Role of the Hypocretin (Orexin) Receptor 2 (Hcrt-r2) in the Regulation of Hypocretin Level and Cataplexy
| Autor: | Jerome M. Siegel, Robert Nienhuis, Nigel T. Maidment, Ming-Fung Wu, Hoa A. Lam |
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| Rok vydání: | 2011 |
| Předmět: |
Male
Receptors Neuropeptide medicine.medical_specialty Cataplexy Physostigmine Blood Pressure Article Receptors G-Protein-Coupled Phenylephrine Hypocretin (orexin) receptor 2 Norepinephrine Dogs Heart Rate Orexin Receptors Internal medicine Heart rate Monoaminergic medicine Animals Hypnotics and Sedatives Sympathomimetics Thiopental Orexins Respiration General Neuroscience Neuropeptides Intracellular Signaling Peptides and Proteins medicine.disease Orexin receptor Disease Models Animal Endocrinology Gene Expression Regulation Mutation Cholinergic Female Cholinesterase Inhibitors medicine.symptom Psychology Narcolepsy medicine.drug |
| Zdroj: | The Journal of Neuroscience. 31:6305-6310 |
| ISSN: | 1529-2401 0270-6474 |
| DOI: | 10.1523/jneurosci.0365-11.2011 |
| Popis: | Hypocretin receptor-2 (Hcrt-r2)-mutated dogs exhibit all the major symptoms of human narcolepsy and respond to drugs that increase or decrease cataplexy as do narcoleptic humans; yet, unlike narcoleptic humans, the narcoleptic dogs have normal hypocretin levels. We find that drugs that reduce or increase cataplexy in the narcoleptic dogs, greatly increase and decrease, respectively, hypocretin levels in normal dogs. The effects of these drugs on heart rate and blood pressure, which were considerable, were not correlated with their effects on cataplexy. Administration of these drugs to Hcrt-r2-mutated dogs produced indistinguishable changes in heart rate and blood pressure, indicating that neither central nor peripheral Hcrt-r2 is required for these cardiovascular effects. However, in contrast to the marked Hcrt level changes in the normal dogs, these drugs did not alter hypocretin levels in the Hcrt-r2 mutants. We conclude that Hcrt-r2 is a vital element in a feedback loop integrating Hcrt, acetylcholine, and norepinephrine function. In the absence of functional Hcrt-r2, Hcrt levels are not affected by monoaminergic and cholinergic drugs, despite the strong modulation of cataplexy by these drugs. Conversely, strong transient reductions of Hcrt level by these drugs do not produce episodes of cataplexy in normal dogs. The Hcrt-r2 mutation causes drug-induced cataplexy by virtue of its long-term effect on the functioning of other brain systems, rather than by increasing the magnitude of phasic changes in Hcrt level. A similar mechanism may be operative in spontaneous cataplexy in narcoleptic dogs as well as in narcoleptic humans. |
| Databáze: | OpenAIRE |
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