Hypocretin, neuronal activity-regulated pentraxin and melanin-concentrating hormone: Relevance to narcolepsy

Hypocretin (Hcrt) is a neuropeptide synthesized in the hypothalamus. Cells containing Hcrt also contain neuronal activity-regulated pentraxin (Narp), a pentraxin involved in the clustering of AMPA receptors. Hcrt/Narp positive cells are located in close proximity to cells containing melanin-concentrating hormone (MCH), and evidence suggests that these two cell groups interact. Narcolepsy is a sleep disorder characterized by sleep attacks and cataplexy triggered by emotion and has been linked to a near complete loss of Hcrt staining, although MCH staining remains unaltered. It is not known whether the loss of Hcrt staining represents the specific loss of the peptide Hcrt or actual loss of the Hcrt-synthesizing cells. We employed immunocytochemistry in post-mortem narcoleptic brains to show that Narp staining is also decreased in the human narcoleptic hypothalamus to the same extent that Hcrt staining is lost. These findings indicate that either both Hcrt and Narp synthesis is lost in narcolepsy or, more likely, that the cells containing both Hcrt and Narp are lost. Because Hcrt cells normally interact with MCH and because the Hcrt cells appear to be lost in narcolepsy, it is unclear how this may affect the MCH system and what functional implications this may have for narcolepsy. Therefore, using microdialysis, we measured Hcrt and MCH release in the non-narcoleptic human brain and in the rat brain to assess the pattern of release of these two peptides during sleep and waking behavior. We found that Hcrt and MCH exhibit an opposite release pattern. Hcrt levels increase at wake onset and are high during wake, while MCH levels increase at sleep onset and are high during sleep. Furthermore, Hcrt levels are high during social interaction and during emotional situations, while MCH levels are low. Because Hcrt and MCH cells likely interact with each other and because they show opposite patterns of release, it is likely that these two systems oppose each other functionally. Thus, without the Hcrt cells, narcoleptics may experience a dysregulation of the MCH system, increases of MCH at inappropriate times such as during emotional and social situations, and invasion of their waking state by components of sleep.