Epigenetic effects of paternal cocaine on reward stimulus behavior and accumbens gene expression in mice.

Paternal cocaine use causes phenotypic alterations in offspring behavior and associated neural processing. In rodents, changes in first generation (F1) offspring include drug reward behavior, circadian timing, and anxiety responses. This study, utilizing a murine (C57BL/6J) oral cocaine model, examines the effects of paternal cocaine exposure on fundamental characteristics of offspring reward responses, including: 1) the extent of cocaine-induced effects after different durations of sire drug withdrawal; 2) sex- and drug-dependent differences in F1 reward preference; 3) effects on second generation (F2) cocaine preference; and 4) corresponding changes in reward area (nucleus accumbens) mRNA expression. We demonstrate that paternal cocaine intake over a single ˜40-day spermatogenic cycle significantly decreased cocaine (but not ethanol or sucrose) preference in a sex-specific manner in F1 mice from sires mated 24 h after drug withdrawal. However, F1 offspring of sires bred 4 months after withdrawal did not exhibit altered cocaine preference. Altered cocaine preference also was not observed in F2's. RNASeq analyses of F1 accumbens tissue revealed changes in gene expression in male offspring of cocaine-exposed sires, including many genes not previously linked to cocaine addiction. Enrichment analyses highlight genes linked to CNS development, synaptic signaling, extracellular matrix, and immune function. Expression correlation analyses identified a novel target, Fam19a4, that may negatively regulate many genes in the accumbens, including genes already identified in addiction. Collectively, these results reveal that paternal cocaine effects in F1 offspring may involve temporally limited epigenetic germline effects and identify new genetic targets for addiction research.