Excitatory Effects of Hypocretin-1 (Orexin-A) in the Trigeminal Motor Nucleus Are Reversed by NMDA Antagonism

Peever, John H.; Lai, Yuan-Yang; Siegel, Jerome M.

doi:10.1152/jn.00968.2002

Cited by 91 publications

(60 citation statements)

References 39 publications

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“…NE inhibition of hypocretin cells may be part of a negative feedback to inhibit runaway arousal, or to allow a high degree of attention to focus by reducing output of other nonselective arousal-related systems including the hypocretin system. Hypocretin neurons may influence motor control, as suggested by the sleep paralysis and cataplexy found in hypocretin-deficient narcoleptics, by reports of direct activation of motor neurons by hypocretin, and by the reduction in the activity of NE cells during cataplexy; catecholamine feedback inhibition of hypocretin cells may therefore be relevant to the fine-tuning of motor tone (Nishino and Mignot, 1997;Peever et al, 2003;John et al, 2004;Yamuy et al, 2004).…”

Section: Functional Importance Of Ne Inhibition Of the Hypocretin Aromentioning

confidence: 99%

Direct and Indirect Inhibition by Catecholamines of Hypocretin/Orexin Neurons

Liu¹,

Pol²

2005

J. Neurosci.

112

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Hypothalamic hypocretin enhances arousal, similar to the actions of norepinephrine (NE). The physiological actions of NE were examined in hypocretin neurons identified by selective green fluorescent protein expression in transgenic mouse hypothalamic slices using whole-cell recording. NE induced an outward current, inhibited spike frequency, and hyperpolarized hypocretin neurons dose dependently. Similar actions were evoked by the selective ␣2 adrenergic agonist clonidine. The ␣2 antagonist idazoxan increased spike frequency, suggesting tonic NE-mediated inhibition. The NE-induced current was inwardly rectified, and the reversal potential was dependent on external potassium concentration; it was blocked by barium in the bath and by GTP-␥-S in the pipette, suggesting activation of a G-protein inward rectifying K ϩ (GIRK) current. NE and clonidine decreased calcium currents evoked by depolarizing voltage steps. The selective ␣1 adrenergic agonist phenylephrine had no effect on membrane potential but did increase IPSC frequency; miniature IPSC frequency was also increased, in some cells without any effect on amplitude, suggesting a facilitative presynaptic action at ␣1 receptors on GABAergic axons that innervate hypocretin neurons. NE therefore inhibits hypocretin neurons directly through two mechanisms: activation of a GIRK current, depression of calcium currents, and indirectly through increased inhibitory GABA input. Similar to NE, dopamine and epinephrine reduced or blocked spikes and, in the presence of TTX, showed direct hyperpolarizing actions. The action of dopamine was blocked by the D2 receptor antagonist eticlopride, whereas a D1/5 antagonist had no effect. These data suggest that catecholamines evoke strong inhibitory actions on hypocretin neurons and suggest negative feedback from catecholamine cells that may be excited by hypocretin.

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Section: Functional Importance Of Ne Inhibition Of the Hypocretin Aromentioning

confidence: 99%

Direct and Indirect Inhibition by Catecholamines of Hypocretin/Orexin Neurons

Liu¹,

Pol²

2005

J. Neurosci.

112

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“…We found that after Hcrt application there was an increase in membrane depolarizing noise in a small number of motoneurons. This indicates that Hcrt is capable of acting presynaptically by increasing the release of neurotransmitter, putatively glutamate, from a population of axon terminals that impinge on spinal motoneurons John et al, 2003;Peever et al, 2003). In favor of a postsynaptic action of Hcrt, (1) applied Hcrt produced large-amplitude, long-lasting membrane depolarization, which would not be expected if the mechanism of action were purely presynaptic (Del Negro and Chandler, 1998;Parker et al, 1998), and (2) preliminary anatomical data indicate that Hcrt-containing fibers are apposed to lumbar motoneurons and that these cells contain Hcrt membrane receptors .…”

