Abstract
Withdrawal from binge-drinking increases negative affect, coinciding with increased expression of the metabotropic glutamate receptor 5 (mGlu5) within the shell of the nucleus accumbens (AcbSh). Supporting a causal-effect relationship, systemic treatment with the mGlu5 receptor antagonist MTEP [3-((2-Methyl-4-thiazolyl)ethynyl)pyridine] is anxiolytic in binge-drinking adult and adolescent mice. Here, we employed neuropharmacological approaches to examine the functional relevance of AcbSh mGlu5 for behavioral indices of alcohol withdrawal-induced hyper-anxiety. Adult (PND 56) and adolescent (PND 28) male C57BL/6J mice consumed alcohol under modified Drinking-in-the-Dark procedures (10, 20, and 40% alcohol v/v) for 14 days. At an alcohol withdrawal time-point when mice manifest robust behavioral signs of hyper-anxiety (1 and 28 days withdrawal for adults and adolescents, respectively), mice were infused intra-AcbSh with 0, 1 or 10 μg MTEP and then affect was assayed in the light-dark shuttle box, marble-burying and forced swim tests. Brain tissue was collected to evaluate changes in Egr1 (early growth response protein 1) induction to index AcbSh neuronal activity. As expected, alcohol-experienced mice exhibited behavioral signs of hyper-emotionality. The anxiolytic effects of intra-AchSh MTEP were modest, but dose-dependent, and varied with age of drinking-onset. In adult-onset mice, only the 1 μg MTEP dose reduced withdrawal-induced hyper-anxiety, whereas only the higher dose was effective in adolescent-onset animals. MTEP reduced Egr1 expression within the AcbSh, irrespective of alcohol drinking history or age of drinking-onset. However, only the high MTEP dose reduced Egr1 expression in adolescent-onset binging mice. These results implicate AcbSh mGlu5 in modulating alcohol withdrawal-induced negative affect and suggest age differences in the neurobiological effects of alcohol withdrawal and behavioral responsiveness to mGlu5 blockade within the AcbSh.
Highlights
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)
On day 11 of drinking, adults consumed an average of 3.69 ± 0.31 g/kg resulting in an average BAC of 69.93 ± 3.17 mg/dl and adolescents consumed an average of 4.94 ± 0.34 g/kg resulting in an average BAC of 78.29 ± 3.01 mg/dl
The accumbens shell (AcbSh) is a component of the emotional circuitry of the extended amygdala, relatively little is known regarding the role of the AcbSh in negative affective states during drug withdrawal
Summary
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 alcoholdrinking 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). These latter findings are in-line with the epidemiological literature demonstrating latent and enduring emotional disturbances in individuals with a history of problem drinking during adolescence (e.g., Hasin and Grant, 2002; Grant et al, 2004; Hasin et al, 2007; Squeglia et al, 2009) and argue that binge-drinking during adolescence perturbs the development of neural circuits controlling emotionality
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