Dixon Claire I, Walker Sophie E, Swinny Jerome, Belelli Delia, Lambert Jeremy J, King Sarah L, Stephens David N
Laboratory of Behavioural and Clinical Neuroscience, School of Psychology, University of Sussex, Brighton.
Department of Pharmacy, University of Portsmouth, Portsmouth.
Behav Pharmacol. 2019 Apr;30(2 and 3-Spec Issue):272-281. doi: 10.1097/FBP.0000000000000466.
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.
已知早年生活应激（ELS）会对脑功能产生长期影响，进而对心理健康的多个方面造成有害后果，包括对滥用药物成瘾的发展。人类的一种潜在机制是基于以下发现提出的：ELS与编码GABAA受体α2亚基的GABRA2基因多态性相互作用，增加创伤后应激障碍的风险以及对可卡因成瘾的易感性。我们使用了一种小鼠模型，其中在出生后早期减少筑巢材料的数量，以研究ELS与含α2的GABAA受体表达之间在影响可卡因相关行为方面的相互作用。对α2缺失杂合的亲本进行繁殖，产生的窝仔包含纯合敲除（α2）、杂合敲除（α2）和野生型（α2）后代。在ELS程序之后，让小鼠发育至成年，然后测试可卡因对运动刺激的急性作用、对重复给予可卡因的行为敏化以及对可卡因条件性活动。暴露于ELS导致所有基因型的小鼠对可卡因的急性运动兴奋作用增强，在α2小鼠中最为明显（其在给予赋形剂后也表现出活动增加）。对未受应激的小鼠重复给予可卡因会导致α2和α2小鼠出现敏化，但与先前的发现一致，α2小鼠未出现敏化。先前暴露于ELS会降低α2小鼠的敏化，尽管不显著，并消除α2小鼠的敏化。在所有动物中，ELS后条件性活动均升高，与基因型无关。因此，虽然ELS后可卡因增强的急性作用在α2小鼠中最为明显，这表明含α2的GABAA受体具有抵御应激的功能，但ELS与基因型在影响敏化方面的相互作用可能更符合ELS降低含α2的GABAA受体的表达。ELS增加可卡因条件性运动活动的能力似乎与含α2的GABAA受体无关。
