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 (Lead / Corresponding author), Delia Belelli, Jeremy J. Lambert (Lead / Corresponding author)

Research output: Contribution to journalArticle

5 Citations (Scopus)
174 Downloads (Pure)

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. Behaviorally, adult male ELA and α2-/- mice exhibited an enhanced locomotor response to acute cocaine and blunted sensitization 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.

Original languageEnglish
Pages (from-to)98-112
Number of pages15
JournalNeuropharmacology
Volume141
Early online date21 Aug 2018
DOIs
Publication statusPublished - Oct 2018

Keywords

  • Cocaine
  • Early-life adversity
  • Early-life stress
  • GABA receptors
  • Nucleus accumbens

Fingerprint Dive into the research topics of 'Early-life adversity selectively impairs α2-GABAA receptor expression in the mouse nucleus accumbens and influences the behavioral effects of cocaine'. Together they form a unique fingerprint.

  • Profiles

    No photo of Jeremy Lambert

    Lambert, Jeremy

    • Systems Medicine - Professor (Teaching and Research) & Personal Chair of Neuropharmacology

    Person: Academic

    Cite this

    Mitchell, S. J., Maguire, E. P., Cunningham, L., Gunn, B. G., Linke, M., Zechner, U., Dixon, C. I., King, S. L., Stephens, D. N., Swinny, J. D., Belelli, D., & Lambert, J. J. (2018). Early-life adversity selectively impairs α2-GABAA receptor expression in the mouse nucleus accumbens and influences the behavioral effects of cocaine. Neuropharmacology, 141, 98-112. https://doi.org/10.1016/j.neuropharm.2018.08.021