Early life stress is a risk factor for excessive alcohol drinking and impulsivity in adults and is mediated via a CRF/GABA_A mechanism

Abstract

Childhood stress and trauma are associated with substance use disorders in adulthood, but the neurological changes that confer increased vulnerability are largely unknown. In this study, maternal separation [MS] stress, restricted to the pre-weaning period, was used as a model to study mechanisms of protracted effects of childhood stress/traumatic experiences on binge drinking and impulsivity. Using an operant self-administration model of binge drinking and a delay discounting assay to measure impulsive-like behavior, we report that early life stress due to MS facilitated acquisition of binge drinking and impulsivity during adulthood in rats. Previous studies have shown heightened levels of corticotropin releasing factor (CRF) after MS, and here, we add that MS increased expression levels of GABAA α2 subunit in central stress circuits. To investigate the precise role of these circuits in regulating impulsivity and binge drinking, the CRF1 receptor antagonist antalarmin and the novel GABAA α2 subunit ligand 3-PBC were infused into the central amygdala [CeA] and medial prefrontal cortex [mPFC]. Antalarmin and 3-PBC at each site markedly reduced impulsivity and produced profound reductions on binge-motivated alcohol drinking, without altering responding for sucrose. Furthermore, whole-cell patch-clamp studies showed that low concentrations of 3-PBC directly reversed the effect of relatively high concentrations of ethanol on α2β3γ2 GABAA receptors, by a benzodiazepine site-independent mechanism. Together, our data provide strong evidence that maternal separation, i.e., early life stress, is a risk factor for binge drinking, and is linked to impulsivity, another key risk factor for excessive alcohol drinking. We further show that pharmacological manipulation of CRF and GABA receptor signaling is effective to reverse binge drinking and impulsive-like behavior in MS rats. These results provide novel insights into the role of the brain stress systems in the development of impulsivity and excessive alcohol consumption.

Epigenetic mechanisms of alcoholism and stress-related disorders

“…In fact, alcohol withdrawal increases CRF synthesis and release in CeA (Funk et al, 2006; Roberto et al, 2010; Sommer et al, 2008), which in turn can regulate GABAergic transmission (Roberto, Gilpin, & Siggins, 2012). Moreover, alterations in the CRF system induced by stressors, such as maternal separation, are predictive of binge drinking and impulsivity behaviors in adulthood (Gondré-Lewis et al, 2016). The involvement of all these molecules in mediating neurobiological responses induced by both alcoholism and stress disorders are well documented.…”

Genetically Informative Mediation Modeling Applied to Stressors and Personality-Disorder Traits in Etiology of Alcohol Use Disorder

“…Removing the AUD-oriented borderline PD criterion #4 from the analysis, antisocial PD criterion #1 (violations of social norms for lawful behavior) emerged from the remaining 79 criteria (Rosenström et al 2018). These criteria are likely to be associated with intermediate phenotypes related to impulsivity that follow from childhood SLEs (Castellanos-Ryan et al 2011; White et al 2014; Barker et al 2015; Gondré-Lewis et al 2016; Mackey et al 2017). On the other hand, these PD traits could also invoke adulthood SLEs, which then increase AUD risk (Boden et al 2014; Kim et al 2014).…”

Effects of the benzodiazepine GABAA α1-preferring antagonist 3-isopropoxy-β-carboline hydrochloride (3-ISOPBC) on alcohol seeking and self-administration in baboons

“…Tiruveedhula, et al (2015) reported that 3-ISOPBC decreased alcohol consumption in a maternally deprived rodent model. Gondre-Lewis et al (2016) reported a similar effect with 3-PBC and proposed some involvement of α2-receptor subunits; however, this effect could not be reversed by administration of flumazenil. Consequently, this cannot be due to an effect at α2β 2/3 γ2 benzodiazepine GABA A receptors.…”

“…Knockout mice without the GABA A α1 receptor have been shown to consume less alcohol under a two-bottle alcohol versus water choice procedure (Blednov et al, 2003) and an operant self-administration procedure (June et al, 2007). The GABA A α1-preferring antagonist 3-PBC has been shown to decrease alcohol self-administration in rodents bred for high alcohol intake (Harvey et al, 2002), as well as binge-like drinking in a maternally deprived rodent model (Gondre-Lewis et al, 2016). A similar reduction in alcohol maintained responding was observed following administration of 3-ISOPBC in the maternal deprivation model (Tiruveedhula et al, 2015).…”

“…Consequently, this cannot be due to an effect at α2β 2/3 γ2 benzodiazepine GABA A receptors. It is possible that the observed effect was mediated by a different set of α2-related receptors (Gondre-Lewis et al., 2016) or to the α1-preferring antagonist effect at benzodiazepine α1 GABA A receptors. Much work remains to understand this observation.…”