Whether the cause of daytime sleepiness in narcolepsy type 1 (NT1) is a direct consequence of the loss of orexin (ORX) neurons or whether low orexin reduces the efficacy of the monoaminergic systems to promote wakefulness is unclear.
Animal models have advanced not only our understanding of the etiology and phenotype of the sleep disorder narcolepsy but have also informed sleep/wake regulation more generally.
The involvement of this system in a disorder characterized by the loss of control over arousal state boundaries also suggested its role as a critical component of endogenous sleep-wake regulatory circuitry.
Orexin/hypocretin-producing and melanin-concentrating hormone-producing (MCH) neurons are co-extensive in the hypothalamus and project throughout the brain to regulate sleep/wakefulness.
Acute Cognitive Effects of the Hypocretin Receptor Antagonist Almorexant Relative to Zolpidem and Placebo: A Randomized Clinical Trial
This study aimed to determine whether ALM produces less acute cognitive impairment than ZOL in human subjects.
Here, we discuss shallow MD as a feasible first step toward synthetic torpor during spaceflight and summarize perspectives following a recent NASA-hosted workshop.
Melanin concentrating hormone-producing neurons (MCH neurons) in the hypothalamus actively contribute to forgetting in rapid eye movement (REM) sleep.
Trace Amine-Associated Receptor 1 Agonism Promotes Wakefulness Without Impairment of Cognition in Cynomolgus Macaques
Trace amine-associated receptor 1 (TAAR1) is a G-protein coupled receptor with affinity for the trace amines. TAAR1 agonists have pro-cognitive, antidepressant-, and antipsychotic-like properties in both rodents and non-human primates (NHPs). TAAR1 agonism also increases wakefulness and suppresses rapid-eye movement (REM) sleep in mice and rats and reduces cataplexy in two mouse models of narcolepsy. We investigated the effects of TAAR1 agonism in Cynomolgus macaques, a diurnal species that exhibits consolidated night-time sleep, and evaluated the effects of TAAR1 agonists on cognition using a working memory (WM) paradigm in this species. Adult male Cynomolgus macaques (n = 6) were surgically implanted to record the electroencephalogram (EEG), electromyogram, and locomotor activity (LMA) and the efficacy of the TAAR1 partial agonist RO5263397 (0.1,1,10 mg/kg, p.o.) on sleep/wake, EEG spectra, and LMA was determined. In a second experiment, the acute effects of RO5263397 (0.1,1,10 mg/kg, p.o.) were assessed on a delayed-match-to-sample test of WM in adult male macaques (n = 7). RO5263397 (10 mg/kg) administered at lights off, when sleep pressure was high, promoted wakefulness and reduced both REM and non-REM sleep without inducing hyperlocomotion. RO5263397 (10 mg/kg) also increased delta/theta activity during all vigilance states. RO5263397 had no effect on WM at either short (2 sec) or long (10 sec) delay intervals. The wake-enhancing and REM-suppressing effects of R05263397 shown here in a diurnal primate are consistent with previous results in nocturnal rodents. These effects and the associated alterations in EEG spectra occurred without inducing hyperlocomotion or affecting WM, encouraging further study of TAAR1 agonists as potential narcolepsy therapeutics.
We have proposed that cortical nNOS/NK1R interneurons have a role in sleep homeostasis.