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Elucidating the Mechanism of Aripiprazole Action in Treating Circadian Rhythm Sleep Disorders

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Aripiprazole enhances the entrainment to external light-dark cycles by weakening the synchronization between neurons in the central circadian clock, thereby improving the symptoms of circadian rhythm sleep disorders.

Tsukuba, Japan—While aripiprazole has long been a standard treatment for psychiatric disorders, such as schizophrenia and bipolar disorder, recent studies indicate that it is effective in treating circadian rhythm sleep disorders, including delayed sleep-phase syndrome. This condition causes patients to sleep and wake extremely late at times. However, the precise mechanism through which aripiprazole addresses these sleep disorder symptoms remains elusive.

Researchers from the University of Tsukuba have discovered that aripiprazole can directly affect the mammalian central circadian clock; specifically, it can modulate the photic entrainment in mice. Located in the hypothalamic suprachiasmatic nucleus (SCN), the central circadian clock comprises clock neurons that synchronize with each other, maintaining a rhythm of approximately 24 h. Simultaneously, SCN is receptive to external inputs like light, aligning itself with the environmental light-dark cycle. The researchers have found that aripiprazole disrupts the synchronization among the clock neurons in the SCN, heightening the responsiveness of these neurons to light stimuli in mice. Additionally, aripiprazole influences intracellular signaling within the SCN by targeting the serotonin 1A receptor, a prominent receptor in the SCN.

These findings suggest that the efficacy of aripiprazole in alleviating circadian rhythm sleep disorder symptoms in psychiatric patients might be attributed to the modulation of the circadian clock by the drug. This study expands the potential clinical usage of aripiprazole as a treatment for circadian rhythm sleep disorders.

This work was supported by Japan Agency for Medical Research and Development (AMED) (grant numbers JP19dm0908001, JP20dm0107162, and JP21zf0127005 to TK; grant number JP21zf0127005 to TS; and grant numbers JP21zf0127003 and JP22gm6410030 to AH), Japan Society for the Promotion of Science (JSPS) KAKENHI (grant number JP19K22465 to TS), Japan Science and Technology Agency (JST) CREST (grant number JPMJCR1655 to TS), JSPS KAKENHI Grant-in- Aid for Scientific Research [(C):19 K08037 and 22K07571 to TK], The Naito Foundation (AH), TMFC Japan Foundation for applied Enzymology (AH), and JSPS Grant-in-Aid for JSPS Fellows (grant number 21 J20226 to RL).

Original Paper

Title of original paper:
Aripiprazole disrupts cellular synchrony in the suprachiasmatic nucleus and enhances entrainment to environmental light-dark cycles in mice
Frontiers in Neuroscience


Professor SAKURAI Takeshi
International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba / Institute of Medicine, University of Tsukuba

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