@article{d213b1546c5d44a7b1d2ca1f34e4d343,
title = "Positive allosteric adenosine A2A receptor modulation suppresses insomnia associated with mania- and schizophrenia-like behaviors in mice",
abstract = "Background: Insomnia is associated with psychiatric illnesses such as bipolar disorder or schizophrenia. Treating insomnia improves psychotic symptoms severity, quality of life, and functional outcomes. Patients with psychiatric disorders are often dissatisfied with the available therapeutic options for their insomnia. In contrast, positive allosteric modulation of adenosine A2A receptors (A2ARs) leads to slow-wave sleep without cardiovascular side effects in contrast to A2AR agonists. Methods: We investigated the hypnotic effects of A2AR positive allosteric modulators (PAMs) in mice with mania-like behavior produced by ablating GABAergic neurons in the ventral medial midbrain/pons area and in a mouse model of schizophrenia by knocking out of microtubule-associated protein 6. We also compared the properties of sleep induced by A2AR PAMs in mice with mania-like behavior with those induced by DORA-22, a dual orexin receptor antagonist that improves sleep in pre-clinical models, and the benzodiazepine diazepam. Results: A2AR PAMs suppress insomnia associated with mania- or schizophrenia-like behaviors in mice. A2AR PAM-mediated suppression of insomnia in mice with mania-like behavior was similar to that mediated by DORA-22, and, unlike diazepam, did not result in abnormal sleep. Conclusion: A2AR allosteric modulation may represent a new therapeutic avenue for sleep disruption associated with bipolar disorder or psychosis.",
keywords = "EEG, Map6 (mouse), REM sleep, dopamine, neuroleptics, sleep disorder, stable tubule-only polypeptide, wakefulness",
author = "Yang Lin and Koustav Roy and Shuji Ioka and Rintaro Otani and Mao Amezawa and Yukiko Ishikawa and Yoan Cherasse and Kaushik, {Mahesh K.} and Daniela Klewe-Nebenius and Li Zhou and Masashi Yanagisawa and Yo Oishi and Tsuyoshi Saitoh and Michael Lazarus",
note = "Funding Information: This work was supported by the project “Social Application of Mobility Innovation and Future Social Engineering Research Phase IV (grant number CRI04006)”, a joint research project between Toyota Motor Corporation and the University of Tsukuba (to ML); the Japan Society for the Promotion of Science (Grant-in-Aid for Scientific Research B [grant number JP21H02802] to ML. Grant-in-Aid for Transformative Research Areas [Glia decoding: deciphering information critical for brain-body interaction, grant number JP23H04148] to ML), and RECONNECT Initiative [grant number JP22K21351] to MY, TS and ML); the Japan Science and Technology Agency (CREST [grant number JPMJCR1655] to MY and ML); Japan Agency for Medical Research and Development (AMED) Moonshot Program (grant number JP21zf0127005) to MY and ML; the Brain Science Foundation (to KR); the Organization for the Promotion of Strategic Research Initiatives of the University of Tsukuba (to KR); and the World Premier International Research Center Initiative (WPI) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) (to KR, MY, YO, TS, and ML). Publisher Copyright: Copyright {\textcopyright} 2023 Lin, Roy, Ioka, Otani, Amezawa, Ishikawa, Cherasse, Kaushik, Klewe-Nebenius, Zhou, Yanagisawa, Oishi, Saitoh and Lazarus.",
year = "2023",
doi = "10.3389/fphar.2023.1138666",
language = "English (US)",
volume = "14",
journal = "Frontiers in Pharmacology",
issn = "1663-9812",
publisher = "Frontiers Media S. A.",
}