Abstract
The hypocretin receptor (HcrtR) antagonist almorexant (ALM) has potent hypnotic actions but little is known about neurocognitive performance in the presence of ALM. HcrtR antagonists are hypothesized to induce sleep by disfacilitation of wake-promoting systems whereas GABAA receptor modulators such as zolpidem (ZOL) induce sleep through general inhibition of neural activity. To test the hypothesis that less functional impairment results from HcrtR antagonist-induced sleep, we evaluated the performance of rats in the Morris Water Maze in the presence of ALM vs. ZOL. Performance in spatial reference memory (SRM) and spatial working memory (SWM) tasks were assessed during the dark period after equipotent sleep-promoting doses (100 mg/kg, po) following undisturbed and sleep deprivation (SD) conditions. ALM-treated rats were indistinguishable from vehicle (VEH)-treated rats for all SRM performance measures (distance traveled, latency to enter, time within, and number of entries into, the target quadrant) after both the undisturbed and 6 h SD conditions. In contrast, rats administered ZOL showed impairments in all parameters measured compared to VEH or ALM in the undisturbed conditions. Following SD, ZOL-treated rats also showed impairments in all measures. ALM-treated rats were similar to VEH-treated rats for all SWM measures (velocity, time to locate the platform and success rate at finding the platform within 60 s) after both the undisturbed and SD conditions. In contrast, ZOL-treated rats showed impairments in velocity and in the time to locate the platform. Importantly, ZOL rats only completed the task 23–50% of the time while ALM and VEH rats completed the task 79–100% of the time. Thus, following equipotent sleep-promoting doses, ZOL impaired rats in both memory tasks while ALM rats performed at levels comparable to VEH rats. These results are consistent with the hypothesis that less impairment results from HcrtR antagonism than from GABAA-induced inhibition.
Highlights
Insomnia is a highly prevalent condition affecting 10–30% of the general population; (NIH, 2005; Roth, 2007; Mai and Buysse, 2008)
More effective hypnotics are needed that facilitate sleep that is reversible in the event of an unexpected awakening that demands unimpaired cognitive and psychomotor performance
TEST OF SPATIAL REFERENCE MEMORY For all performance measures analyzed, rats treated with ZOL showed significant impairments while ALM- and VEH-treated rats were indistinguishable (Figure 3)
Summary
Insomnia is a highly prevalent condition affecting 10–30% of the general population; (NIH, 2005; Roth, 2007; Mai and Buysse, 2008). Known to induce sleep, these compounds have been shown to significantly impair psychomotor and memory functions in rodents (Huang et al, 2010; Uslaner et al, 2013; Zanin et al, 2013), non-human primates (Makaron et al, 2013; Soto et al, 2013; Uslaner et al, 2013) and humans (Balkin et al, 1992; Wesensten et al, 1996, 2005; Mattila et al, 1998; Mintzer and Griffiths, 1999; Verster et al, 2002; Storm et al, 2007; Otmani et al, 2008; Gunja, 2013) Such impairment can be troubling when there is an urgent need for highly functional performance in the presence of drug such as with first responders, military personnel, and caregivers. More effective hypnotics are needed that facilitate sleep that is reversible in the event of an unexpected awakening that demands unimpaired cognitive and psychomotor performance
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