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).…”

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).…”

Morning and Evening Circadian Pacemakers Independently Drive Premotor Centers via a Specific Dopamine Relay

“…Previous studies in flies and mice have shown that DA modulates circadian pacemaker circuits (Chang et al, 2006;Grippo et al, 2017;Hirsh et al, 2010;Klose et al, 2016;Landgraf et al, 2016;Shang et al, 2011Shang et al, , 2013. Our findings here show that circadian pacemaker neurons also regulate DA neuron activity.…”

Neurobiological and behavioral mechanisms of circadian rhythm disruption in bipolar disorder: A critical multi‐disciplinary literature review and agenda for future research from the ISBD task force on chronobiology

“…In DAT‐KD mice, valproic acid shortened period of wheel running behavior in vivo and PER2 expression in SCN slices in vitro, returning period length to control levels. Similar period shortening effects were observed in BD patient fibroblasts that had a longer period prior to treatment 277 . Therefore, one common mechanism shared by GSK3 inhibitors and valproic acid is the association with shortening of circadian period and beneficial changes in mood‐related behaviors.…”

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).…”

Morning and Evening Circadian Pacemakers Independently Drive Premotor Centers via a Specific Dopamine Relay

“…Previous studies in flies and mice have shown that DA modulates circadian pacemaker circuits (Chang et al, 2006;Grippo et al, 2017;Hirsh et al, 2010;Klose et al, 2016;Landgraf et al, 2016;Shang et al, 2011Shang et al, , 2013. Our findings here show that circadian pacemaker neurons also regulate DA neuron activity.…”

Neurobiological and behavioral mechanisms of circadian rhythm disruption in bipolar disorder: A critical multi‐disciplinary literature review and agenda for future research from the ISBD task force on chronobiology

“…In DAT‐KD mice, valproic acid shortened period of wheel running behavior in vivo and PER2 expression in SCN slices in vitro, returning period length to control levels. Similar period shortening effects were observed in BD patient fibroblasts that had a longer period prior to treatment 277 . Therefore, one common mechanism shared by GSK3 inhibitors and valproic acid is the association with shortening of circadian period and beneficial changes in mood‐related behaviors.…”

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).…”

Morning and Evening Circadian Pacemakers Independently Drive Premotor Centers via a Specific Dopamine Relay

“…Previous studies in flies and mice have shown that DA modulates circadian pacemaker circuits (Chang et al, 2006;Grippo et al, 2017;Hirsh et al, 2010;Klose et al, 2016;Landgraf et al, 2016;Shang et al, 2011Shang et al, , 2013. Our findings here show that circadian pacemaker neurons also regulate DA neuron activity.…”

Neurobiological and behavioral mechanisms of circadian rhythm disruption in bipolar disorder: A critical multi‐disciplinary literature review and agenda for future research from the ISBD task force on chronobiology

“…In DAT‐KD mice, valproic acid shortened period of wheel running behavior in vivo and PER2 expression in SCN slices in vitro, returning period length to control levels. Similar period shortening effects were observed in BD patient fibroblasts that had a longer period prior to treatment 277 . Therefore, one common mechanism shared by GSK3 inhibitors and valproic acid is the association with shortening of circadian period and beneficial changes in mood‐related behaviors.…”