Adenosine A_2A receptors in the olfactory bulb suppress rapid eye movement sleep in rodents

Rapid eye movement (REM) sleep behavior disorder in humans is often accompanied by a reduced ability to smell and detect odors, and olfactory bulbectomized rats exhibit increased REM sleep, suggesting that the olfactory bulb (OB) is involved in REM-sleep regulation. However, the molecular mechanism of REM-sleep regulation by the OB is unknown. Adenosine promotes sleep and its A_2A receptors (A_2AR) are expressed in the OB. We hypothesized that A_2AR in the OB regulate REM sleep. Bilateral microinjections of the A_2AR antagonist SCH58261 into the rat OB increased REM sleep, whereas microinjections of the A_2AR agonist CGS21680 decreased REM sleep. Similar to the A_2AR antagonist, selective A_2AR knockdown by adeno-associated virus carrying short-hairpin RNA for A_2AR in the rat OB increased REM sleep. Using chemogenetics on the basis of designer receptors exclusively activated by designer drugs, we demonstrated that the inhibition of A_2AR neurons increased REM sleep, whereas the activation of these neurons decreased REM sleep. Moreover, using a conditional anterograde axonal tract-tracing approach, we found that OB A_2AR neurons innervate the piriform cortex and olfactory tubercle. These novel findings indicate that adenosine suppresses REM sleep via A_2AR in the OB of rodents.