The mood stabilizer valproic acid opposes the effects of dopamine on circadian rhythms

Abstract

a b s t r a c tEndogenous 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 manialike 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.

Disrupted Social Hierarchy in Prenatally Valproate-Exposed Autistic-Like Rats

“…Indeed, our results showed a 2-h shift in the circadian rhythm of the VPA group. In parallel with our result, an earlier report showed that VPA shortened circadian period in vivo and in vitro and suppressed behavioral activity across species (Landgraf et al, 2016). ASD patients often have sleep problems and altered social timing, and it has been correlated with identified single nucleotide polymorphisms (SNPs) of Per1 and Npas2 genes (Nicholas et al, 2007).…”

Chronotype and cellular circadian rhythms predict the clinical response to lithium maintenance treatment in patients with bipolar disorder

“…These changes in period may facilitate phase shifting, improve entrainment and have important implications for lithium's effects on mood. In the dopamine transporter (DAT) knockdown model of mania, mice have a longer circadian period, and the period was shortened by the mood stabilizer valproic acid [33]. Similar period shortening effects of valproic acid were observed in gene expression rhythms in cells from BD patients [33], an effect on rhythms similar to selective GSK3 inhibitors [32].…”

Dopamine D2 receptors and the circadian clock reciprocally mediate antipsychotic drug-induced metabolic disturbances

“…86 These components of the dopamine signaling network provide inputs into the circadian clock. Indeed, we have shown previously that D1R modulate circadian period length in SCN slices from PER2::LUC mice, 88 while others demonstrated that D2Rs and D3Rs affect modulation of the CLOCK/BMAL1 dimerization in the retina. 89 Moreover, the same dopamine receptors determine the time of peak PER2 expression in the striatum.…”