Accumbens Homer2‐mediated signaling: a factor contributing to mouse strain differences in alcohol drinking?

• Published in: Genes, brain and behavior Vol. 10; no. 1; pp. 111 - 126
• Main Authors: Goulding, S. P., Obara, I., Lominac, K. D., Gould, A. T., Miller, B. W., Klugmann, M., Szumlinski, K. K.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-02-2011; John Wiley & Sons, Inc
• Subjects: Alcohol; Alcohol Drinking - genetics; Alcohol Drinking - psychology; Alcoholism; Animals; Blotting, Western; C57BL/6J; Carrier Proteins - genetics; Chromatography, High Pressure Liquid; Corpus Striatum - physiology; DBA2/J; Dependovirus - genetics; Drinking behavior; Drug abuse; Ethanol; Etiology; Genetic variance; Genetic Vectors; glutamate; Glutamic Acid - metabolism; Glutamic Acid - physiology; Glutamic acid receptors; Glutamic acid receptors (metabotropic); Group1 metabotropic glutamate receptors; Homer Scaffolding Proteins; Homer2; Immunohistochemistry; Inbreeding; Male; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Microdialysis; N-Methyl-D-aspartic acid receptors; Neostriatum; Nerve Tissue Proteins - biosynthesis; Nerve Tissue Proteins - genetics; Nucleus accumbens; Nucleus Accumbens - physiology; Phenotype; PI3 kinase; PKCɛ; Polymorphism, Genetic - genetics; Protein kinase C; Reinforcement; Signal Transduction - genetics; Signal Transduction - physiology; Species Specificity; strain differences
• ISSN: 1601-1848; 1601-183X
• DOI: 10.1111/j.1601-183X.2010.00647.x

Alcohol‐induced increases in nucleus accumbens glutamate actively regulate alcohol consumption, and the alcohol responsiveness of corticoaccumbens glutamate systems relates to genetic variance in alcohol reward. Here, we extend earlier data for inbred mouse strain differences in accumbens glutamate by examining for differences in basal and alcohol‐induced changes in the striatal expression of glutamate‐related signaling molecules between inbred C57BL/6J and DBA2/J mice. Repeated alcohol treatment (8 × 2 g/kg) increased the expression of Group1 metabotropic glutamate receptors, the NR2a/b subunits of the N‐methyl‐d‐aspartate receptor, Homer2a/b, as well as the activated forms of protein kinase C (PKC) epsilon and phosphoinositol‐3‐kinase within ventral, but not dorsal, striatum. Regardless of prior alcohol experience, C57BL/6J mice exhibited higher accumbens levels of mGluR1/5, Homer2a/b, NR2a and activated kinases vs. DBA2/J mice, whereas an alcohol‐induced rise in dorsal striatum mGluR1/5 expression was observed only in C57BL/6J mice. We next employed virus‐mediated gene transfer approaches to ascertain the functional relevance of the observed strain difference in accumbens Homer2 expression for B6/D2 differences in alcohol‐induced glutamate sensitization, as well as alcohol preference/intake. Manipulating nucleus accumbens shell Homer2b expression actively regulated these measures in C57BL/6J mice, whereas DBA2/J mice were relatively insensitive to the neurochemical and behavioral effects of virus‐mediated changes in Homer2 expression. These data support the over‐arching hypothesis that augmented accumbens Homer2‐mediated glutamate signaling may be an endophenotype related to genetic variance in alcohol consumption. If relevant to humans, such data pose polymorphisms affecting glutamate receptor/Homer2 signaling in the etiology of alcoholism.