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

Abstract

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.

Genetic Base of Behavioral Disorders in Mucopolysaccharidoses: Transcriptomic Studies

“…HOMER2 function has been associated with deafness [29], and hearing deficiency is common in MPS patients. Moreover, recent report suggested connection of Homer 2 is the regulation of basal anxiety [30], and anxiety-related behavioral problems occur frequently in MPS patients. Therefore, we suggest that changed expression of HOMER2 may contribute to such MPS symptoms.…”

mGlu5 Receptor Blockade Within the Nucleus Accumbens Shell Reduces Behavioral Indices of Alcohol Withdrawal-Induced Anxiety in Mice

“…Binge-drinking is defined as a pattern of consumption that elevates blood alcohol concentrations (BAC) to ≥80 mg/dl, which equates to approximately 4–5 drinks in a 2-h period ( National Institute on Alcohol Abuse Alcoholism [NIAAA], 2004 ). In both humans and laboratory animal models, a history of binge alcohol-drinking augments symptoms of negative affect and dysphoria during periods of abstinence (e.g., Hasin and Grant, 2002 ; Grant et al, 2004 ; Squeglia et al, 2009 ; Lee et al, 2015 , 2016 , 2017a , b , 2018 ) and this withdrawal-induced negative affect is theorized to drive the negative reinforcing properties of alcohol ( Becker, 2012 ; Tunstall et al, 2017 ). While both adults and adolescents engage in binge-drinking, this pattern of alcohol consumption is especially prevalent amongst adolescents and young adults ( National Institute on Alcohol Abuse Alcoholism [NIAAA], 2017 ).…”

Interneuronal δ-GABAA receptors regulate binge drinking and are necessary for the behavioral effects of early withdrawal

“…Though only 1 in 9 of these binge drinkers will be diagnosed with an alcohol use disorder [2], this pattern of heavy episodic use is also implicated in the development of negative affect and anxiety [3,4]. Preclinical findings also support the development of anxiety-like behavior during withdrawal from this pattern of alcohol use [5][6][7]. Given the increasing prevalence of binge drinking, there is a critical need to clarify the biological underpinnings of this type of alcohol intake.…”