Motivated cocaine seeking lead to transgenerational epigenetic inheritance of vulnerability to cocaine addiction. Rattus norvegicus

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. Overall design: In order to investigate the transgenerational inheritance of acquired cocaine motivation traits by DNA methylation, we performed reduced-representation bisulfite sequencing (RRBS) to assess the DNA methylation-enriched sites in sperms of Saline-F0, Addict-like F0, Non-Addict-like F0, Addict-like F1, Non-Addict-like F1 rats. Sequencing was performed with sperms from three to four individual rats of each group at 20M-read scale, respectively.