Optochemical control of slow-wave sleep in the nucleus accumbens of male mice by a photoactivatable allosteric modulator of adenosine A 2A receptors

• Published in: Nature communications 2024-04, Vol.15 (1), p.3661
• Main Authors: Roy, Koustav, Zhou, Xuzhao, Otani, Rintaro, Yuan, Ping-Chuan, Ioka, Shuji, Vogt, Kaspar E, Kondo, Tamae, Farag, Nouran H T, Ijiri, Haruto, Wu, Zhaofa, Chitose, Youhei, Amezawa, Mao, Uygun, David S, Cherasse, Yoan, Nagase, Hiroshi, Li, Yulong, Yanagisawa, Masashi, Abe, Manabu, Basheer, Radhika, Wang, Yi-Qun, Saitoh, Tsuyoshi, Lazarus, Michael
• Format: Article
• Language: English
• Subjects: Adenosine - metabolism; Adenosine - pharmacology; Adenosine A2 Receptor Agonists - pharmacology; Allosteric Regulation; Animals; Astrocytes - drug effects; Astrocytes - metabolism; Humans; Light; Male; Mice; Mice, Inbred C57BL; Neurons - drug effects; Neurons - metabolism; Nucleus Accumbens - drug effects; Nucleus Accumbens - metabolism; Nucleus Accumbens - physiology; Receptor, Adenosine A2A - genetics; Receptor, Adenosine A2A - metabolism; Sleep, Slow-Wave - drug effects; Sleep, Slow-Wave - physiology
• ISSN: 2041-1723
• DOI: 10.1038/s41467-024-47964-4

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 A receptors (A Rs) to induce SWS. Here, we developed a brain-permeable positive allosteric modulator of A Rs (A R 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.