Abstract
Major mood disorders have been linked to abnormalities in circadian rhythms, leading to disturbances in sleep, mood, temperature, and hormonal levels. We provide evidence that ketamine, a drug with rapid antidepressant effects, influences the function of the circadian molecular machinery. Ketamine modulates CLOCK:BMAL1-mediated transcriptional activation when these regulators are ectopically expressed in NG108-15 neuronal cells. Inhibition occurs in a dose-dependent manner and is attenuated after treatment with the GSK3β antagonist SB21673. We analyzed the effect of ketamine on circadian gene expression and observed a dose-dependent reduction in the amplitude of circadian transcription of the Bmal1, Per2, and Cry1 genes. Finally, chromatin-immunoprecipitation analyses revealed that ketamine altered the recruitment of the CLOCK:BMAL1 complex on circadian promoters in a time-dependent manner. Our results reveal a yet unsuspected molecular mode of action of ketamine and thereby may suggest possible pharmacological antidepressant strategies.
Highlights
Major depressive disorder (MDD) is a serious and recurrent psychiatric illness with a prevalence rate of 6.7% in the United States in any 12 month period [1,2]
We demonstrate that ketamine acts by modulating the activation potential of the CLOCK:BMAL1 complex by interfering with their recruitment to chromatin at a target circadian promoter
While ketamine has no effect on the basal mPer1 promoter activity, it significantly induced a dose-dependent reduction of CLOCK:BMAL1-driven activation (Fig. 1A)
Summary
Major depressive disorder (MDD) is a serious and recurrent psychiatric illness with a prevalence rate of 6.7% in the United States in any 12 month period [1,2]. Available monoaminergic antidepressant drugs require weeks to months for a full clinical response [3] during which time patients may be at risk for suicidal behavior [4]. A significant number of patients fail to respond to currently available antidepressant medications [5,6]. A non-competitive high affinity NMDA (N-methyl-D-aspartate) glutamate receptor antagonist, has rapid and robust antidepressant actions in animal models of depression when administered intravenously in low subanaesthetic doses [7]. Clinical studies of low-dose intravenous ketamine report improvement within 24 hours (for review see [8]). An estimated 70% of MDD patients respond to ketamine [9,10]. 35% of responders have sustained improvement up to 7 days after a single dose [10,11] or longer after repeated doses [12,13]
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