An adenosine A2A receptor agonist induces sleep by increasing GABA release in the tuberomammillary nucleus to inhibit histaminergic systems in rats

Abstract

The adenosine A_2A receptor (A_2AR) has been demonstrated to play a crucial role in the regulation of the sleep process. However, the molecular mechanism of the A_2AR-mediated sleep remains to be elucidated. Here we used electroencephalogram and electromyogram recordings coupled with in vivo microdialysis to investigate the effects of an A_2AR agonist, CGS21680, on sleep and on the release of histamine and GABA in the brain. In freely moving rats, CGS21680 applied to the subarachnoid space underlying the rostral basal forebrain significantly promoted sleep and inhibited histamine release in the frontal cortex. The histamine release was negatively correlated with the amount of non-rapid eye movement sleep (r = − 0.652). In urethane-anesthetized rats, CGS21680 inhibited histamine release in both the frontal cortex and medial pre-optic area in a dose-dependent manner, and increased GABA release specifically in the histaminergic tuberomammillary nucleus but not in the frontal cortex. Moreover, the CGS21680-induced inhibition of histamine release was antagonized by perfusion of the tuberomammillary nucleus with a GABA_A antagonist, picrotoxin. These results suggest that the A_2AR agonist induced sleep by inhibiting the histaminergic system through increasing GABA release in the tuberomammillary nucleus.