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Insomnia is one of the most common sleep problems with an estimated prevalence of 10%-15% in the general population. Although adenosine A2A receptor (A2AR) agonists strongly induce sleep, their cardiovascular effects preclude their use in treating sleep disorders. Enhancing endogenous A2AR signaling, however, may be an alternative strategy for treating insomnia, because adenosine levels in the brain accumulate during wakefulness. In the present study, we found that 3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzoic acid, denoted A2AR positive allosteric modulator (PAM)-1, enhanced adenosine signaling at the A2AR and induced slow wave sleep (SWS) without affecting body temperature in wild-type male mice after intraperitoneal administration, whereas the SWS-inducing effect of this benzoic acid derivative was abolished in A2AR KO mice. In contrast to the A2AR agonist CGS 21680, the A2AR PAM-1 did not affect blood pressure or heart rate. These findings indicate that enhancing A2AR signaling promotes SWS without cardiovascular effects. Therefore, small molecules that allosterically modulate A2ARs could help people with insomnia to fall asleep.

Summary Individuals with the neuropsychiatric disorder mania exhibit hyperactivity, elevated mood, and a decreased need for sleep. The brain areas and neuronal populations involved in mania-like behaviors, however, have not been elucidated. In this study, we found that ablating the ventral medial midbrain/pons (VMP) GABAergic neurons induced mania-like behaviors in mice, including hyperactivity, anti-depressive behaviors, reduced anxiety, increased risk-taking behaviors, distractibility, and an extremely shortened sleep time. Strikingly, these mice also showed no rebound sleep after sleep deprivation, suggesting abnormal sleep homeostatic regulation. Dopamine D2 receptor deficiency largely abolished the sleep reduction induced by ablating the VMP GABAergic neurons without affecting the hyperactivity and anti-depressive behaviors. Our data demonstrate that VMP GABAergic neurons are involved in the expression of mania-like behaviors, which can be segregated to the short-sleep and other phenotypes on the basis of the dopamine D2 receptors., Graphical Abstract, Highlights • Hyperactivity and anti-depressive behaviors are induced by loss of VMP GABA neurons • Homeostatic sleep rebound is lost together with largely shorten daily sleep • Dopamine D2 receptors mediate the daytime sleep loss, Neuroscience; Behavioral Neuroscience; Cellular Neuroscience

Adenosine is formed by various processes in all cell types, and its basal level depends only on the fundamental mechanisms of cell biology. Therefore, adenosine in the central nervous system is not a neurotransmitter or a typical neuromodulator, but rather functions as an autacoid, a biological factor that acts near the site of synthesis, where it is also rapidly metabolized. Surprisingly, although adenosine has long been studied as a sleep-promoting substance, the source of adenosine and the brain regions where adenosine receptors control sleep/wake behavior are poorly understood. In this chapter, we present an overview of current knowledge regarding the regulation of sleep and wake by adenosine. As knowledge of the molecular and circuit bases of sleep/wake regulation expands, new roles of adenosine receptors in modulating different aspects of sleep emerge. For example, A2A receptors appear to gate sleep by suppressing arousal, whereas sleep need is mediated by A1 receptors, and these receptors may thus play a crucial role in the function of sleep.