Neurophysiological aspects of the regulation of serotonin neurons by the orexinergic system

Orexin (also called hypocretin) is a neurotransmitter that influences central arousal and vigilance state, especially by coupling the level of arousal to energy balance. Localized uniquely to neurons with cell bodies in the lateral hypothalamus, orexin has widespread projections throughout the neuraxis, including the raphe nuclei. Dense orexinergic innervation has been noted in the dorsal raphe, where direct axodendritic contacts between orexinergic fibers and serotoninergic processes have also been described. Orexin depolarizes dorsal raphe serotoninergic cells, an effect that is consistent with activation of the canonical form of the transient receptor potential channel. Thus, the effect of orexin will be integrated with other neurotransmitters that also depolarize serotoninergic cells through this channel, including noradrenaline and histamine. However, in addition to the direct action, orexin at higher concentrations also depolarizes GABAergic interneurons and reduces glutamatergic release at local terminals through a retrograde endocannabinoid signal. The functional consequences of these interactions between orexin and serotonin remain to be elucidated, although they are consistent with synaptic modification. Hence orexin may modulate the serotoninergic influence in the forebrain as part of an adaptive response to homeostatic disequilibrium.