIH HHS, Id: R01 DA024038
  • Agency: NIAAA NIH HHS, Id: R21 AA015351
  • Agency: NIAAA NIH HHS, Id: R21 AA015351-01A2
  • Agency: NIAAA NIH HHS, Id: R21 AA015351-02
  • Agency: NIDA NIH HHS, Id: R37 DA010309
  • Agency: NIAAA NIH HHS, Id: U01 AA013478
  • Agency: NIAAA NIH HHS, Id: U01 AA013478-01
  • Agency: NIAAA NIH HHS, Id: U01 AA013478-02
  • Agency: NIAAA NIH HHS, Id: U01 AA013478-03
  • Agency: NIAAA NIH HHS, Id: U01 AA013478-04
  • Agency: NIAAA NIH HHS, Id: U01 AA013478-05
  • Agency: NIAAA NIH HHS, Id: U01 AA013519
  • Agency: NIAAA NIH HHS, Id: U01 AA013519-01
  • Agency: NIAAA NIH HHS, Id: U01 AA013519-02
  • Agency: NIAAA NIH HHS, Id: U01 AA013519-03
  • Agency: NIAAA NIH HHS, Id: U01 AA013519-04
  • Agency: NIAAA NIH HHS, Id: U01 AA013519-05
  • Agency: NIAAA NIH HHS, Id: U01 AA013519-06
  • Agency: NIAAA NIH HHS, Id: U01 AA016650
  • Agency: NIAAA NIH HHS, Id: U01 AA016650-01
  • Agency: NIAAA NIH HHS, Id: U01 AA016650-02
  • Agency: NIAAA NIH HHS, Id: U01 AA016650-03

Mesh Terms

  • Alcoholism
  • Animals
  • Carrier Proteins
  • Ethanol
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Nucleus Accumbens
  • Phenotype
  • Phosphatidylinositol 3-Kinases
  • Receptor, Metabotropic Glutamate 5
  • Receptors, Metabotropic Glutamate
  • Signal Transduction
  • Up-Regulation