Cocaine use creates a long term lengthening of circadian period (tau), which could underlie the significant health issues of cocaine addiction. Additionally the rewarding effects of paternal cocaine are transgenerational. We hypothesize that the tau lengthening effect of cocaine may also be transgenerational, causing altered subjective cocaine reward response in offspring. Male mice were exposed to forced cocaine-water (0.5 mg/ml; experimental) or water (control) and harem-mated with cocaine naïve females. Offspring were behaviorally phenotyped for drug or sucrose preference and circadian behaviors were analyzed in individual mice. RNA was isolated from the nucleus accumbens of cocaine naïve F1 males and a HiSeq RNA analysis was run. A long-term lengthening of tau after drug withdrawal was evident in sires with forced cocaine (p=0.041). Tau, alpha, and subjective daytime bouts were not altered in the F1’s. Cocaine preference was decreased in cocaine-sired F1 males compared to those from control sires (p=0.006); however, no difference was found in females. There were no differences in sucrose preference or ethanol preference. RNAseq and analysis revealed a significant correlation between genes upregulated in CocSire Males and genes upregulated by the expression of CREB and short-term ΔFosB. These data reveal that there is no transgenerational transmission of a cocaine-lengthened tau phenotype. However, paternal cocaine exposure significantly altered F1 preference for cocaine, but not sucrose or ethanol, suggesting a selective effect on cocaine reward mechanisms. Thus, cocaine addiction can be influenced by transgenerational paternal mode(s) of inheritance that alters gene expression.
Cocaine use creates a long-term lengthening of circadian period (tau), possibly underlying health issues of addiction. Additionally, rewarding effects of paternal cocaine are transgenerational. We hypothesize that cocaine’s tau lengthening effect may also be inherited. Male mice exposed to forced cocaine-water or water were harem-mated with cocaine naïve females. Offspring were phenotyped for drug preference and circadian behaviors. Striatum RNA was isolated from F1 males and analysed with HiSeq RNA analysis. Lengthening of tau was evident in cocaine sires. Circadian behaviors were not altered in the F1’s, but CocSire Males had a decreased preference for cocaine. RNAseq analysis revealed a correlation between genes upregulated in CocSire Males and in the expression CREB and short-term ΔFosB. These data reveal a paternal effect on cocaine reward mechanisms.