Binge Drinking Upregulates Accumbens mGluR5-Homer2-PI3K Signaling: Functional Implications for Alcoholism

Abstract

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 (ϳ1.5 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 g/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.

Role for mammalian target of rapamycin complex 1 signaling in neuroadaptations underlying alcohol-related disorders

“…We further show that rapamycin blocked alcohol-mediated increase in Homer level in the NAc of mice. Our results are in line with Cozzoli et al, showing that Homer expression is elevated in the NAc of mice that experienced alcohol binge drinking (34). Homer plays a key role in the expression of adverse phenotypes associated with exposure to alcohol by modulating glutamate neurotransmission (35).…”

Selective Disruption of Metabotropic Glutamate Receptor 5-Homer Interactions Mimics Phenotypes of Fragile X Syndrome in Mice

“…Congenic mGlu5F1128R knock-in mice (mGlu5 R/R ) were generated as described previously (Cozzoli et al, 2009) and backcrossed at least 5 generations onto the C57BL/6J mice from the University of Texas Southwestern mouse breeding core facility. Congenic Fmr1 KO mice (Dutch-Belgian Fragile X Consortium, 1994) were bred on the C57BL/6J background.…”

“…To determine whether a specific disruption in mGlu5-Homer is sufficient to mimic known phenotypes of Fmr1 KO mice, we examined an mGlu5 knock-in mouse with a point mutation (F1128R) in the C-terminal, intracellular Homer-binding site (mGlu5 R/R ) (Tu et al, 1998;Cozzoli et al, 2009). We first confirmed that the mGlu5 R/R mice had reduced Homer interactions with mGlu5 and determined whether Homer interactions with other known Homer binding proteins were affected.…”

“…To test this idea, we examined a mouse with a knockin of mGlu5 harboring a single amino acid mutation in the Homer binding domain (F1128R; mGlu5 R/R ) (Cozzoli et al, 2009). We find that the mGlu5 R/R mutation does not affect Homer interactions with other binding partners or FMRP levels but is sufficient to mimic multiple phenotypes of Fmr1 KO mice, including altered mGlu5 signaling, neurophysiology, and behavior.…”

Synaptic Effects Induced by Alcohol

“…Chronic EtOH intake has also been shown to enhance intracellular signaling associated with mGluRs, particularly mGluR5, in the nucleus accumbens (NAc) (Cozzoli et al 2009). While chronic EtOH drinking can induce increases in mGluR1 and mGluR5 protein expression in NAc and amygdala (Szumlinski et al 2008;Obara et al 2009), changes in mGluR5 signaling in NAc are not always associated with an increase in the protein itself (Szumlinski et al 2008).…”