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Orexin replacement therapy using orexin receptor agonists is expected as a mechanistic treatment for narcolepsy. Orexins act on two receptor subtypes, OX1R and OX2R, the latter being more strongly implicated in sleep\/wake regulation. 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. 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. Intracerebroventricular [Ala<jats:sup>11<\/jats:sup>, <jats:sub>D<\/jats:sub>-Leu<jats:sup>15<\/jats:sup>]-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. Administration of [Ala<jats:sup>11<\/jats:sup>, <jats:sub>D<\/jats:sub>-Leu<jats:sup>15<\/jats:sup>]-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. Furthermore, intracerebroventricular orexin-A but not [Ala<jats:sup>11<\/jats:sup>, <jats:sub>D<\/jats:sub>-Leu<jats:sup>15<\/jats:sup>]-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. Collectively, these findings provide a proof-of-concept for safer mechanistic treatment of narcolepsy-cataplexy through OX2R-selective agonism.<\/jats:p>","DOI":"10.1371\/journal.pone.0271901","type":"journal-article","created":{"date-parts":[[2022,7,22]],"date-time":"2022-07-22T17:30:10Z","timestamp":1658511010000},"page":"e0271901","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":17,"title":["OX2R-selective orexin agonism is sufficient to ameliorate cataplexy and sleep\/wake fragmentation without inducing drug-seeking behavior in mouse model of narcolepsy"],"prefix":"10.1371","volume":"17","author":[{"given":"Hikari","family":"Yamamoto","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasuyuki","family":"Nagumo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yukiko","family":"Ishikawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoko","family":"Irukayama-Tomobe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yukiko","family":"Namekawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tsuyoshi","family":"Nemoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiromu","family":"Tanaka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Genki","family":"Takahashi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akihisa","family":"Tokuda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tsuyoshi","family":"Saitoh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Nagase","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiromasa","family":"Funato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7358-4022","authenticated-orcid":true,"given":"Masashi","family":"Yanagisawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2022,7,22]]},"reference":[{"issue":"27","key":"pone.0271901.ref001","doi-asserted-by":"crossref","first-page":"2654","DOI":"10.1056\/NEJMra1500587","article-title":"Narcolepsy","volume":"373","author":"TE 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