Serotonergic System in the Central Nucleus of Amygdala Mediates Cannabidiol- Induced Sleep Alteration

Cannabidiol (CBD) is one of the psycho-inactive constituents of marijuana, the Cannabis sativa. The pharmacological property of CBD, especially the anxiolytic effect, is significant in the therapeutic purposes. The central nucleus of amygdala (CeA) plays a key role in the anxiety and its related behavioral responses (e.g. sleep-wake activity), and serotonin is one of the major mediators. However, the sleep-wake effect of CBD remains unclear. This study was designed to elucidate the effects of CBD on sleep-wake alteration and the involvement of serotonin in the CeA. Administrations of 5- hydroxytryptamine (5-HT), 5-HT1A receptor partial agonist (buspirone), 5-HT2 antagonist (ritanserin), cannabinoid CB1 receptor agonist (ACEA), or CB1 antagonist (AM-251) were employed to elucidate the action of CBD on CeA presynaptic CB1 receptors, serotonergic activity and the subsequent sleep alteration. We found that microinjection of CBD into the CeA prior to the beginning of the light period dose-dependently decreased slow wave sleep (SWS) with limited effect on rapid eye movement sleep (REMS). CBD-induced SWS suppression during the light period could be mimicked by administering serotonin into the CeA. Buspirone and ritanserin dose-dependently blocked CBD-induced SWS decrease. Furthermore, administration of AM-251 exhibits similar effect as that of CBD on sleep-wake activity, and the CBD-induced SWS decrease was partially blocked by ACEA. These observations suggest that CBD acting on the CeA neurons decreases SWS during the light phase, which is at least partially mediated by the consequence of antagonizing presynaptic CB1 receptors, enhancing serotonin release from the presynaptic terminals and subsequently acting on the postsynaptic 5- HT2 receptors.