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The dual orexin receptor antagonist almorexant induces sleep and decreases orexin-induced locomotion by blocking orexin 2 receptors

Mang, Geraldine, Duerst, Thomas, Imobersteg, Stefan, Buerki, Hugo, Abramowski, Dorothee, Schuepbach, Edi, Hoyer, Daniel, Fendt, Markus and Gee, Christine (2012) The dual orexin receptor antagonist almorexant induces sleep and decreases orexin-induced locomotion by blocking orexin 2 receptors. Sleep, 35 (12). pp. 1625-1635. ISSN 0161-8105


Orexin peptides regulate locomotor activity and sleep-wake balance by activating orexin 1 and orexin 2 receptors (OX1R and OX2R). Dual OX1R and OX2R antagonists reduce activity and promote sleep in multiple species, including man. We tested the effects of orexin A and almorexant, a dual OX1R/OX2R antagonist, in C57BL/6J mice and in mice lacking OX1Rs, OX2Rs or both to investigate the roles of the two receptors in orexin-induced locomotion and in sleep/wake regulation. Orexin A induced locomotion primarily by activating OX2Rs as locomotion was increased following intracerebroventricular orexin in OX1R-/- mice but not in OX2R-/- or OX1R-/-/OX2R-/- mice. Almorexant attenuated the orexin A-induced locomotion, demonstrating in vivo that almorexant specifically inhibits the actions of orexin. As in other species, almorexant dose-dependently increased rapid eye movement (REM) and non-REM (NREM) sleep in C57BL/6J mice. Sleep promotion by almorexant was mediated by inhibition of the known OXRs as almorexant was ineffective in OX1R-/-/OX2R-/- mice. Almorexant induced sleep in OX1R-/- mice but not in OX2R-/- mice, demonstrating that antagonism of OX2Rs is sufficient for sleep induction. When almorexant was incubated with the receptors for short periods of time, it behaved as a dual antagonist against orexin A-induced Ca2+ responses. However, with increasing incubation times, almorexant acquired OX2R selectivity confirming the findings from binding assays and further suggesting it may behave as an OX2R antagonist in vivo. Thus, OX2R activation mediates the stimulatory effects of orexin A on locomotion and antagonism of OX2R is sufficient to promote sleep in mice.

Item Type: Article
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Additional Information: first author was a Master's student the sleep studies were part of her Master's thesis
Keywords: orexin, sleep, mouse, hypocretin
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Date Deposited: 13 Oct 2015 13:15
Last Modified: 13 Oct 2015 13:15


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