The novel brain neuropeptide, orexin‐A, modulates the sleep–wake cycle of rats

Abstract

Orexin-A is a novel neuropeptide initially isolated from hypothalamic extracts but now known to be present in fibres distributed throughout the rat CNS including many regions associated with sleep-wake regulation. The recognition of a particularly dense innervation of orexinergic nerves in the locus coeruleus, together with the observed increase in firing rate of locus coeruleus neurons following application of orexin-A in vitro, further highlighted a potential involvement of the peptide in modulating the arousal state. The present study was undertaken to determine the effects of intracerebroventricularly (ICV) administered orexin-A on the sleep-wake cycle of conscious rats using electroencephalographic and electromyographic recordings. When administered at the onset of the normal sleep period, orexin-A (1, 10 or 30 microg/rat ICV) produced a dose-dependent increase in the time rats spent awake during the second and third hours after dosing. The enhancement of arousal was accompanied by a marked reduction in paradoxical sleep and deep slow wave sleep at the highest dose. The latency to the first occurrence of paradoxical sleep was also prolonged. This overall profile of increased arousal and decreased paradoxical sleep is consistent with a high rate of firing of locus coeruleus neurons as would be expected to occur following ICV administration of orexin-A. It is concluded that orexin-A may play an important physiological role in regulating the sleep-wake state, a hypothesis considerably strengthened by the recently reported narcoleptic phenotype of prepro-orexin (the precursor for orexin-A) knockout mice.

Distribution of orexinergic neurons and their terminal networks in the brains of two species of African mole rats

“…Orexin (also known as hypocretin) is a neuropeptide that has been reported to play a role in the regulation of feeding, drinking, body temperature, general activity (Lubkin and Stricker-Krongrad, 1998;Edwards et al, 1999;Hagan et al, 1999;Kunii et al, 1999;Mondal et al, 1999;Piper et al, 2000;Estabrooke et al, 2001;Hungs et al, 2001;Yoshimichi et al, 2001;Kotz et al, 2002;Berthoud et al, 2005), energy homeostasis (Mintz et al, 2001), stimulation of gastric secretion in rats (Takahashi et al, 1999), increasing metabolic rate in rats (Lubkin and Stricker-Krongard, 1998), altering luteinising hormone release in rats (Pu et al, 1998) and in the regulation of the sleepwake cycle specifically associated with increased wakefulness and inhibition of REM sleep (Sakurai et al, 1998;Chemelli et al, 1999;Siegel, 1999;Bourgin et al, 2000;Kilduff and Peyron, 2000;Thannickal et al, 2000;van den Pol, 2000).…”

The Orexin-1 Receptor Antagonist SB-334867 Blocks the Effects of Antipsychotics on the Activity of A9 and A10 Dopamine Neurons: Implications for Antipsychotic Therapy

“…Orexin-A has a ten-fold higher affinity than orexin-B for the orexin-1 receptor, whereas orexin-A and orexin-B have equal affinity for the orexin-2 receptor (Smart et al, 1999(Smart et al, , 2000. The orexin system has been hypothesized to play a role in a number of brain functions including modulation of the neuroendocrine system, control of feeding and energy metabolism, and regulation of the sleep-wake cycle (Sakurai et al, 1998;Van den Pol et al, 1998;Piper et al, 2000). Recently, a selective antagonist of orexin-1 receptors, SB-334867, has been described (Smart et al, 2001).…”

Hypothalamic prepro-orexin mRNA level is inversely correlated to the non-rapid eye movement sleep level in high-fat diet-induced obese mice

“…Deficits in the orexin system lead to narcolepsy, which is characterized by excessive daytime sleepiness and sleep fragmentation [5]. Orexin administration reduces sleep [25] whereas sleep is induced by a reversible antagonist of orexins 1r and 2r that is currently in clinical development for the treatment of insomnia [26].…”