Paternal Cocaine Disrupts Offspring Circadian Clock Function in a Sex-Dependent Manner in Mice

The present study is the first to explore the multigenerational effects of mammalian paternal cocaine intake on offspring (F1) circadian clock regulation. Parental cocaine use poses significant health risks to the offspring, through both maternal and paternal drug influences. With respect to the latter, recent evidence suggests that a paternal mode of cocaine inheritance involves epigenetic germ line actions that can ultimately disrupt offspring behavior. Based on our previous report in mice that free-running circadian period (tau) is chronically lengthened following withdrawal from long-term cocaine treatment, the present study was undertaken to explore potential epigenetic effects of paternal exposure to cocaine over the ∼40-day murine spermatogenic cycle on F1 circadian regulatory functions. Here we show that, although withdrawal of sires from the cocaine treatment lengthened their tau, such an effect did not persist in adult F1 male or female offspring born from drug-naïve dams. Notably, however, there was a distinct deficit in the ability of F1 cocaine-sired males, but not females, to undergo light-induced phase delay shifts of the circadian clock. In contrast, F1 cocaine-sired females, but not males, had suppressed circadian phase advance shifting responses to two non-photic stimuli: acute i.p. injections of cocaine and the serotonin agonist ([+]8-OH-DPAT). The reduced cocaine shifting in females was not due to suppressed cocaine-induced behavioral arousal. Collectively, these results reveal that a father's cocaine use can disrupt major circadian entrainment mechanisms in his adult progeny in a sex-dependent manner.