Adenosine A_2Areceptors regulate the activity of sleep regulatory GABAergic neurons in the preoptic hypothalamus

Abstract

The median preoptic nucleus (MnPN) and the ventrolateral preoptic area (VLPO) are two hypothalamic regions that have been implicated in sleep regulation, and both nuclei contain sleep-active GABAergic neurons. Adenosine is an endogenous sleep regulatory substance, which promotes sleep via A1 and A2A receptors (A2AR). Infusion of A2AR agonist into the lateral ventricle or into the subarachnoid space underlying the rostral basal forebrain (SS-rBF), has been previously shown to increase sleep. We examined the effects of an A2AR agonist, CGS-21680, administered into the lateral ventricle and the SS-rBF on sleep and c-Fos protein immunoreactivity (Fos-IR) in GABAergic neurons in the MnPN and VLPO. Intracerebroventricular administration of CGS-21680 during the second half of lights-on phase increased sleep and increased the number of MnPN and VLPO GABAergic neurons expressing Fos-IR. Similar effects were found with CGS-21680 microinjection into the SS-rBF. The induction of Fos-IR in preoptic GABAergic neurons was not secondary to drug-induced sleep, since CGS-21680 delivered to the SS-rBF significantly increased Fos-IR in MnPN and VLPO neurons in animals that were not permitted to sleep. Intracerebroventricular infusion of ZM-241385, an A2AR antagonist, during the last 2 h of a 3-h period of sleep deprivation caused suppression of subsequent recovery sleep and reduced Fos-IR in MnPN and VLPO GABAergic neurons. Our findings support a hypothesis that A2AR-mediated activation of MnPN and VLPO GABAergic neurons contributes to adenosinergic regulation of sleep.

Circuit-based interrogation of sleep control

“…In A2A receptor knockout mice, caffeine (an A1 and A2A receptor antagonist) failed to promote wakefulness 106 and deprivation-induced NREM sleep rebound was reduced 107 . In vivo application of an A2A receptor agonist increased NREM sleep and enhanced c-Fos expression in the VLPO and MnPO 108,109 , whereas application of an antagonist in the VLPO attenuated sleep-deprivation-induced increases in the firing rates of sleep-active neurons 110 . In brain slices, VLPO neurons were shown to be activated directly or indirectly via A2A receptors 111,112 .…”

Focusing on Adenosine Receptors as a Potential Targeted Therapy in Human Diseases

“…Similarly, A 2A AR and A 1 AR of hippocampal CA1 have the opposite effect in spreading piriform cortex kindled seizures, in which A 2A AR tends to have a convulsive effect [201]. In fact, the A 2A AR antagonist ZM241385 had a potent anticonvulsant profile with few adverse effects [202] and suppressed subsequent recovery sleep [203]. Concerning sleep and arousal, the A 2A AR agonist CGS21680 promoted both rapid eye movement (REM) and NREM sleep [133].…”

Estradiol Action at the Median Preoptic Nucleus is Necessary and Sufficient for Sleep Suppression in Female Rats

“…5 Additionally, the VLPO and MnPN have been shown as sites of sensitivity to adenosine, an important mediator of homeostatic sleep pressure. 151 Further exploration of these molecular and neurological pathways could provide greater insight into precisely how E2 is affecting sleep need and behavior.…”