Elsevier

Neuroscience

Volume 201, 10 January 2012, Pages 219-230
Neuroscience

Cognitive, Behavioral, and Systems Neuroscience
Research Paper
The noradrenaline reuptake inhibitor atomoxetine phase-shifts the circadian clock in mice

https://doi.org/10.1016/j.neuroscience.2011.11.002Get rights and content

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.

Highlights

▶We examined the effects atomoxetine on circadian rhythms in the mouse. ▶Atomoxetine induces large phase delays in constant light during the subjective day. ▶Atomoxetine suppresses c-Fos and CLOCK in the suprachiasmatic nucleus. ▶The effects of atomoxetine are mimicked by reboxetine, and attenuated by prazosin. ▶Atomoxetine enhanced the phase shifting effects of a light during the early night.

Section snippets

Animals and housing

Male C57BL/6 mice (22–25 g) obtained from Harlan Laboratories (Leicestershire, UK) were used throughout this study. Animals were singly housed in polypropylene cages equipped with running wheels (11 cm diameter) with food and water available ad libitum and temperature held constant at 21±1 °C and humidity at 50±10%. Cages were then housed in an environmental isolation cabinet to allow for full control of the photic environment. They were illuminated using a fluorescent white light source, with

Atomoxetine phase shifts circadian locomotor rhythms

We examined the effects of atomoxetine administration at different times of the circadian cycle (CT6, CT13, CT18) and against different photic backgrounds (LL vs. DD) on free-running circadian locomotor rhythms. Two-way factorial ANOVA with time of treatment and photic background as the independent variables reveals main effects of time of treatment (F(2,32)=60.1, P<0.001) and photic background (F(1,32)=63, P<0.001), as well as a significant interaction between time of treatment and photic

Discussion

The results of the present study describe for the first time the phase-resetting properties of specific noradrenaline reuptake inhibitors that are used in clinical practice for the management of ADHD and depression. As such it is the first report suggesting that drugs that specifically target the noradrenergic system can phase shift the circadian clock as assessed at the behavioural level. Somewhat surprisingly we report that treatment with atomoxetine in the subjective day against a background

Conclusion

The findings that atomoxetine can alter circadian rhythmicity is of possible clinical importance in considering the mechanisms of its therapeutic effects in ADHD. Circadian abnormalities, including phase-delays of the melatonin rhythms and delayed sleep-onset insomnia have been described in ADHD, as well as association with clock gene polymorphisms (Van Veen et al., 2010, Van der Heijden et al., 2005, Kissling et al., 2008). Given that atomoxetine clearly has the potential to alter circadian

Acknowledgments

We acknowledge financial support from NARSAD. J.T. is supported by pharmaceutical companies (AstraZeneca, Bristol-Myers Squibb, Janssen, Lundbeck, MEDICE, Merz, Novartis, Pfizer, Servier) including some manufacturers of ADHD medication. S.M.O'K. and A.N.C. have no disclosures.

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