Role of adenosine A1 receptor in the perifornical–lateral hypothalamic area in sleep–wake regulation in rats

The perifornical–lateral hypothalamic area (PF-LHA) has been implicated in the regulation of arousal. The PF-LHA contains wake-active neurons that are quiescent during non-REM sleep and in the case of neurons expressing the peptide hypocretin (HCRT), quiescent during both non-REM and REM sleep. Adenosine is an endogenous sleep factor and recent evidence suggests that adenosine via A1 receptors may act on PF-LHA neurons to promote sleep. We examined the effects of bilateral activation as well as blockade of A1 receptors in the PF-LHA on sleep–wakefulness in freely behaving rats. The sleep–wake profiles of male Wistar rats were recorded during reverse microdialysis perfusion of artificial cerebrospinal fluid (aCSF) and two doses of adenosine A1 receptor antagonist, 1,3-dipropyl-8-phenylxanthine (CPDX; 5 μM and 50 μM) or A1 receptor agonist, N6-cyclopentyladenosine (CPA; 5 μM and 50 μM) into the PF-LHA for 2 h followed by 4 h of aCSF perfusion. CPDX perfused into the PF-LHA during lights-on phase produced arousal (F = 7.035, p < 0.001) and concomitantly decreased both non-REM (F = 7.295, p < 0.001) and REM sleep (F = 3.456, p < 0.004). In contrast, CPA perfused into the PF-LHA during lights-off phase significantly suppressed arousal (F = 7.891, p < 0.001) and increased non-REM (F = 8.18, p <0.001) and REM sleep (F = 30.036, p < 0.001). These results suggest that PF-LHA is one of the sites where adenosine, acting via A1 receptors, inhibits PF-LHA neurons to promote sleep.