Binge alcohol drinking is the most prevalent form of alcoholism within the United States yet the neurobiology of binge drinking is not well-understood. A significant body of functional data from my laboratory demonstrates that alcohol-induced increases in mGluR5/Homer2 pathway activity (via PI3K and PKC?) within the nucleus accumbens (NAC) shell as important for the propensity to consume alcohol in murine models of binge alcohol drinking. The NAC shell shares cytoarchitectural, anatomical and functional features with other members of the extended amygdala subcircuit, including the central nucleus of the amygdala (CeA) - a brain region highly implicated in the neurobiology of alcoholism. Homer2 is enriched in the CeA and its levels are up-regulated in concert with those of mGluR1/5 in models of chronic alcohol drinking. Preliminary functional data indicates that, as observed for the NAC shell, inhibiting CeA mGluR5, as well as PI3K, activity reduces binge alcohol drinking in mice, a finding consistent with existing reports for a reduction in limited access alcohol intake upon CeA PKC? knock-down. Such data point to an important role also for mGluR5-mediated signaling through both PI3K and PKC? within the CeA in the regulation of, and perhaps genetic vulnerability to, binge drink. This project will expand upon these recent observations and employ our combination of behavioral pharmacological and genetic approaches to test the over-arching hypothesis that idiopathic or alcohol-induced increases in mGluR-mediated signaling through its ?q subunit to PKC? and its ?? subunit to PI3K within extended amygdala structures, notably the CeA, is important for the manifestation of, and genetic vulnerability to, binge alcohol drinking.
Aim 1 of this proposal will employ a combination of pharmacological and genetic approaches to test the specific hypothesis that intact signaling through the mGluR5-Homer2-PI3K and mGluR5-Homer2-PKC? pathways within the CeA is necessary and/or sufficient for maintaining excessive alcohol intake in mice.
Aim 2 will relate these functional studies to the short- and long-term effects of a history of binge drinking upon the expression and activational state of mGluR5-mediated signaling pathways within extended amygdala structures and their prefrontal cortical interconnected regions.
Aim 3 will relate basal and alcohol-stimulated mGluR5-Homer2-kinase pathway activation to genetic propensity to binge drink, using several animal models. It is anticipated that the results obtained will greatly increase our understanding of the role for mGluR/Homer2-mediated signaling within the extended amygdala regulates the maintenance of, and vulnerability to, excessive alcohol drinking. Such knowledge will point to alcohol-induced alterations in mGluR5/Homer-mediated regulation of post-synaptic aspects of glutamate transmission within extended amygdala structures and their prefrontal cortical interconnections as critical neuroadaptations regulating the propensity to binge drink, which has high relevance for understanding of alcoholism vulnerability and its treatment with glutamate-targeting pharmacotherapies.
Repeated alcohol administration induces persistent, maladaptive changes in the excitatory neurotransmitter glutamate within the extended amygdala and some of these neuroadaptations are central to maintaining excessive alcohol drinking behavior. Thus, an understanding of the molecular mechanisms involved in the capacity of repeated bouts of binge alcohol drinking upon the postsynaptic mechanisms mediating extended amygdala glutamate transmission will assist in the identification of novel therapeutic targets for the treatment of alcoholism, as well as assist in screening at risk individuals or predicting individual treatment outcomes. To this end, this project will employ a combination of behavioral, genetic and immunological approaches to characterize the short- and long-term influences of binge drinking upon mGluR5-mediated signaling within the extended amygdala and its relation to binge drinking vulnerability.
|Bell, Richard L; Hauser, Sheketha R; McClintick, Jeanette et al. (2016) Ethanol-Associated Changes in Glutamate Reward Neurocircuitry: A Minireview of Clinical and Preclinical Genetic Findings. Prog Mol Biol Transl Sci 137:41-85|
|Cozzoli, Debra K; Courson, Justin; Rostock, Charlotte et al. (2016) Protein Kinase C Epsilon Activity in the Nucleus Accumbens and Central Nucleus of the Amygdala Mediates Binge Alcohol Consumption. Biol Psychiatry 79:443-51|
|Quadir, Sema G; Santos, Jaqueline Rocha Borges Dos; Campbell, Rianne R et al. (2016) Homer2 regulates alcohol and stress cross-sensitization. Addict Biol 21:613-33|
|Haider, Arshad; Woodward, Nicholas C; Lominac, Kevin D et al. (2015) Homer2 within the nucleus accumbens core bidirectionally regulates alcohol intake by both P and Wistar rats. Alcohol 49:533-42|
|Lee, Kaziya M; Coehlo, Michal; McGregor, Hadley A et al. (2015) Binge alcohol drinking elicits persistent negative affect in mice. Behav Brain Res 291:385-98|
|Bateman, Nicholas W; Goulding, Scott P; Shulman, Nicholas J et al. (2014) Maximizing peptide identification events in proteomic workflows using data-dependent acquisition (DDA). Mol Cell Proteomics 13:329-38|
|Cozzoli, Debra K; Courson, Justin; Wroten, Melissa G et al. (2014) Binge alcohol drinking by mice requires intact group 1 metabotropic glutamate receptor signaling within the central nucleus of the amygdala. Neuropsychopharmacology 39:435-44|
|Lum, Emily N; Campbell, Rianne R; Rostock, Charlotte et al. (2014) mGluR1 within the nucleus accumbens regulates alcohol intake inÂ mice under limited-access conditions. Neuropharmacology 79:679-87|
|Cui, Changhai; Noronha, Antonio; Morikawa, Hitoshi et al. (2013) New insights on neurobiological mechanisms underlying alcohol addiction. Neuropharmacology 67:223-32|
|Obara, Ilona; Goulding, Scott P; Hu, Jia-Hua et al. (2013) Nerve injury-induced changes in Homer/glutamate receptor signaling contribute to the development and maintenance of neuropathic pain. Pain 154:1932-45|
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