Involvement of the GABA_A Receptor in Age‐Dependent Differences in Binge‐Like Ethanol Intake

Abstract

This study adds to the existing literature demonstrating the crucial role of the GABAA receptor in alcohol consumption. In addition, it suggests that age differences in the GABAA receptor modulation of binge alcohol drinking might be more dependent on extrasynaptic GABAA receptors.

Activation of extrasynaptic δ-GABAA receptors globally or within the posterior-VTA has estrous-dependent effects on consumption of alcohol and estrous-independent effects on locomotion

“…Previous studies from our lab (Moore et al, 2007; Fritz and Boehm, 2014; Quoilin and Boehm, 2016) and others (Ramaker et al, 2011, 2012, 2014a, 2014b) have shown that THIP can significantly reduce voluntary ethanol consumption and operant responding for the drug. Given THIP’s high affinity for δ-GABA A Rs, these data support a possible role for these extrasynaptically located GABA A receptors in mediating this pattern of ethanol use.…”

“…Indeed, genetic inactivation of δ-GABA A R in the nucleus accumbens reduces alcohol-drinking behavior in male mice (Nie et al, 2011). Further, pharmacological manipulation using 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-3-ol (THIP/gaboxadol), an agonist with high efficacy and selectivity for δGABA A Rs (Boehm et al, 2006; Bhattarai, 2011; Meera, 2011; Mortensen 2010), reduces binge alcohol consumption in mice (Moore et al, 2007; Fritz and Boehm, 2014; Quoilin and Boehm, 2016). However, no study has explored the effect that estrous cycle may have on the role that δ-GABA A Rs play in mediating binge drinking in females.…”

Differential Sensitivity to Ethanol‐Induced Circadian Rhythm Disruption in Adolescent and Adult Mice

“…It is also noteworthy that adolescent rats are initially less sensitive to ethanol-induced sleep disruption (Ehlers et al, 2013). Thus, it is conceivable that the initial lack of circadian- and sleep-related consequences adolescent rodents experience with acute ethanol may contribute to their higher alcohol consumption (Holstein et al, 2011, Melendez, 2011, Moore et al, 2010, Quoilin and Boehm, 2016). However, given that adolescent rats also show greater slow wave sleep suppression the day following acute ethanol compared to adults (Ehlers et al, 2013), it is also tempting to speculate that heavy drinking in adolescents may be reinforced during hangover to induce sleep.…”

“…Results from studies employing C57BL/6J mice are somewhat more variable, although generally comparable to those in rats. During adolescence, mice of this strain consume more alcohol than adults, particularly in models of limited access, intermittent access, and binge-drinking (Holstein et al, 2011, Melendez, 2011, Moore et al, 2010, Quoilin and Boehm, 2016; but see also Hefner and Holmes, 2007). Adolescent C57BL/6J mice also show differential sensitivity to acute ethanol, including increased sensitivity to ethanol-induced locomotor stimulation (Hefner and Holmes, 2007, Melon and Boehm, 2011), anxiolysis (Hefner and Holmes, 2007), and certain memory impairments (Lacaille et al, 2015, Spanos et al, 2012), and decreased sensitivity to ethanol-induced conditioned taste aversion (CTA; (Holstein et al, 2011, Moore et al, 2013), sedation (Hefner and Holmes, 2007, Linsenbardt et al, 2009), hypothermia and locomotor suppression (Lopez et al, 2003).…”

Glyoxalase (GLO1) inhibition or genetic overexpression does not alter ethanol’s locomotor effects: implications for GLO1 as a therapeutic target in alcohol use disorders

“…As a positive control, we also assessed the effects of the non-selective GABA A agonist muscimol, which has been previously shown to potentiate the sedative effects of ethanol (Holstein et al, 2004). We selected doses of pBBG and Muscimol that had been previously shown to inhibit ethanol drinking (McMurray et al, 2017a;Quoilin & Boehm, 2016). To further explore whether GLO1 alterations affect the locomotor response to ethanol, we also assessed the effect of Glo1 overexpression on the locomotor response to ethanol.…”