Homer2 within the central nucleus of the amygdala modulates withdrawal-induced anxiety in a mouse model of binge-drinking

• Published in: Neuropharmacology 2018-01, Vol.128, p.448-459
• Main Authors: Lee, K.M., Coelho, M.A., Sern, K.R., Szumlinski, K.K.
• Format: Article
• Language: English
• Subjects: Adolescence; Age Factors; Alcohol Drinking - physiopathology; Alcohol Drinking - psychology; Alcoholism; Amygdala; Animals; Anxiety; Anxiety - etiology; Anxiety - pathology; Binge drinking; Central Amygdaloid Nucleus - metabolism; Central Amygdaloid Nucleus - pathology; Choice Behavior - physiology; Dark Adaptation - drug effects; Dark Adaptation - physiology; Disease Models, Animal; Ethanol - administration & dosage; Gene Expression Regulation - drug effects; Gene Expression Regulation - physiology; Green Fluorescent Proteins - genetics; Green Fluorescent Proteins - metabolism; Homer Scaffolding Proteins - genetics; Homer Scaffolding Proteins - metabolism; Homer2; Male; Mice; Mice, Inbred C57BL; Neurons - drug effects; Neurons - metabolism; Substance Withdrawal Syndrome - complications; Transduction, Genetic
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2017.11.001

A history of binge-drinking decreases protein expression of the glutamate-related scaffolding protein Homer2 within the central nucleus of the amygdala (CEA), coinciding with behavioral signs of negative affect. To assess the functional relevance of this protein change for withdrawal-induced hyper-anxiety, adult (PND 56) and adolescent (PND 28) male C57BL/6J mice were administered an intra-CEA infusion of an adeno-associated viral vector (AAV) carrying either cDNA to express Homer2 (H2-cDNA) or GFP as control. Mice underwent 14 days of binge-drinking under multi-bottle, limited-access conditions and were assayed for behavioral signs of negative affect during withdrawal using the light-dark box, marble burying, and forced swim tests (FST). Following behavioral testing, all animals experienced 5 days of drinking to evaluate the effects of prior alcohol experience and Homer2 manipulation on subsequent alcohol consumption. During protracted (4 weeks) withdrawal, adolescent alcohol-experienced GFP controls showed increased signs of negative affect across all 3 assays, compared to water-drinking GFP animals, and also showed elevated alcohol consumption during the subsequent drinking period. Homer2-cDNA infusion in adolescent-onset alcohol-drinking animals was anxiolytic and reduced subsequent alcohol consumption. Conversely, Homer2-cDNA was anxiogenic and increased drinking in water-drinking adolescents. Unfortunately, the data from adult-onset alcohol-drinking animals were confounded by low alcohol consumption and negligible behavioral signs of anxiety. Nevertheless, the present results provide novel cause-effect evidence supporting a role for CEA Homer2 in the regulation of both basal anxiety and the time-dependent intensification of negative affective states in individuals with a history of binge-drinking during adolescence. •Age-related differences were observed with respect to alcohol intake and the subsequent manifestation of a negative affective state during withdrawal.•The negative affective state elicited by adolescent-onset binge-drinking incubated with the passage of time in withdrawal.•Homer2 over-expression within the central nucleus of the amygdala was anxiolytic and reduced drinking in adolescent-onset mice.•Conversely, Homer2 over-expression was anxiogenic and increased drinking in alcohol-naïve controls.