Figure 2.

Hypothesized role of hypocretin (Hcrt) cells in the cataplexy and sleepiness of narcolepsy. Hcrt cell projections are shown in bold. Normally, the descending projections from Hcrt cells excite norepinephrine- and serotonin (5-hydroxytryptamine or 5-HT)-containing cells, which in turn excite motor neurons. Hcrt cells might also directly excite motor neurons. A phasic excitation of norepinephrine cells by Hcrt cells counters the phasic inhibition of norepinephrine cells mediated by the limbic system, typically in response to sudden strong positive emotions, such as laughter, the most common precipitant of cataplexy in humans. Norepinephrine and medullary inhibitory neurons discharge reciprocally, so that cessation of norepinephrine discharge is linked to increased activity in descending inhibitory systems. When the majority of Hcrt cells are destroyed in narcolepsy, the emotionally triggered inhibition of norepinephrine and 5-HT cells, coupled with the excitation of glycine- and GABA-containing cells in the medulla and spinal cord, reduces muscle tone, resulting in cataplexy. The ascending projections from Hcrt neurons directly and indirectly excite thalamic and cortical neurons, particularly through their action on histamine, dopamine neurons and acetylcholine neurons, thereby maintaining arousal. The loss of this influence results in the persistent sleepiness of narcolepsy. Abbreviations: 5-HT, 5-hydroxytryptamine; GABA, γ-aminobutyric acid.