Cocaine modulation of the mammalian circadian clock: potential therapeutic targets

The circadian system plays an integral role in regulating physiological and behavioral responses to cocaine, which contribute to abuse and relapse. To date, however, little is known of the mechanism(s) underlying cocaine effects on biological timing, and in particular, how this drug may impact the regulation of the master circadian clock of the suprachiasmatic nucleus (SCN).  This review summarizes our current research into the chronotypic actions of acute and chronic cocaine. In initial experiments, it was shown that acute systemic and in vitro cocaine blocks the nocturnal SCN photic phase-resetting response critical for circadian entrainment to the light-dark cycle (LD). Cocaine treatment at midday also advances circadian clock phase, showing that this drug possess non-photic circadian phase-resetting properties. Next, chronic (weeks-months) cocaine regimens were used to model human drug abuse patterns.  Such long-term oral drug exposures caused dramatic alterations in intrinsic circadian period and entrainment to LD that persisted long after cocaine withdrawal, suggesting long-term (possibly permanent) circadian disruptive effects. Lastly, we found that the acute systemic cocaine effects described above are blocked using a serotonin receptor antagonist (metergoline) targeted to the SCN in vivo, as well as in vitro , suggesting involvement of a serotonergic mechanism. Consistent with this hypothesis, mutant mice with a cocaine-insensitive serotonin transporter exhibited little or no circadian response to cocaine. Collectively, these results indicate that cocaine-induced perturbations of clock timing could produce chronic psychological and physiological stress, contributing to increased cocaine use and dependence. Earmarking the serotonergic system in mediating these cocaine effects offers a potential chrono-pharmacological approach for the treatment of cocaine abuse and addiction.