Researcher Discovers a Way to Control Internal Clocks

Finding has potential to treat sleep disorders, anxiety by managing circadian rhythm.

In research published in Nature Communications, Thomas Burris, Ph.D., chair of pharmacological and physiological science at Saint Louis University, reports intriguing findings about a small molecule that directs the activity of key “clock proteins,” offering the potential to manage circadian rhythm and treat problems that are associated with its dysfunction, like sleep and anxiety disorders.

Circadian rhythm refers to biological processes that cycle every 24 hours. In mammals, the internal clock that maintains circadian rhythm is essential for normal physiological functions. The rhythms can, however, be disrupted, and dysregulation of circadian rhythm is associated with many disorders, including metabolic disease and neuropsychiatric disorders including bipolar disorder, anxiety, depression, schizophrenia and sleep disorders.

Burris and his colleagues examined compounds that target a protein called REV-ERB, which appears to play a key role in regulating mammals’ internal clocks.

“It has been suggested that REV-ERB is a core component of our clock,” said Burris. “Mice without it are arrhythmic. This study demonstrated that when we give mice a synthetic compound that turns REV-ERB on, it altered their circadian rhythm.”

The image is a drawing of a sunset and an island. Sitting on the island is a girl under a tree. The top of the tree is a brain.

Circadian rhythm refers to biological processes that cycle every 24 hours. In mammals, the internal clock that maintains circadian rhythm is essential for normal physiological functions. This image is for illustrative purposes only. Credit 95C.

The team examined effects of the REV-ERB drug on patterns of sleep and wakefulness and found that the compound increases wakefulness, reduces REM and slow-wave sleep, and, notably, decreases anxiety.

This is an interesting finding because it is unusual. Frequently, drugs that increase arousal (wakefulness) also increase anxiety (ex. cocaine, amphetamines). And, vice versa: Drugs that decrease anxiety also decrease arousal (ex. benzodiazepines and ethanol). An exception to this common pattern is nicotine.

The REV-ERB drug, on the other hand, appears to target the clock in a way that is distinct from these common pathways.

Further, the REV-ERB drug appears to be associated with a suppression of reward-seeking behavior.

Drug addiction has a circadian component and mice with mutations in “clock genes” (genes that affect our internal clocks) have altered responsiveness to the reward associated with cocaine, morphine and alcohol. Burris speculates that REV-ERB targeted drug effect on the clock would modulate reward-seeking behavior, and so may be useful in treating addiction.

The team hypothesizes that targeting components of the mammalian clock with small molecules like REV-ERB drugs may lead to new treatments for sleep disorders and anxiety disorders. It also is possible that REV-ERB drugs may be leveraged to help in the treatment of addiction.

About this circadian rhythm research

The research was funded in part by grants from the NIH (MH092769; MH093429; and DK088499).

Other researchers on the team include Subhashis Banerjee, Yongjun Wang, Laura A. Solt, Kristine Griffett, Melissa Kazantzis, Ariadna Amador, Bahaa M. El-Gendy, Salvador Huitron-Resendiz, Amanda J. Roberts, Youseung Shin, and Theodore M. Kamenecka.

Contact: Carrie Bebermeyer – St. Louis University
Source: St. Louis University press release
Image Source: The image is credited to 95C and is in the public domain
Original Research: Abstract for “Pharmacological targeting of the mammalian clock regulates sleep architecture and emotional behaviour” by Subhashis Banerjee, Yongjun Wang, Laura A. Solt, Kristine Griffett, Melissa Kazantzis, Ariadna Amador, Bahaa M. El-Gendy, Salvador Huitron-Resendiz, Amanda J. Roberts, Youseung Shin, Theodore M. Kamenecka and Thomas P. Burris in Nature Communications. Published online December 23 2014 doi:10.1038/ncomms6759

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