Early-life stress influences acute and sensitized responses of adult mice to cocaine by interacting with GABAA 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 2 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 2-containing GABA(A) receptors in influencing cocaine-related behaviour. Breeding of parents heterozygous for a deletion of 2 resulted in litters containing homozygous knockout (2(-/-)), heterozygous knockout (2(+/-)) and wild-type (2(+/+)) 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 2(-/-) mice (which also showed increased activity following vehicle). Repeated cocaine administration to nonstressed mice resulted in sensitization in 2(+/+) and 2(+/-) mice, but, in keeping with previous findings, not in 2(-/-) mice. Previous exposure to ELS reduced sensitization in 2(+/+) mice, albeit not significantly, and abolished sensitization in 2(+/-) 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 2(-/-) mice suggests a function of 2-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 2-containing GABA(A) receptors. The ability of ELS to increase cocaine-conditioned locomotor activity appears to be independent of 2-containing GABA(A) receptors.