Schwartz MD, Dittrich L, Fisher SP, Lincoln W, Liu H, Miller MA, Warrier DR, Wilk AJ, Morairty SR, Kilduff TS (2012) Effects of a dual hypocretin receptor antagonist on sleep and wakefulness in rats. Neuroscience 2012 Abstracts 799.23. Society for Neuroscience, New Orleans, LA.
Summary: Benzodiazepine receptor agonists promote sleep by activating GABAA receptors, leading to generalized reduction in cortical activity. They are widely used as hypnotic medications, but have side effects including risk for tolerance and/or dependence, as well as cognitive impairment while under their influence. The excitatory hypocretin (HCRT) neuropeptides promote wakefulness by activating multiple subcortical wake-promoting neurotransmitter systems which, in turn, project to and regulate cortical activity. Blocking HCRT signaling should therefore promote sleep by acting specifically on subcortical brain areas regulating sleep and wake without adversely impacting cortical function. Here, we assessed the ability of the dual HCRT receptor antagonist almorexant (ALM) to promote sleep in rats following ablation of a major sleep-wake regulatory region, the cholinergic basal forebrain (BF). We predicted that ALM would be less effective at inducing sleep in BF-lesioned rats compared to neurologically-intact rats, whereas benzodiazepine-based compounds should be equally as effective in lesioned and intact rats. Male rats received bilateral stereotaxic injections of saline or the selective cholinergic neurotoxin192-IgG-saporin (SAP) directed at the BF and were implanted with telemetry for recording sleep EEG. Following recovery, animals were given increasing doses of ALM, the GABA-A receptor agonist zolpidem (ZOL), or vehicle. Spontaneous sleep/wake regulation and homeostatic recovery from sleep deprivation was also assessed. At baseline, NREM sleep in the dark (active) phase was reduced in SAP rats compared to intact rats; SAP rats also exhibited decreased NREM recovery sleep following 6 h sleep deprivation in the dark phase. Sleep in the light (rest) phase was unaffected by SAP. Analysis of ALM and ZOL administration in these animals is currently in progress.
Related Products: 192-IgG-SAP (Cat. #IT-01)