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

Claire I. Dixon, Sophie E. Walker, Jerome Swinny, Delia Belelli, Jeremy J. Lambert, Sarah L. King, David N. Stephens (Lead / Corresponding author)

Research output: Contribution to journalArticle

Abstract

Early-life stress (ELS) is known to exert long-term effects on brain function, with resulting deleterious consequences for several aspects of mental health, including the development of addiction to drugs of abuse. One potential mechanism in humans is suggested by findings that ELS interacts with polymorphisms of the GABRA2 gene, encoding α2 subunits of GABAA receptors, to increase the risk for both post-traumatic stress disorder and vulnerability to cocaine addiction. We used a mouse model, in which the amount of material for nest building was reduced during early postnatal life, to study interactions between ELS and expression of α2-containing GABAA receptors in influencing cocaine-related behaviour. Breeding of parents heterozygous for a deletion of α2 resulted in litters containing homozygous knockout (α2), heterozygous knockout (α2) and wild-type (α2) offspring. Following the ELS procedure, the mice were allowed to develop to adulthood before being tested for the acute effect of cocaine on locomotor stimulation, behavioural sensitization to repeated cocaine and to cocaine-conditioned activity. Exposure to ELS resulted in increased acute locomotor stimulant effects of cocaine across all genotypes, with the most marked effects in α2 mice (which also showed increased activity following vehicle). Repeated cocaine administration to nonstressed mice resulted in sensitization in α2 and α2 mice, but, in keeping with previous findings, not in α2 mice. Previous exposure to ELS reduced sensitization in α2 mice, albeit not significantly, and abolished sensitization in α2 mice. Conditioned activity was elevated following ELS in all animals, independently of genotype. Thus, while the enhanced acute effects of cocaine following ELS being most marked in α2 mice suggests a function of α2-containing GABAA receptors in protecting against stress, the interaction between ELS and genotype in influencing sensitization may be more in keeping with ELS reducing expression of α2-containing GABAA receptors. The ability of ELS to increase cocaine-conditioned locomotor activity appears to be independent of α2-containing GABAA receptors.

Original languageEnglish
Pages (from-to)272-281
Number of pages10
JournalBehavioural Pharmacology
Volume30
Issue number2-3
Early online date4 Feb 2019
DOIs
Publication statusPublished - 1 Apr 2019

Fingerprint

GABA-A Receptors
Cocaine
Psychological Stress
Genotype
Cocaine-Related Disorders
Aptitude
Street Drugs
Locomotion
Post-Traumatic Stress Disorders
Breeding
Mental Health

Keywords

  • addiction
  • behavioural sensitization
  • conditioned activity
  • knockout
  • mouse

Cite this

Dixon, Claire I. ; Walker, Sophie E. ; Swinny, Jerome ; Belelli, Delia ; Lambert, Jeremy J. ; King, Sarah L. ; Stephens, David N. / Early-life stress influences acute and sensitized responses of adult mice to cocaine by interacting with GABAA α2 receptor expression. In: Behavioural Pharmacology. 2019 ; Vol. 30, No. 2-3. pp. 272-281.
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Early-life stress influences acute and sensitized responses of adult mice to cocaine by interacting with GABAA α2 receptor expression. / Dixon, Claire I.; Walker, Sophie E.; Swinny, Jerome; Belelli, Delia; Lambert, Jeremy J.; King, Sarah L.; Stephens, David N. (Lead / Corresponding author).

In: Behavioural Pharmacology, Vol. 30, No. 2-3, 01.04.2019, p. 272-281.

Research output: Contribution to journalArticle

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