title: The mood stabilizer valproic acid opposes the effects of dopamine on circadian rhythms.
abstract: Endogenous circadian (∼24 h) clocks regulate key physiological and cognitive processes via rhythmic expression of clock genes. The main circadian pacemaker is the hypothalamic suprachiasmatic nucleus (SCN). Mood disorders, including bipolar disorder (BD), are commonly associated with disturbed circadian rhythms. Dopamine (DA) contributes to mania in BD and has direct impact on clock gene expression. Therefore, we hypothesized that high levels of DA during episodes of mania contribute to disturbed circadian rhythms in BD. The mood stabilizer valproic acid (VPA) also affects circadian rhythms. Thus, we further hypothesized that VPA normalizes circadian disturbances caused by elevated levels of DA. To test these hypotheses, we examined locomotor rhythms and circadian gene cycling in mice with reduced expression of the dopamine transporter (DAT-KD mice), which results in elevated DA levels and mania-like behavior. We found that elevated DA signaling lengthened the circadian period of behavioral rhythms in DAT-KD mice and clock gene expression rhythms in SCN explants. In contrast, we found that VPA shortened circadian period of behavioral rhythms in DAT-KD mice and clock gene expression rhythms in SCN explants, hippocampal cell lines, and human fibroblasts from BD patients. Thus, DA and VPA have opposing effects on circadian period. To test whether the impact of VPA on circadian rhythms contributes to its behavioral effects, we fed VPA to DAT-deficient Drosophila with and without functioning circadian clocks. Consistent with our hypothesis, we found that VPA had potent activity-suppressing effects in hyperactive DAT-deficient flies with intact circadian clocks. However, these effects were attenuated in DAT-deficient flies in which circadian clocks were disrupted, suggesting that VPA functions partly through the circadian clock to suppress activity. Here, we provide in vivo and in vitro evidence across species that elevated DA signaling lengthens the circadian period, an effect remediated by VPA treatment. Hence, VPA may exert beneficial effects on mood by normalizing lengthened circadian rhythm period in subjects with elevated DA resulting from reduced DAT.
authors.affiliation: VA San Diego Healthcare System, San Diego, CA, USA; Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA; Center for Circadian Biology, University of California, San Diego, La Jolla, CA, USA. Electronic address: dolandgraf@gmail.com.
authors.forename: Dominic
authors.initials: D
authors.lastname: Landgraf
authors.affiliation: Center for Circadian Biology, University of California, San Diego, La Jolla, CA, USA; Department of Pharmacology, University of California, San Diego, La Jolla, CA, USA.
authors.forename: William J
authors.initials: WJ
authors.lastname: Joiner
authors.affiliation: VA San Diego Healthcare System, San Diego, CA, USA; Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA; Center for Circadian Biology, University of California, San Diego, La Jolla, CA, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: McCarthy
authors.affiliation: Laboratory of Molecular Chronobiology, Douglas Mental Health University Institute, McGill University, Montreal, QC, Canada.
authors.forename: Silke
authors.initials: S
authors.lastname: Kiessling
authors.affiliation: VA San Diego Healthcare System, San Diego, CA, USA; Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA; Center for Circadian Biology, University of California, San Diego, La Jolla, CA, USA; Department of Psychiatry, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Lisbon, Portugal; Faculty of Medicine, University of Lisbon, Lisbon, Portugal.
authors.forename: Rita
authors.initials: R
authors.lastname: Barandas
authors.affiliation: VA San Diego Healthcare System, San Diego, CA, USA; Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA.
authors.forename: Jared W
authors.initials: JW
authors.lastname: Young
authors.affiliation: Laboratory of Molecular Chronobiology, Douglas Mental Health University Institute, McGill University, Montreal, QC, Canada.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Cermakian
authors.affiliation: VA San Diego Healthcare System, San Diego, CA, USA; Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA; Center for Circadian Biology, University of California, San Diego, La Jolla, CA, USA.
authors.forename: David K
authors.initials: DK
authors.lastname: Welsh
mesh_terms: D000818:Animals; D018692:Antimanic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002478:Cells, Cultured; D002940:Circadian Rhythm / Q000187:drug effects* / Q000502:physiology; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000172:deficiency; D004330:Drosophila; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008124:Locomotion / Q000187:drug effects* / Q000502:physiology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D019964:Mood Disorders / Q000188:drug therapy / Q000378:metabolism; D014635:Valproic Acid / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D018692:Antimanic Agents; D050483:Dopamine Plasma Membrane Transport Proteins; D014635:Valproic Acid; D004298:Dopamine
keywords: Bipolar disorder; Circadian rhythms; Dopamine; Drosophila; Human; Mania; Mouse; Valproic acid