Adenosine A2A receptors regulate the activity of sleep regulatory GABAergic neurons in the preoptic hypothalamus

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 A(1) and A(2A) receptors (A(2A)R). Infusion of A(2A)R 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 A(2A)R 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 A(2A)R 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 A(2A)R-mediated activation of MnPN and VLPO GABAergic neurons contributes to adenosinergic regulation of sleep.