Insomnia is one of the most common sleep problems with an estimated prevalence of 10% to 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-4iodophenyl)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.

Social conflict is a major source of stress in humans. Animals also experience social conflicts and cope with them by stress responses that facilitate arousal and activate sympathetic and neuroendocrine systems. The effect of acute social defeat (SoD) stress on the sleep/wake behavior of mice has been reported in several models based on a resident-intruder paradigm. However, the post-SoD stress sleep/wake effects vary between the studies and the contribution of specific effects in response to SoD or non-specific effects of the SoD procedure (e.g., sleep deprivation) is not well established. In this study, we established a mouse model of acute SoD stress based on strong aggressive mouse behavior toward unfamiliar intruders. In our model, we prevented severe attacks of resident mice on submissive intruder mice to minimize behavioral variations during SoD. In response to SoD, slow-wave sleep (SWS) strongly increased during 9 h. Although some sleep changes after SoD stress can be attributed to non-specific effects of the SoD procedure, most of the SWS increase is likely a specific response to SoD. Slow-wave activity was only enhanced for a short period after SoD and dissipated long before the SWS returned to baseline. Moreover, SoD evoked a strong corticosterone response that may indicate a high stress level in the intruder mice after SoD. Our SoD model may be useful for studying the mechanisms and functions of sleep in response to social stress.

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