Early life stress influences acute and sensitised 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 L, King, Sarah and Stephens, David N (2018) Early life stress influences acute and sensitised responses of adult mice to cocaine by interacting with GABAA α2 receptor expression. Behavioural Pharmacology. ISSN 0955-8810 (Accepted)

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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 alpha2 subunits of GABAA receptors, to increase risk for both posttraumatic 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 alpha2-containing GABAA receptors in influencing cocaine-related behaviour. Breeding of parents heterozygous for deletion of alpha2 resulted in litters containing homozygous knockout (alpha2-/-), heterozygous knockout (alpha2+/-), and wildtype (alpha2+/+) 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 sensitisation 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 alpha2-/- mice (which also showed increased activity following vehicle). Repeated cocaine administration to non-stressed mice resulted in sensitisation in alpha2+/+ and alpha2+/- mice, but, in keeping with previous findings, not in alpha2-/- mice. Prior exposure to ELS reduced sensitisation in alpha2+/+ mice, albeit not significantly, and abolished sensitisation in alpha2+/- 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 alpha2-/- mice suggests a function of alpha2-containing GABAA receptors in protecting against stress, the interaction between ELS and genotype in influencing sensitisation may be more in keeping with ELS reducing expression of alpha2-containing GABAA receptors. The ability of ELS to increase cocaine-conditioned locomotor activity appears to be independent of alpha2-containing GABAA receptors.

Item Type: Article
Keywords: addiction; knockout; conditioned activity; behavioural sensitisation
Schools and Departments: School of Psychology > Psychology
Research Centres and Groups: Sussex Addiction Research and Intervention Centre (SARIC)
Depositing User: Dai Stephens
Date Deposited: 01 Feb 2019 10:47
Last Modified: 01 Feb 2019 10:52
URI: http://srodev.sussex.ac.uk/id/eprint/81593

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Project NameSussex Project NumberFunderFunder Ref
UnsetUnsetMRCG0802715 & G1000008