The noradrenaline reuptake inhibitor atomoxetine phase-shifts the circadian clock in mice

Abstract

Circadian rhythms are recurring cycles in physiology and behaviour that repeat with periods of near 24 h and are driven by an endogenous circadian timekeeping system with a master circadian pacemaker located in the suprachiasmatic nucleus (SCN). Atomoxetine is a specific noradrenaline reuptake inhibitor that is used in the clinical management of attention-deficit/hyperactivity disorder (ADHD). In the current study we examined the effects of atomoxetine on circadian rhythms in mice. Atomoxetine (i.p.; 3 mg/kg) treatment of mice free-running in constant light (LL) at circadian time (CT) 6 induced large phase delays that were significantly different to saline controls. Treatment of animals with atomoxetine at CT13 or CT18 did not elicit any significant phase shifts. We also examined the effects of atomoxetine treatment of animals free-running in constant darkness (DD). Atomoxetine treatment at CT6 in these animals leads to more modest, but significant, phase advances, whereas treatment at CT18 did not elicit significant phase shifts. The effects of atomoxetine in LL were attenuated by pretreatment with the α-1 adrenoreceptor antagonist prazosin and were mimicked by another noradrenaline reuptake inhibitor, reboxetine. Further, atomoxetine treatment at CT6 induced a downregulation of c-Fos and CLOCK in the SCN, but did not alter the expression of PER2 and BMAL1. Atomoxetine during the night phase did not alter any of these factors. Atomoxetine treatment preceding a light pulse at CT15 enhanced the magnitude of the photic-phase shift, whereas it altered photic induction of the immediate early gene products c-Fos and ARC in the SCN. These data indicate that atomoxetine can reset the circadian clock and indicate that part of the therapeutic profile of atomoxetine may be through circadian rhythm modulation.