Section: Mode Of Action Of Hcrt On Motoneuronsmentioning

confidence: 99%

Hypocretinergic Control of Spinal Cord Motoneurons

Yamuy

Fung²,

Xi³

et al. 2004

Journal of Neuroscience

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Hypocretinergic (orexinergic) neurons in the lateral hypothalamus project to motor columns in the lumbar spinal cord. Consequently, we sought to determine whether the hypocretinergic system modulates the electrical activity of motoneurons. Using in vivo intracellular recording techniques, we examined the response of spinal motoneurons in the cat to electrical stimulation of the lateral hypothalamus. In addition, we examined the membrane potential response to orthodromic stimulation and intracellular current injection before and after both hypothalamic stimulation and the juxtacellular application of hypocretin-1. It was found that (1) hypothalamic stimulation produced a complex sequence of depolarizing-hyperpolarizing potentials in spinal motoneurons; (2) the depolarizing potentials decreased in amplitude after the application of SB-334867, a hypocretin type 1 receptor antagonist; (3) the EPSP induced by dorsal root stimulation was not affected by the application of SB-334867; (4) subthreshold stimulation of dorsal roots and intracellular depolarizing current steps produced spike potentials when applied in concert to stimulation of the hypothalamus or after the local application of hypocretin-1; (5) the juxtacellular application of hypocretin-1 induced motoneuron depolarization and, frequently, high-frequency discharge; (6) hypocretin-1 produced a significant decrease in rheobase (36%), membrane time constant (16.4%), and the equalizing time constant (23.3%); (7) in a small number of motoneurons, hypocretin-1 produced an increase in the synaptic noise; and (8) the input resistance was not affected after hypocretin-1. The juxtacellular application of vehicle (saline) and denatured hypocretin-1 did not produce changes in the preceding electrophysiological properties.We conclude that hypothalamic hypocretinergic neurons are capable of modulating the activity of lumbar motoneurons through presynaptic and postsynaptic mechanisms. The lack of hypocretin-induced facilitation of motoneurons may be a critical component of the pathophysiology of cataplexy.

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“…Receptors for orexin-A are located on neurons in many different brain regions making it possible for this peptide, once released, to activate a large number of areas affected by sleep and sleep deprivation (Hagan et al, 1999;Bourgin et al, 2000;Kilduff and Peyron, 2000;Piper et al, 2000;Gerashchenko et al, 2001;Yoshida et al, 2001;Wu et al, 2002;Peever et al, 2003;Lee et al, 2005;Mileykovskiy et al, 2005;Vittoz and Berridge 2006), It has recently been shown that manipulation of this system via administration of a orexin antagonist can increase sleep in rats, dogs and humans (Brisbare-Roch et al, 2007). The loss of orexin cells has been shown to cause human and animal narcolepsy (Chemelli et al, 1999;Lin et al, 1999;Nishino et al, 2000;Peyron et al, 2000;Thannickal et al, 2000;Gerashchenko et al, 2001;Wu et al, 2002;Mieda et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Systemic and Nasal Delivery of Orexin-A (Hypocretin-1) Reduces the Effects of Sleep Deprivation on Cognitive Performance in Nonhuman Primates

Deadwyler¹,

Porrino²,

Siegel³

et al. 2007

J. Neurosci.

242

192

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Hypocretin-1 (orexin-A) was administered to sleep-deprived (30 -36 h) rhesus monkeys immediately preceding testing on a multi-image delayed match-to-sample (DMS) short-term memory task. The DMS task used multiple delays and stimulus images and effectively measures cognitive defects produced by sleep deprivation (Porrino et al., 2005). Two methods of administration of orexin-A were tested, intravenous injections (2.5-10.0 g/kg, i.v.) and a novel method developed for nasal delivery via an atomizer spray mist to the nostrils (dose estimated 1.0 g/kg). Results showed that orexin-A delivered via the intravenous and nasal routes significantly improved performance in sleep-deprived monkeys; however, the nasal delivery method was significantly more effective than the highest dose (10 g/kg) of intravenous orexin-A tested. The improvement in performance by orexin-A was specific to trials classified as high versus low cognitive load as determined by performance difficulty under normal testing conditions. Except for the maximum intravenous dose (10 g/kg), neither delivery method affected task performance in alert non-sleep-deprived animals. The improved performance in sleep-deprived animals was accompanied by orexin-A related alterations in local cerebral glucose metabolism (CMRglc) in specific brain regions shown previously to be engaged by the task and impaired by sleep deprivation (Porrino et al., 2005). Consistent with the differential effects on performance, nasal delivered orexin-A produced a more pronounced reversal of sleep deprivation induced changes in brain metabolic activity (CMRglc) than intravenous orexin-A. These findings provide strong evidence for the effectiveness of intranasal orexin-A in alleviating cognitive deficits produced by loss of sleep.

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Excitatory Effects of Hypocretin-1 (Orexin-A) in the Trigeminal Motor Nucleus Are Reversed by NMDA Antagonism

Cited by 91 publications

References 39 publications

Direct and Indirect Inhibition by Catecholamines of Hypocretin/Orexin Neurons

Direct and Indirect Inhibition by Catecholamines of Hypocretin/Orexin Neurons

Hypocretinergic Control of Spinal Cord Motoneurons

Systemic and Nasal Delivery of Orexin-A (Hypocretin-1) Reduces the Effects of Sleep Deprivation on Cognitive Performance in Nonhuman Primates

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