Light-activated drugs targeting adenosine A2A receptors in the brain that induce sleep

Tsukuba, Japan—The nucleus accumbens plays a pivotal role in motivational behavior and sleep regulation, modulated by adenosine A_2A receptors (A_2AR). Hence, selective A_2AR regulation within this brain region could control sleep and motivation. However, A2ARs are distributed across various organs, including the heart, posing challenges for precise brain-specific modulation without genetic interventions.

A research team led by Professor Michael Lazarus and Associate Professor Tsuyoshi Saitoh (TRiSTAR Fellow) from the Institute of Medicine and the International Institute for Integrative Sleep Medicine (WPI-IIIS) at the University of Tsukuba delved into optochemistry. They aimed to develop a novel light-sensitive drug that enhances extracellular adenosine activity. By administering this drug to mice and selectively irradiating the nucleus accumbens with light, they succeeded in inducing sleep artificially without genetic modification for the first time.

Conventional photosensitive drugs have faced hurdles in mammals and other living organisms due to problems such as phototoxicity caused by ultraviolet light, blood-brain barrier permeability, and photoreaction efficiency. The newly developed photosensitive drug overcomes these issues, showcasing optochemistry's potential in developing drugs targeting A_2AR in the brain and regulating brain function by targeting other central drug receptors.

###
This research was conducted as part of a research project funded by the World Premier International Research Center Initiative (WPI), Japan Science and Technology Agency CREST Grant (JPMJCR1655), Grants-in-Aid for Scientific Research (JP21H02802, JP23H04148), and AMED (JP21zf0127005).

_{Original Paper}

Title of original paper:
Optochemical control of slow-wave sleep in the nucleus accumbens of male mice by a photoactivatable allosteric modulator of adenosine A_2A receptors

Journal:
Nature Communications

DOI:
10.1038/s41467-024-47964-4

_{Correspondence}

Professor Michael Lazarus
Associate Professor SAITOH, Tsuyoshi

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

_{Related Link}

Institute of Medicine

International Institute for Integrative Sleep Medicine (WPI-IIIS)

About the World Premier International Research Center Initiative (WPI)
The WPI program was launched in 2007 by Japan's Ministry of Education, Culture, Sports, Science and Technology (MEXT) to foster globally visible research centers boasting the highest standards and outstanding research environments. Numbering more than a dozen and operating at institutions throughout the country, these centers are given a high degree of autonomy, allowing them to engage in innovative modes of management and research. The program is administered by the Japan Society for the Promotion of Science (JSPS).

See the latest research news from the centers at the WPI News Portal: https://www.eurekalert.org/newsportal/WPI
Main WPI program site:  www.jsps.go.jp/english/e-toplevel

About International Institute for Integrative Sleep Medicine (IIIS), University of Tsukuba
World-class institute for sleep medicine, aiming to solve the mechanism of sleep/wakefulness by conducting basic to translational research
The mission of IIIS is to be a multidisciplinary, international hub for the research to elucidate the function of sleep and the fundamental mechanisms of sleep/wake regulation, to elucidate molecular pathogenesis of sleep disorders and related diseases, to develop preventive measures, diagnostic methods, and treatments for sleep.