The mPer2 clock gene modulates cocaine actions in the mouse circadian system

Abstract

Cocaine is a potent disruptor of photic and non-photic pathways for circadian entrainment of the master circadian clock of the suprachiasmatic nucleus (SCN). These actions of cocaine likely involve its modulation of molecular (clock gene) components for SCN clock timekeeping. At present, however, the physiological basis of such an interaction is unclear. To address this question, we compared photic and non-photic phase-resetting responses between wild-type (WT) and Per2 mutant mice expressing nonfunctional PER2 protein to systemic and intra-SCN cocaine administrations. In the systemic trials, cocaine was administered i.p. (20 mg/kg) either at midday or prior to a light pulse in the early night to assess its non-photic and photic behavioral phase-resetting actions, respectively. In the intra-SCN trial, cocaine was administered by reverse microdialysis at midday to determine if the SCN is a direct target for its non-photic phase-resetting action. Non-photic phase-advancing responses to i.p. cocaine at midday were significantly (~3.5-fold) greater in Per2 mutants than WTs. However, the phase-advancing action of intra-SCN cocaine perfusion at midday did not differ between genotypes. In the light pulse trial, Per2 mutants exhibited larger photic phase-delays than did WTs, and the attenuating action of cocaine on this response was proportionately larger than in WTs. These data indicate that the Per2 clock gene is a potent modulator of cocaine’s actions in the circadian system. With regard to non-photic phase-resetting, the SCN is confirmed as a direct target of cocaine action; however, Per2 modulation of this effect likely occurs outside of the SCN.

Cocaine modulates mammalian circadian clock timing by decreasing serotonin transport in the SCN

“…A third important issue is how the effects of cocaine shown here and in previous studies (Glass et al, 2012;Brager et al, 2013) relate to long-term disruptions in circadian rhythms that occur during chronic cocaine use. The cocaine-induced phase advances, inhibition of photic-like phase delays, and altered free-running period are all consistent with cocaine-induced disruptions of circadian clock genes, as shown in other studies (Yuferov et al, 2005;Falcon et al, 2013).…”

“…Our research has shown that cocaine functions, at least in part, through direct actions within the SCN, where it can inhibit photic signaling processes in vivo and in vitro and can induce its own phase shifts in circadian clock-regulated behavioral and SCN neuronal activity rhythms when applied during the day (Glass et al, 2012;Brager et al, 2013). Although cocaine can enhance DA, norepinephrine, and 5-HT signaling by inhibiting their respective transporters throughout the brain, our previous pharmacological data suggest that cocaine primarily acts by enhancing 5-HT signaling in the SCN (Glass et al, 2012).…”

“…Our previous data suggest that, in addition to its actions in the SCN, cocaine is also able to alter circadian rhythms through extra-SCN actions. We have shown that both the photic and non-photic effects of systemically administered cocaine on circadian rhythms are potentiated in Per2 mutant mice (Brager et al, 2013). However, the enhanced non-photic responsiveness in these mice is not seen when cocaine is administered directly into the SCN via reverse microdialysis (Brager et al, 2013).…”

“…We have shown that both the photic and non-photic effects of systemically administered cocaine on circadian rhythms are potentiated in Per2 mutant mice (Brager et al, 2013). However, the enhanced non-photic responsiveness in these mice is not seen when cocaine is administered directly into the SCN via reverse microdialysis (Brager et al, 2013). Thus, at least with respect to its interactions with the Per2 gene, cocaine can influence circadian behavioral rhythms through distinct intra- and extra-SCN mechanisms.…”

“…Conversely, decreased expression in each of these genes can alter cocaine preference and use (Abarca et al, 2002;McClung et al, 2005;Gabriele et al, 2009). Moreover, decreased Per2 expression leads to enhanced cocaine-induced phase shifts during the day and decreased cocaine-induced inhibition of photic phase resetting at night (Brager et al, 2013). …”