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

Scott J Mitchell,Edward P Maguire,Linda Cunningham,Benjamin G Gunn,Matthias Linke,Ulrich Zechner,Claire I Dixon,Sarah L King,David N Stephens,Jerome D Swinny,Delia Belelli,Jeremy J Lambert

doi:10.1016/j.neuropharm.2018.08.021

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.

Highlights

Drug addiction has both social and biological causes (Bierut, 2011; Enoch, 2012; Kalda and Zharkovsky, 2015)
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-GABAA receptor (GABAAR) in the nucleus accumbens (NAc) are involved in these perturbed behaviors
We reported that medium spiny neurons (MSNs) of the neonatal mouse NAc express synaptic α2-GABAARs and that in the adult, accumbal α2-GABAARs influence the behavioral effects of cocaine (Dixon et al, 2010)

Summary

Introduction

Drug addiction has both social and biological causes (Bierut, 2011; Enoch, 2012; Kalda and Zharkovsky, 2015). Studies with twins revealed that heritability accounted for ∼50% and 60–70% of the risk of an individual developing alcoholism and cocaine and opiate. Linkage and association studies identify variations in a region of chromosome 4 containing four GABAAR-subunit genes, (Gabra, Gabra, Gabrb, Gabrg1), that confer an increased risk for developing substance abuse disorder (SAD; Edenberg et al, 2004). We reported that haplotypes of the Gabra gene encoding the GABAAR α2-subunit are associated with cocaine abuse in addicts (Dixon et al, 2010). The genetic association of Gabra haplotypes with cocaine addiction, and other forms of drug abuse, was evident only in individuals with experience of childhood trauma (Enoch et al, 2010)

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