The Dual Hypocretin Receptor Antagonist Almorexant Is Permissive for the Activation of Wake-Promoting Systems | SRI International

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The Dual Hypocretin Receptor Antagonist Almorexant Is Permissive for the Activation of Wake-Promoting Systems

November, 2014


Parks, G. S., Warrier, D. R., Dittrich, L., Wilk, A. J., Schwartz, M. D., Neylan, T. C., . . . Kilduff, T. S. (2014, 15-19 November). The dual hypocretin receptor antagonist almorexant is permissive for the activation of wake-promoting systems. Paper presented at Neuroscience 2014, Washington, DC.


The dual hypocretin receptor (HcrtR) antagonist almorexant (ALM) has potent hypnotic actions and is thought to promote sleep by selective disfacilitation of wake-promoting systems whereas benzodiazepine receptor agonists (BzRAs) such as zolpidem (ZOL) induce sleep through general inhibition of neural activity. Consequently, HcrtR antagonists are predicted to cause less functional impairment than BzRAs. Recent behavioral studies have supported this hypothesis as ALM causes less impairment in spatial memory tasks in rats awoken from hypnotic-induced sleep than ZOL does. Other dual HcrtR antagonists also promote sleep at doses that do not disrupt locomotor activity or cognition. In order to gain insight into the neural mechanisms underlying the differential functional impairment of these drugs, we compared the effects of ALM and ZOL on functional activation of the currently known wake-promoting systems. Sprague Dawley rats, implanted for EEG/EMG recording, were orally administered vehicle (VEH), 100mg/kg ALM, or 100mg/kg ZOL during their active phase and were either left undisturbed or kept awake (i.e., sleep-deprived; SD) for 90 min after which their brains were collected. We measured Fos coexpression with markers for wake-promoting cell groups in the basal forebrain (BF; ChAT), tuberomammillary nuclei (ADA), lateral hypothalamus (Hcrt), and dorsal raphe (DR; 5HT). In the locus coeruleus (LC), we counted singly-labelled Fos+ cells because the density of DBH staining obscured Fos immunoreactivity in double-labeled sections. Following sustained wakefulness, Fos coexpression in histamine and Hcrt neurons was higher in VEH and ALM-treated rats than in ZOL-treated rats; moreover, the level of co-expression was indistinguishable between the VEH- and ALM-treated groups. In these neuronal populations, Fos levels were consistently elevated in ALM-treated SD rats compared to undisturbed animals whereas Fos levels were unchanged by SD in ZOL-treated animals. In contrast, no significant differences were found between groups regardless of treatment in the BF and DR. Interestingly, there were no differences in Fos expression between VEH and ALM-treated animals in the LC following SD, but ZOL-treated rats exhibited elevated Fos compared to vehicle. These results indicate that, in contrast to ZOL, ALM does not inhibit activation of the histamine and Hcrt systems and is thus unlikely to prevent activation of wake-promoting systems in response to situational demands. These results may also relate to the lower levels of cognitive impairment produced by dual HcrtR antagonists compared to ZOL.

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