Positive allosteric adenosine A2A receptor modulation suppresses insomnia associated with mania- and schizophrenia-like behaviors in mice

Yang Lin; Koustav Roy; Shuji Ioka; Rintaro Otani; Mao Amezawa; Yukiko Ishikawa; Yoan Cherasse; Mahesh K Kaushik; Daniela Klewe-Nebenius; Li Zhou; Masashi Yanagisawa; Yo Oishi; Tsuyoshi Saitoh; Michael Lazarus

doi:10.3389/fphar.2023.1138666

Positive allosteric adenosine A_2A receptor modulation suppresses insomnia associated with mania- and schizophrenia-like behaviors in mice

Front Pharmacol. 2023 Apr 19:14:1138666. doi: 10.3389/fphar.2023.1138666. eCollection 2023.

Authors

Yang Lin¹, Koustav Roy¹, Shuji Ioka¹, Rintaro Otani¹, Mao Amezawa¹, Yukiko Ishikawa¹, Yoan Cherasse¹, Mahesh K Kaushik¹, Daniela Klewe-Nebenius¹, Li Zhou¹, Masashi Yanagisawa¹, Yo Oishi^{1

2}, Tsuyoshi Saitoh^{1

2}, Michael Lazarus^{1

2}

Affiliations

¹ International Institute for Integrative Sleep Medicine (WPI-IIIS), Tsukuba, Ibaraki, Japan.
² Institute of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.

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 A_2A receptors (A_2ARs) leads to slow-wave sleep without cardiovascular side effects in contrast to A_2AR agonists. Methods: We investigated the hypnotic effects of A_2AR 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 A_2AR 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: A_2AR PAMs suppress insomnia associated with mania- or schizophrenia-like behaviors in mice. A_2AR 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: A_2AR 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.

Grants and funding

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).