title: Role of the hypocretin (orexin) receptor 2 (Hcrt-r2) in the regulation of hypocretin level and cataplexy.
abstract: 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.
authors.affiliation: Neurobiology Research (151A3), Veterans Administration Greater Los Angeles Healthcare System, North Hills, California 91343, USA.
authors.forename: Ming-Fung
authors.initials: MF
authors.lastname: Wu
authors.forename: Robert
authors.initials: R
authors.lastname: Nienhuis
authors.forename: Nigel
authors.initials: N
authors.lastname: Maidment
authors.forename: Hoa A
authors.initials: HA
authors.lastname: Lam
authors.forename: Jerome M
authors.initials: JM
authors.lastname: Siegel
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000235:genetics; D002385:Cataplexy / Q000134:cerebrospinal fluid / Q000188:drug therapy / Q000503:physiopathology*; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D004195:Disease Models, Animal; D004285:Dogs; D005260:Female; D005786:Gene Expression Regulation; D006339:Heart Rate / Q000187:drug effects / Q000235:genetics; D006993:Hypnotics and Sedatives; D047908:Intracellular Signaling Peptides and Proteins / Q000134:cerebrospinal fluid*; D008297:Male; D009154:Mutation / Q000235:genetics; D009479:Neuropeptides / Q000134:cerebrospinal fluid*; D064446:Orexin Receptors; D000068797:Orexins; D010656:Phenylephrine / Q000494:pharmacology; D010830:Physostigmine / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D018013:Receptors, Neuropeptide / Q000378:metabolism*; D012119:Respiration / Q000187:drug effects / Q000235:genetics; D013566:Sympathomimetics / Q000494:pharmacology; D013874:Thiopental / Q000627:therapeutic use
chemical_list: D002800:Cholinesterase Inhibitors; C578626:HCRTR2 protein, human; D006993:Hypnotics and Sedatives; D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; D064446:Orexin Receptors; D000068797:Orexins; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide; D013566:Sympathomimetics; D010656:Phenylephrine; D010830:Physostigmine; D013874:Thiopental