Orexin A attenuates the sleep-promoting effect of adenosine in the lateral hypothalamus of rats

Abstract

Orexin neurons within the lateral hypothalamus play a crucial role in the promotion and maintenance of arousal. Studies have strongly suggested that orexin neurons are an important target in endogenous adenosine-regulated sleep homeostasis. Orexin A induces a robust increase in the firing activity of orexin neurons, while adenosine has an inhibitory effect. Whether the excitatory action of orexins in the lateral hypothalamus actually promotes wakefulness and reverses the sleep-producing effect of adenosine in vivo is less clear. In this study, electroencephalographic and electromyographic recordings were used to investigate the effects of orexin A and adenosine on sleep and wakefulness in rats. We found that microinjection of orexin A into the lateral hypothalamus increased wakefulness with a concomitant reduction of sleep during the first 3 h of post-injection recording, and this was completely blocked by a selective antagonist for orexin receptor 1, SB 334867. The enhancement of wakefulness also occurred after application of the excitatory neurotransmitter glutamate in the fi rst 3 h post-injection. However, in the presence of the NMDA receptor antagonist APV, orexin A did not induce any change of sleep and wakefulness in the first 3 h. Further, exogenous application of adenosine into the lateral hypothalamus induced a marked increase of sleep in the fi rst 3-h post-injection. No signifi cant change in sleep and wakefulness was detected after adenosine application followed by orexin A administration into the same brain area. These findings suggest that the sleep-promoting action of adenosine can be reversed by orexin A applied to the lateral hypothalamus, perhaps by exciting glutamatergic input to orexin neurons via the action of orexin receptor 1.

Continuous intrathecal orexin delivery inhibits cataplexy in a murine model of narcolepsy

“…We showed that slow continuous infusion of orexin-A via intrathecal route did not appreciably alter the sleep/wake profile of animals. These observations are in contrast with previous reports where a robust increase in arousal was observed in mice (17,34) and rats (35) upon ICV administration of orexin. These latter studies used bolus injections, thus rapidly and transiently increased the concentration of peptide at the vicinity of orexin receptors, resulting in an acute increase in wakefulness.…”

REM sleep loss associated changes in orexin-A levels in discrete brain areas in rats

“…As Orx has been reported to stimulate the glutamatergic neurons in the PH, a synergistic interaction between Orx-ergic glutamatergic neurons has been proposed to maintain arousal [32]. Also, Orx activated glutamate from the subcortical areas may contribute to maintain wakefulness [33]. Further, as the PH is known to be responsible for maintenance of homeostasis [13], we propose that normally the Orx-A may participate in maintaining sleep-waking homeostasis, which is disturbed upon REMSD resulting in elevated level of Orx-A or vice versa.…”

Sleep Homeostasis, Metabolism, and Adenosine

“…Local injection of the selective A 1 receptor antagonist 1,3-diethyl-8-phenylxanthine (DPX) enhances activity in hypocretinergic neurons and promotes waking [112]. By contrast, activation of A 1 receptors in the LHA by adenosine promotes sleep [113,114]. These findings illustrate that adenosine may contribute to sleep-wake regulation, as well as metabolism and feeding by modulating the activity of hypocretin neurons in vivo.…”