The neural circuits that maintain wakefulness remain incompletely understood, as do the mechanisms of impaired consciousness in many patients. Wakefulness is necessary for consciousness, and impaired wakefulness is a symptom of many diseases. Collectively, these findings provide a proof-of-concept for safer mechanistic treatment of narcolepsy-cataplexy through OX2R-selective agonism. Furthermore, intracerebroventricular orexin-A but not -orexin-B induced drug-seeking behaviors in a dose-dependent manner in wild-type mice, suggesting that OX2R-selective agonism has a lower propensity for reinforcing/drug-seeking effects. Administration of -orexin-B extended wake time, reduced state transition frequency between wake and NREM sleep, and reduced the number of cataplexy-like episodes, to the same degree as compared with orexin-A. Intracerebroventricular -orexin-B, a peptidic OX2R-selective agonist, selectively activated OX2R-expressing histaminergic neurons in vivo, whereas intracerebroventricular orexin-A, an OX1R/OX2R non-selective agonist, additionally activated OX1R-positive noradrenergic neurons in vivo. In the present study, we examined whether the selective activation of OX2R is sufficient to rescue the phenotype of cataplexy and sleep/wake fragmentation in orexin knockout mice.
However, it has been unclear whether the activation of only OX2R, or both OX1R and OX2R, is required to replace the endogenous orexin functions in the brain. Orexins act on two receptor subtypes, OX1R and OX2R, the latter being more strongly implicated in sleep/wake regulation. Orexin replacement therapy using orexin receptor agonists is expected as a mechanistic treatment for narcolepsy. (Bar, 3 mm for a, c, e, and g and 0.5 mm for b, d, f, and h).Īcquired loss of hypothalamic orexin (hypocretin)-producing neurons causes the chronic sleep disorder narcolepsy-cataplexy. f, fornix Arc, arcuate nucleus of the hypothalamus 3V, third ventricle. (a Inset) The location and size of magnified images in b, d, f, and h. In contrast, orexinataxin-3 CAGorexindouble-transgenic mice exhibit only the ectopic pattern of orexin-A native neurons are absent (g and h). CAGorexin-transgenic mice have widespread, diffuse, ectopic production of orexin-A in addition to that observed in native neurons (e and f ). Note the punctate staining of native orexin-A-immunoreactive neurons clustered in the perifornical LH of wild-type mice (a and b) and the absence of orexin-A in the brains of orexinataxin-3-transgenic mice in which native orexinergic neurons have degenerated (c and d). Antiorexin-A immunostaining of coronal sections of brain tissue from wild-type, orexinataxin-3-hemizygous-transgenic-, CAGorexin-hemizygous-transgenic-, and double-hemizygous-transgenic mice were performed as described (31). Immunohistochemical analysis of brains from transgenic mice. Orexin receptor agonists would be of potential value for treating human narcolepsy. These results indicate that orexin neuron-ablated mice retain the ability to respond to orexin neuropeptides and that a temporally regulated and spatially targeted secretion of orexins is not necessary to prevent narcoleptic symptoms. Central administration of orexin-A acutely suppressed cataplectic behavioral arrests and increased wakefulness for 3 h. Ectopic expression of a prepro-orexin transgene in the brain completely prevented cataplectic arrests and other abnormalities of rapid eye movement sleep in the absence of endogenous orexin neurons. Here, we demonstrate rescue of the narcolepsy-cataplexy phenotype of orexin neuron-ablated mice by genetic and pharmacological means. Currently available treatments for narcolepsy are only palliative, symptom-oriented pharmacotherapies. The vast majority of narcoleptic-cataplectic individuals have low or undetectable levels of orexin (hypocretin) neuropeptides in the cerebrospinal fluid, likely due to specific loss of the hypothalamic orexin-producing neurons. Narcolepsy-cataplexy is a neurological disorder associated with the inability to maintain wakefulness and abnormal intrusions of rapid eye movement sleep-related phenomena into wakefulness such as cataplexy.
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