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)

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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

Fingerprint

Nucleus Accumbens
GABA-A Receptors
Cocaine
Haplotypes
Cocaine-Related Disorders
Substance-Related Disorders
Wounds and Injuries
Neurons
Inhibitory Postsynaptic Potentials
Knockout Mice
Genes
Messenger RNA
Pharmaceutical Preparations

Keywords

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

Cite this

Mitchell, Scott J. ; Maguire, Edward P. ; Cunningham, Linda ; Gunn, Benjamin G. ; Linke, Matthias ; Zechner, Ulrich ; Dixon, Claire I. ; King, Sarah L. ; Stephens, David N. ; Swinny, Jerome D. ; Belelli, Delia ; Lambert, Jeremy J. / Early-life adversity selectively impairs α2-GABAA receptor expression in the mouse nucleus accumbens and influences the behavioral effects of cocaine. In: Neuropharmacology. 2018 ; Vol. 141. pp. 98-112.
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title = "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. 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.",
keywords = "Cocaine, Early-life adversity, Early-life stress, GABA receptors, Nucleus accumbens",
author = "Mitchell, {Scott J.} and Maguire, {Edward P.} and Linda Cunningham and Gunn, {Benjamin G.} and Matthias Linke and Ulrich Zechner and Dixon, {Claire I.} and King, {Sarah L.} and Stephens, {David N.} and Swinny, {Jerome D.} and Delia Belelli and Lambert, {Jeremy J.}",
note = "The study was supported by the Medical Research Council U.K. (G0802715 & G1000008) and by an MRC PhD studentship (1313951) to support SJM. The work was performed within the MRC Addiction Cluster “GABAA receptors in neurobiology of drug and alcohol addictions”.",
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Early-life adversity selectively impairs α2-GABAA receptor expression in the mouse nucleus accumbens and influences the behavioral effects of cocaine. / Mitchell, Scott J.; Maguire, Edward P.; Cunningham, Linda; Gunn, Benjamin G.; Linke, Matthias; Zechner, Ulrich; Dixon, Claire I.; King, Sarah L.; Stephens, David N.; Swinny, Jerome D. (Lead / Corresponding author); Belelli, Delia; Lambert, Jeremy J. (Lead / Corresponding author).

In: Neuropharmacology, Vol. 141, 10.2018, p. 98-112.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Early-life adversity selectively impairs α2-GABAA receptor expression in the mouse nucleus accumbens and influences the behavioral effects of cocaine

AU - Mitchell, Scott J.

AU - Maguire, Edward P.

AU - Cunningham, Linda

AU - Gunn, Benjamin G.

AU - Linke, Matthias

AU - Zechner, Ulrich

AU - Dixon, Claire I.

AU - King, Sarah L.

AU - Stephens, David N.

AU - Swinny, Jerome D.

AU - Belelli, Delia

AU - Lambert, Jeremy J.

N1 - The study was supported by the Medical Research Council U.K. (G0802715 & G1000008) and by an MRC PhD studentship (1313951) to support SJM. The work was performed within the MRC Addiction Cluster “GABAA receptors in neurobiology of drug and alcohol addictions”.

PY - 2018/10

Y1 - 2018/10

N2 - 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.

AB - 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.

KW - Cocaine

KW - Early-life adversity

KW - Early-life stress

KW - GABA receptors

KW - Nucleus accumbens

U2 - 10.1016/j.neuropharm.2018.08.021

DO - 10.1016/j.neuropharm.2018.08.021

M3 - Article

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