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We evaluated the efficacy of two small molecule hypocretin\/orexin receptor\u20102 (HCRTR2) agonists in narcoleptic male <jats:italic>orexin\/tTA; TetO\u2010DTA<\/jats:italic> mice. TAK\u2010925 (1\u201310\u00a0mg\/kg, s.c.) and ARN\u2010776 (1\u201310\u00a0mg\/kg, i.p.) were injected 15\u2009min before dark onset in a repeated measures design. EEG, EMG, subcutaneous temperature (<jats:italic>T<\/jats:italic><jats:sub>sc<\/jats:sub>) and activity were recorded by telemetry; recordings for the first 6 h of the dark period were scored for sleep\/wake and cataplexy. At all doses tested, TAK\u2010925 and ARN\u2010776 caused continuous wakefulness and eliminated sleep for the first hour. Both TAK\u2010925 and ARN\u2010776 caused dose\u2010related delays in NREM sleep onset. All doses of TAK\u2010925 and all but the lowest dose of ARN\u2010776 eliminated cataplexy during the first hour after treatment; the anti\u2010cataplectic effect of TAK\u2010925 persisted into the second hour for the highest dose. TAK\u2010925 and ARN\u2010776 also reduced the cumulative amount of cataplexy during the 6 h post\u2010dosing period. The acute increase in wakefulness produced by both HCRTR2 agonists was characterised by increased spectral power in the gamma EEG band. Although neither compound provoked a NREM sleep rebound, both compounds affected NREM EEG during the second hour post\u2010dosing. TAK\u2010925 and ARN\u2010776 also increased gross motor activity, running wheel activity, and <jats:italic>T<\/jats:italic><jats:sub>sc<\/jats:sub>, suggesting that the wake\u2010promoting and sleep\u2010suppressing activities of these compounds could be a consequence of hyperactivity. Nonetheless, the anti\u2010cataplectic activity of TAK\u2010925 and ARN\u2010776 is encouraging for the development of HCRTR2 agonists.<\/jats:p>","DOI":"10.1111\/jsr.13839","type":"journal-article","created":{"date-parts":[[2023,2,21]],"date-time":"2023-02-21T03:25:55Z","timestamp":1676949955000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Evaluation of the efficacy of the hypocretin\/orexin receptor agonists <scp>TAK<\/scp>\u2010925 and <scp>ARN<\/scp>\u2010776 in narcoleptic <scp><i>orexin\/tTA; TetO\u2010DTA<\/i><\/scp> mice"],"prefix":"10.1111","volume":"32","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5002-1414","authenticated-orcid":false,"given":"Yu","family":"Sun","sequence":"first","affiliation":[{"name":"Biosciences Division SRI International  Menlo Park California 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