Effect of a Hypocretin/Orexin Antagonist on Neurocognitive Performance

During Year 2, a new laboratory for behavioral performance assessment and microdialysis sampling was occupied and two new HPLCs were purchased and calibrated. Both the benzodiazepine receptor agonist zolpidem ZOL and the hypocretin Hcrt receptor antagonist almorexant ALM induced sleep in rodents. However, ALM did not impair performance in a spatial reference memory test whereas ZOL did. Preliminary results indicate that the wake-active Hcrt neurons could be activated in the presence of ALM but not in the presence of ZOL. In contrast, a sleep-active cortical neuron population was equally activated by ALM and ZOL. ALM caused a significant decrease in basal forebrain BF glutamate and concurrently increased BF GABA and adenosine during NREMREM sleep compared to ZOL or VEH. These results are consistent withthe hypothesis that the disfacilitation of wake-promoting systems by ALM results in less functional impairment than the general inhibition of neural activity produced by ZOL.