Dopamine adjusts the circadian gene expression of Per2 and Per3 in human dermal fibroblasts from ADHD patients

Frank Faltraco,Adriana Uzoni,Frederick Simon,Oliver Tucha,Lena Borchert,Denise Palm,Johannes Thome

doi:10.1007/s00702-021-02374-4

Frank Faltraco, Adriana Uzoni + Show 5 more

Open Access

https://doi.org/10.1007/s00702-021-02374-4

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Abstract

A link between dopamine levels, circadian gene expression, and attention deficit hyperactivity disorder (ADHD) has already been demonstrated. The aim of this study was to investigate the extent of these relationships by measuring circadian gene expression in primary human-derived dermal fibroblast cultures (HDF) after dopamine 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 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 dopamine concentrations in human dermal fibroblast (HDF) cultures, the rhythmicity of circadian gene expression (Clock, Bmal1, Per1-3, Cry1) was analyzed via qRT-PCR. We found no statistical significant effect in the actigraphy of both groups (healthy controls, ADHD group) for mid-sleep on weekend days, mid-sleep on weekdays, social jetlag, wake after sleep onset, and total number of wake bouts. D-MEQ scores indicated that healthy controls had no evening preference, whereas subjects with ADHD displayed both definitive and moderate evening preferences. Dopamine has no effect on Per3 expression in healthy controls, but produces a significant difference in the ADHD group at ZT24 and ZT28. In the ADHD group, incubation with dopamine, either 1 µM or 10 µM, resulted in an adjustment of Per3 expression to control levels. A similar effect also was found in the expression of Per2. Statistical significant differences in the expression of Per2 (ZT4) in the control group compared to the ADHD group were found, following incubation with dopamine. The present study illustrates that dopamine impacts on circadian function. The results lead to the suggestion that dopamine may improve the sleep quality as well as ADHD symptoms by adjustment of the circadian gene expression, especially for Per2 and Per3.

Highlights

Dopamine is produced by dopaminergic neurons in the brain from aminoacid tyrosine, which is converted into dihydroxyphenylalanine (DOPA) by a rate-limiting enzyme, tyrosine hydroxylase (TH) (Tekin et al 2014)
The incubation of human dermal fibroblast cultures with 1 μM dopamine induced the rhythmicity of Clock gene
Preliminary results from our work has shown that Clock gene rhythmicity is linked with the neurotransmitter norepinephrine

Summary

Introduction

Dopamine is produced by dopaminergic neurons in the brain from aminoacid tyrosine, which is converted into dihydroxyphenylalanine (DOPA) by a rate-limiting enzyme, tyrosine hydroxylase (TH) (Tekin et al 2014). Dopamine β hydroxylase (DBH) is an enzyme responsible for the conversion of dopamine into catecholamine neurotransmitter noradrenaline (Catelas et al 2020). A plasma membrane protein dopamine transporter (DAT), encoded by SLC6A3 gene, controls both extracellular and intracellular concentrations of dopamine (McHugh and Buckley 2015; Salatino-Oliveira et al 2018). Dopamine neurotransmitters bind to five subtypes of dopamine receptors: D1, D2, D3, D4, and D5, divided into two major subclasses: D-1-like and D-2-like members of the G-protein coupled receptor family (Beaulieu et al 2015; Xin et al 2019).

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