Optochemical control of slow-wave sleep in the nucleus accumbens of male mice by a photoactivatable allosteric modulator of adenosine A2A receptors

Koustav Roy, Xuzhao Zhou, Rintaro Otani, Ping-Chuan Yuan, Shuji Ioka, Kaspar E. Vogt, Tamae Kondo, Nouran H. T. Farag, Haruto Ijiri, Zhaofa Wu, Youhei Chitose, Mao Amezawa, David S. Uygun, Yoan Cherasse, Hiroshi Nagase, Yulong Li, Masashi Yanagisawa, Manabu Abe, Radhika Basheer, Yi-Qun Wang (), Tsuyoshi Saitoh () and Michael Lazarus ()
Additional contact information
Koustav Roy: University of Tsukuba
Xuzhao Zhou: University of Tsukuba
Rintaro Otani: University of Tsukuba
Ping-Chuan Yuan: Fudan University
Shuji Ioka: University of Tsukuba
Kaspar E. Vogt: University of Tsukuba
Tamae Kondo: University of Tsukuba
Nouran H. T. Farag: University of Tsukuba
Haruto Ijiri: University of Tsukuba
Zhaofa Wu: Chinese Academy of Sciences
Youhei Chitose: Hiroshima University
Mao Amezawa: University of Tsukuba
David S. Uygun: Veterans Administration Boston Healthcare System and Harvard Medical School
Yoan Cherasse: University of Tsukuba
Hiroshi Nagase: University of Tsukuba
Yulong Li: Peking University
Masashi Yanagisawa: University of Tsukuba
Manabu Abe: Hiroshima University
Radhika Basheer: Veterans Administration Boston Healthcare System and Harvard Medical School
Yi-Qun Wang: Fudan University
Tsuyoshi Saitoh: University of Tsukuba
Michael Lazarus: University of Tsukuba

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract Optochemistry, an emerging pharmacologic approach in which light is used to selectively activate or deactivate molecules, has the potential to alleviate symptoms, cure diseases, and improve quality of life while preventing uncontrolled drug effects. The development of in-vivo applications for optochemistry to render brain cells photoresponsive without relying on genetic engineering has been progressing slowly. The nucleus accumbens (NAc) is a region for the regulation of slow-wave sleep (SWS) through the integration of motivational stimuli. Adenosine emerges as a promising candidate molecule for activating indirect pathway neurons of the NAc expressing adenosine A2A receptors (A2ARs) to induce SWS. Here, we developed a brain-permeable positive allosteric modulator of A2ARs (A2AR PAM) that can be rapidly photoactivated with visible light (λ > 400 nm) and used it optoallosterically to induce SWS in the NAc of freely behaving male mice by increasing the activity of extracellular adenosine derived from astrocytic and neuronal activity.

Date: 2024
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DOI: 10.1038/s41467-024-47964-4

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