Zolpidem Impairs Attention/Motivation in the Rodent Psychomotor Vigilance Task More Than Almorexant

Abstract

The dual hypocretin receptor (HcrtR) antagonist almorexant (ALM) has potent hypnotic actions but less is known about its effects on performance. Since Hcrt antagonists produce sleep by disfacilitation of wake-promoting systems whereas benzodiazepine receptor agonists (BzRAs) such as zolpidem (ZOL) induce sleep through a generalized inhibition of neural activity, we hypothesized that ALM would produce less functional impairment than ZOL. We have previously shown that rats tested in spatial reference memory or spatial working memory tasks in a water maze show no impairment following ALM whereas significant impairment was evident following ZOL. Here, we tested the effects of ALM and ZOL on the Rodent Psychomotor Vigilance Task (rPVT), a sensitive test of attention and motivation.

10 rats were implanted with telemetry devices for recording EEG and EMG. The effects of ALM and ZOL on attention/motivation administered in the middle of the active period were assessed at 2 sleep-promoting concentrations (30 & 100 mpk, po) following undisturbed and sleep deprived (SD, 6 h prior to dosing) conditions. 90 min following dosing, trained, water-restricted rats were placed in operant chambers with infrared detection beams in front of the water dispenser. rPVT testing consisted of a stimulus light (duration of 0.5 s) followed by a 3 s response period. The inter-trial interval varied between 3-7 s. Errors resulted in a cued 10 s “time out” period. Performance measures were 1) response latencies (RL), 2) correct responses (CR), 3) omissions (OM), and 4) premature errors (PE). Impaired performance is indicated by increases in RL, OM and PE and decreases in CR.

SD had a relatively small but significant effect on performance following VEH: RL decreased (96.2%), CR decreased (95.5%) and OM increased (146.1%) while PE decreased (95.1%) following SD+90 min recovery compared to baseline. Following ALM at 30 mpk compared to VEH, OM and RL decreased (51.7 & 96.2%; indicative of increased performance) while CR decreased and PE increased (indicative of impaired performance). ZOL at 30 mpk decreased performance markedly: RL increased (131.3%), CR decreased (30.4%) and OM increased (724.1%) while PE decreased (36.9%) compared to VEH. However, performance decreased significantly following both drugs at 100 mpk, particularly with ZOL. Following ALM at 100 mpk, RL and OM increased (150.6 & 556.3%) and CR and PE decreased (42.8 & 58.0%). Following ZOL at 100 mpk, RL and OM increased (126.6 & 855.6%) and CR and PE decreased (9.2 & 26.0%).

These results are consistent with the hypothesis that less functional impairment results from HcrtR antagonism than from BzRA-induced inhibition.