Abstract
Atomoxetine (ATO) is a second line medication for attention-deficit hyperactivity disorder (ADHD). We proposed that part of the therapeutic profile of ATO may be through circadian rhythm modulation. Thus, the aim of this study was to investigate the circadian gene expression in primary human-derived dermal fibroblast cultures (HDF) after ATO exposure. We analyzed circadian preference, behavioral circadian and sleep parameters as well as the circadian gene expression in a cohort of healthy controls and participants with a diagnosis of ADHD. Circadian preference was evaluated with German Morningness-Eveningness-Questionnaire (D-MEQ) and rhythms of sleep/wake behavior were assessed via actigraphy. After ex vivo exposure to different ATO concentrations in HDF cultures, the rhythmicity of circadian gene expression was analyzed via qRT-PCR. No statistical significant effect of both groups (healthy controls, ADHD group) for mid-sleep on weekend days, mid-sleep on weekdays, social jetlag, sleep WASO and total number of wake bouts was observed. D-MEQ scores indicated that healthy controls had no evening preference, whereas subjects with ADHD displayed both definitive and moderate evening preferences. ATO induced the rhythmicity of Clock in the ADHD group. This effect, however, was not observed in HDF cultures of healthy controls. Bmal1 and Per2 expression showed a significant ZT × group interaction via mixed ANOVA. Strong positive correlations for chronotype and circadian genes were observed for Bmal1, Cry1 and Per3 among the study participants. Statistical significant different Clock, Bmal1 and Per3 expressions were observed in HDFs exposed to ATO collected from ADHD participants exhibiting neutral and moderate evening preference, as well as healthy participants with morning preferences. The results of the present study illustrate that ATO impacts on circadian function, particularly on Clock, Bmal1 and Per2 gene expression.
Highlights
Circadian rhythmicity is a fundamental feature of mammalian physiology that has developed under the continuous evolutionary pressure of energy conservation and efficiency
We investigate the effects of ATO on circadian rhythm using human dermal fibroblasts (HDFs) derived from attention-deficit hyperactivity disorder (ADHD) and healthy individuals
There were no significant differences in age, body mass index (BMI), IQ, D-MEQ or gender across the two study groups
Summary
Circadian rhythmicity is a fundamental feature of mammalian physiology that has developed under the continuous evolutionary pressure of energy conservation and efficiency. Evolution has fine-tuned the inner clock to anticipate and respond to several environmental stimuli. Circadian entrainment is subjected to alterations from artificial lighting as well as lifestyle changes. These alterations lead to the increased development of disorders, e.g. attention-deficit hyperactivity disorder (ADHD), depression, obesity, as well as diabetes (Gerhart-Hines and Lazar 2015). Attention deficit hyperactivity disorder (ADHD) is one of the most common childhood psychiatric disorders. The disease persists into adulthood in 40% of children with ADHD (Biederman et al 2000). ADHD symptoms are characterized by inattention and/or hyperactivity-impulsivity. The disorder is associated with characteristic behavioral difficulties and impairments of day-to-day functioning
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