Cognitive, Behavioral, and Systems NeuroscienceResearch PaperThe noradrenaline reuptake inhibitor atomoxetine phase-shifts the circadian clock in mice
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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2018, Neuroscience and Biobehavioral ReviewsCitation Excerpt :Atomoxetine may thus be a better treatment for ADHD when symptoms also include sleep problems. Interestingly, in mice, atomoxetine treatment during the light phase has been found to be able to shift the circadian clock and reduce the expression of c-Fos and CLOCK in the SCN, suggesting that atomoxetine might exert its therapeutic effects through the modulation of the circadian rhythm (O’Keeffe et al., 2012). In conclusion, several clock genes have been associated with ADHD: altered BMAL1 and PER2 gene expression have been reported in ADHD (Baird et al., 2012) and a polymorphism in the 3′-UTR region of the CLOCK gene has been found to increase sleep problems and increase the risk for adult ADHD (Kissling et al., 2008; Xu et al., 2010).
Limited evidence for affective and diurnal rhythm responses to dim light-at-night in male and female C57Bl/6 mice
2018, Physiology and BehaviorCitation Excerpt :Animals were also weighed at the end of each experimental week. Diurnal rhythms of running wheel activity were recorded as previously described [27]. Briefly, animals were singly housed in polypropylene cages equipped with running wheels (11 cm diameter) housed in an environmental isolation cabinet to allow for full control of the photic environment.