Early-life adversity selectively impairs α2-GABAA receptor expression in the mouse nucleus accumbens and influences the behavioral effects of cocaine

Abstract

Haplotypes of the Gabra2 gene encoding the α2-subunit of the GABAA receptor (GABAAR) are associated with drug abuse, suggesting that α2-GABAARs may play an important role in the circuitry underlying drug misuse. The genetic association of Gabra2 haplotypes with cocaine addiction appears to be evident primarily in individuals who had experienced childhood trauma. Given this association of childhood trauma, cocaine abuse and the Gabra2 haplotypes, we have explored in a mouse model of early life adversity (ELA) whether such events influence the behavioral effects of cocaine and if, as suggested by the human studies, α2-GABAARs in the nucleus accumbens (NAc) are involved in these perturbed behaviors. In adult mice prior ELA caused a selective decrease of accumbal α2-subunit mRNA, resulting in a selective decrease in the number and size of the α2-subunit (but not the α1-subunit) immunoreactive clusters in NAc core medium spiny neurons (MSNs). Functionally, in adult MSNs ELA decreased the amplitude and frequency of GABAAR-mediated miniature inhibitory postsynaptic currents (mIPSCs), a profile similar to that of α2 “knock-out” (α2−/−) mice. Behaviourally, adult male ELA and α2−/− mice exhibited an enhanced locomotor response to acute cocaine and blunted sensitisation upon repeated cocaine administration, when compared to their appropriate controls. Collectively, these findings reveal a neurobiological mechanism which may relate to the clinical observation that early trauma increases the risk for substance abuse disorder (SAD) in individuals harbouring haplotypic variations in the Gabra2 gene.

Early-life stress influences acute and sensitized responses of adult mice to cocaine by interacting with GABAA α2 receptor expression

“…In our experiment, the ability of ELS to enhance the acute effects of cocaine was numerically most marked in 2 -/mice, consistent with animals without  receptors being more reactive to ELS, and confirming in keeping with our recent report (Mitchell et al, 2018). However, 2 -/mice were also more sensitive to the effect of vehicle injection (no genotype x drug interaction), and also to a sham injection during the habituation procedure.…”

“…Our experiments reveal three different patterns of interaction between early life stress and GABAA 2 receptors in determining responses to cocaine. Firstly, in keeping with our recent report (Mitchell et al, 2018), exposure to ELS resulted in increased acute effects of cocaine in stimulating locomotor activity in all genotypes. A similar increase in responsiveness to the acute effects of cocaine has also been reported in male (but not female) mice following a different method of inducing early life stress, repeated maternal separation (Kikusui et al, 2005), and in rats (Marin and Planeta, 2004).…”

“…Thus, we might speculate that impairment of transmission at 2-containing receptors may decrease resistance to stressful events in childhood, leading to more severe consequences for adult behaviour, including vulnerability to substance abuse. Alternatively, there is evidence from rodent studies (Caldji et al, 2000, Hsu et al, 2003, Skilbeck et al, 2017, Mitchell et al, 2018 that early life stress itself affects expression levels of GABAA receptor subunits, especially 2 subunits (Mitchell et al, 2018). Importantly, these effects may be regionally different, and depend on the early life stress procedure used.…”

“…We therefore investigated potential interactions between early life stress and expression of the Gabra2 gene in a mouse model, employing disrupted mother-pup interactions, in which we have previously shown that deletion of the gene encoding 2 subunits alters behavioural adaptations to cocaine (Dixon et al, 2010, Mitchell et al, 2018. A number of studies have already shown that early life stress alters both acute and sensitised responses to psychostimulants (Brake et al, 2004, Kikusui et al, 2005, Li et al, 2003, Marin and Planeta, 2004, Mitchell et al, 2018). In the current report, we extended our previous findings by breeding mice from parents heterozygous for deletion of 2 (2 +/-), so that the resulting litters contained a mixture of 2 +/+ .…”

“…2 +/-, and 2 -/offspring, but ensuring that the mother's genotype did not contribute differentially to the stress manipulation (i.e., our previous study bred either 2 +/+ or 2 -/parents to derive wildtype and knockout offspring, leaving open the possibility that the procedure gave rise to different levels of stress in the wildtype and knockout mothers. Indeed, we reported that 2 -/mothers showed altered mothering relative to wildtype mothers even under non-stress conditions (Mitchell et al, 2018). We then exposed half of the litters to early life stress (ELS) by reducing the bedding material available for nest building for 7 days, before rearing the mice to adulthood under standard conditions, at which time they entered behavioural testing.…”