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

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 GABA_A 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 GABA_A 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 GABA_A 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 GABA_A receptors. The ability of ELS to increase cocaine-conditioned locomotor activity appears to be independent of α2-containing GABA_A receptors.