Fig. 4.

Putative mechanisms underlying intranasal orexin entry and action within the brain. Orexins administered via the intranasal route are hypothesized to enter the brain via two main mechanisms: 1) diffusion across the olfactory epithelium into olfactory and rostral brain areas and 2) extra-axonal diffusion along trigeminal sensory pathways into brainstem regions. After accessing the CNS, our data suggests that orexins activate basal forebrain cholinergic neurons via the orexin-1 or orexin-2 receptor. Excitation of these neurons by orexins ultimately increases acetylcholine efflux within the prefrontal cortex, a putative neurochemical correlate of attention. We also observed that intranasal orexin-A administration increases neuronal activation of excitatory pyramidal neurons and decreases neuronal activation of inhibitory parvalbumin-positive GABAergic interneurons within the prefrontal cortex. This dichotomy may ultimately arise from orexin-2 receptor mediated excitation of parvalbumin-positive GABAergic neurons within the basal forebrain. These inhibitory projections neurons of the basal forebrain preferentially synapse onto cortical GABAergic interneurons. Finally, we observed that intranasal orexin-A administration can activate brainstem neurons of the pedunculopontine tegmental nucleus, which may also modulate activity within the basal forebrain and/or cortex.