Lin Yang, Roy Koustav, Ioka Shuji, Otani Rintaro, Amezawa Mao, Ishikawa Yukiko, Cherasse Yoan, Kaushik Mahesh K, Klewe-Nebenius Daniela, Zhou Li, Yanagisawa Masashi, Oishi Yo, Saitoh Tsuyoshi, Lazarus Michael
International Institute for Integrative Sleep Medicine (WPI-IIIS), Tsukuba, Ibaraki, Japan.
Institute of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.
Front Pharmacol. 2023 Apr 19;14:1138666. doi: 10.3389/fphar.2023.1138666. eCollection 2023.
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 receptors (ARs) leads to slow-wave sleep without cardiovascular side effects in contrast to AR agonists. We investigated the hypnotic effects of AR 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 AR 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. AR PAMs suppress insomnia associated with mania- or schizophrenia-like behaviors in mice. AR 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. AR allosteric modulation may represent a new therapeutic avenue for sleep disruption associated with bipolar disorder or psychosis.
失眠与双相情感障碍或精神分裂症等精神疾病相关。治疗失眠可改善精神病症状的严重程度、生活质量和功能结局。患有精神疾病的患者通常对现有的失眠治疗方案不满意。相比之下，与腺苷A受体（AR）激动剂不同，腺苷A受体的正变构调节可导致慢波睡眠且无心血管副作用。我们研究了AR正变构调节剂（PAM）对通过损毁腹内侧中脑/脑桥区域的γ-氨基丁酸能神经元产生躁狂样行为的小鼠以及通过敲除微管相关蛋白6建立的精神分裂症小鼠模型的催眠作用。我们还比较了AR PAM在具有躁狂样行为的小鼠中诱导的睡眠特性与双重食欲素受体拮抗剂DORA-22（一种在临床前模型中可改善睡眠的药物）和苯二氮䓬类药物地西泮诱导的睡眠特性。AR PAM可抑制小鼠中与躁狂样或精神分裂症样行为相关的失眠。AR PAM介导的对具有躁狂样行为小鼠失眠的抑制作用与DORA-22介导的相似，并且与地西泮不同，不会导致异常睡眠。AR变构调节可能代表了一种治疗与双相情感障碍或精神病相关的睡眠障碍的新途径。
