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

Haplotypes of the Gabra2 gene encoding the alpha 2-subunit of the GABAA receptor (GABA(A)R) are associated with drug abuse, suggesting that alpha 2-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, alpha 2-GABA(A)Rs in the nucleus accumbens (NAc) are involved in these perturbed behaviors. In adult mice prior ELA caused a selective decrease of accumbal alpha 2-subunit mRNA, resulting in a selective decrease in the number and size of the alpha 2-subunit (but not the alpha 1-subunit) immunoreactive clusters in NAc core medium spiny neurons (MSNs). Functionally, in adult MSNs ELA decreased the amplitude and frequency of GABA(A)R-mediated miniature inhibitory postsynaptic currents (mIPSCs), a profile similar to that of alpha 2 knock-out (alpha 2(-/-)) mice. Behaviourally, adult male ELA and alpha 2(-/-) 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.