Motivated cocaine seeking lead to transgenerational epigenetic inheritance of vulnerability to cocaine addiction

Familial transmission and high heritability of liability for drug abuse has been demonstrated by large scale epidemiological and twin studies, but the role of pre-existing susceptibility to addiction is still not clear. Our data show that F1 and F2 offspring sired by rats with high motivation for drug reinforcement and drug intake during cocaine self-administration maintained their ancestor’s addict-like behavior. This paternal transmission of drug addiction is an acquired trait that is dependent on cocaine induced high motivation in F0. Reduced representation bisulfite sequencing of F0 and F1 sperm DNA reveal a few persistent epigenetic changes in genes that critically regulate early development and morphogenesis. These epigenetic traits may underlie alterations in the neurological basis that lead to the transmission of cocaine motivation. Our results reveal the epigenetic transgenerational inheritance of drug craving and provide a potential etiology in cocaine abuse vulnerability.大规模流行病学研究与双生子研究已证实，药物滥用易感性具有家族传递特性与较高遗传力，但成瘾的先天易感因素所发挥的作用仍不明确。本研究数据显示，由对药物强化具有高动机且在可卡因自身给药实验中存在药物摄入行为的雄性大鼠所繁育的F1与F2代子代，仍保留了其亲代的成瘾样行为。这种药物成瘾的父系传递属于获得性性状，其依赖于F0代大鼠经可卡因诱导产生的高动机行为。对F0与F1代精子DNA开展的简化代表性亚硫酸氢盐测序（Reduced Representation Bisulfite Sequencing）结果显示，在关键调控早期发育与形态发生的基因中，存在若干持续存在的表观遗传（epigenetic）修饰改变。这些表观遗传特征可能是引发可卡因动机传递的神经生物学基础发生改变的潜在机制。本研究结果揭示了药物渴求的表观遗传跨代遗传现象，并为可卡因滥用易感性提供了潜在的病因学解释。