Figure 1.

Possible Role of the Hypocretins (Orexins) in the Pathology of Narcolepsy

The hypocretin (orexin)–containing neurons are known to project to brainstem regions linked to motor inhibition as well as to locus coeruleus (norepinephrine), raphe (serotonin), and laterodorsal tegmental nuclei (acetylcholine) and ventral tegmental (dopamine) neurons. They also project to forebrain regions including posterior hypothalamus (histamine), septal nucleus, and diagonal band (acetylcholine) neurons and have major projections to the amygdala and basal forebrain hypnogenic regions. Loss of function of the hypocretin system could cause cataplexy by disfacilitating the brainstem’s motor excitatory systems or by disinhibiting the brainstem’s motor inhibitory system. Loss of function of the hypocretins could increase sleepiness by disfacilitating the cholinergic and aminergic arousal systems or by disinhibiting the forebrain’s hypnogenic systems. The few physiological studies done to date suggest that the hypocretins are usually excitatory; therefore, these two possibilities are highlighted in the figure.