Adenosine A2A receptor deficiency attenuates the somnogenic effect of prostaglandin D2 in mice.

Prostaglandin D2 (PGD2) is one of the most potent endogenous sleep promoting substances. PGD2 activates the PGD2 receptor (DPR) and increases the extracellular level of adenosine in wild-type (WT) mice but not DPR knockout (KO) mice, suggesting that PGD2-induced sleep is DPR-dependent, and adenosine may be the signaling molecule that mediates the somnogenic effect of PGD2. The aim of this study was to determine the involvement of the adenosine A2A receptor (A2AR) in PGD2-induced sleep. We infused PGD2 into the lateral ventricle of WT and A2AR KO mice between 20:00 and 2:00 for 6 h, and electroencephalograms and electromyograms were simultaneously recorded. In WT mice, PGD2 infusion dose-dependently increased non-rapid eye movement (non-REM, NREM) sleep, which was 139.1%, 145.0% and 202.7% as large as that of vehicle-treated mice at doses of 10, 20 and 50 pmol/min, respectively. PGD2 infusion at doses of 20 and 50 pmol/min also increased REM sleep during the 6-h PGD2 infusion and 4-h post-dosing periods in WT mice to 148.9% and 166.7%, respectively. In A2AR KO mice, however, PGD2 infusion at 10 pmol/min did not change the sleep profile, whereas higher doses at 20 and 50 pmol/min increased the NREM sleep during the 6-h PGD2 infusion to 117.5% and 155.6%, respectively, but did not change the sleep in the post-dosing period. Moreover, PGD2 infusion at 50 pmol/min significantly increased the episode number in both genotypes but only enhanced the episode duration in WT mice. The results demonstrate that PGD2-induced sleep in mice is mediated by both adenosine A2AR-dependent and -independent systems.

Interleukin-1ß induces sleep independent of prostaglandin D2 in rats and mice.

Interleukin-1ß (IL-1ß) and prostaglandin (PG) D2 are endogenous sleep-promoting substances. Since it was reported that a highly selective cyclooxygenase-2 (COX-2) inhibitor, NS398, completely inhibited IL-1ß-induced sleep in rats, IL-1ß-induced sleep had been believed to be mediated by prostanoids, most probably PGD2. However, in the present study, pretreatment of rats with NS398 (3mg/kg) did not suppress the 64.2% increased non-rapid eye movement (non-REM, NREM) sleep during infusion of IL-1ß (10ng) for 6h in the nocturnal (active) period between 23:00 and 5:00 into the subarachnoid space of the PGD2-sensitive sleep-promoting zone of the basal forebrain. Meanwhile, IL-1ß at doses of 1.7 and 5µg/kg also significantly increased NREM sleep for 6h after intraperitoneal injection at 20:00 (light-off time) by 76.8% and 121.1%, respectively, in wild-type (WT) mice, by 67.7% and 147.3%, respectively, in WT mice pretreated with NS398 (5mg/kg) and by 108.9% and 121.6%, respectively, in PGD2 receptor (DP1R) knockout mice. These results indicate that IL-1ß-induced NREM sleep is independent of the PGD2/DP1R system and other COX-2-derived prostaglandins in rats and mice.

Slow-wave sleep is controlled by a subset of nucleus accumbens core neurons in mice.

Sleep control is ascribed to a two-process model, a widely accepted concept that posits homoeostatic drive and a circadian process as the major sleep-regulating factors. Cognitive and emotional factors also influence sleep-wake behaviour; however, the precise circuit mechanisms underlying their effects on sleep control are unknown. Previous studies suggest that adenosine has a role affecting behavioural arousal in the nucleus accumbens (NAc), a brain area critical for reinforcement and reward. Here, we show that chemogenetic or optogenetic activation of excitatory adenosine A2A receptor-expressing indirect pathway neurons in the core region of the NAc strongly induces slow-wave sleep. Chemogenetic inhibition of the NAc indirect pathway neurons prevents the sleep induction, but does not affect the homoeostatic sleep rebound. In addition, motivational stimuli inhibit the activity of ventral pallidum-projecting NAc indirect pathway neurons and suppress sleep. Our findings reveal a prominent contribution of this indirect pathway to sleep control associated with motivation.In addition to circadian and homoeostatic drives, motivational levels influence sleep-wake cycles. Here the authors demonstrate that adenosine receptor-expressing neurons in the nucleus accumbens core that project to the ventral pallidum are inhibited by motivational stimuli and are causally involved in the control of slow-wave sleep.