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

Jan 22, 2013Behavioural brain research

The mPer2 clock gene may influence how cocaine affects the mouse body clock

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Abstract

Non-photic phase-advancing responses to systemic cocaine were significantly 3.5-fold greater in Per2 mutant mice than in wild-type mice.

Cocaine disrupts both light and non-light pathways that help regulate the master circadian clock in the brain.
The Per2 clock gene appears to influence how cocaine affects circadian rhythms.
Photic phase-delays were larger in Per2 mutants compared to wild-type mice when exposed to light pulses.
Cocaine's impact on photic responses was proportionately greater in Per2 mutants than in wild-type mice.
While the suprachiasmatic nucleus (SCN) is targeted by cocaine for non-photic phase-resetting, Per2 modulation likely occurs outside of the SCN.

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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.

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

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