Central alpha 1 adrenoceptor subtypes in narcolepsy-cataplexy: a disorder of REM sleep.
The present study suggests the specific involvement within the central nervous system of an alpha 1 adrenoceptor subtype in a behavior, the control of cataplexy, a pathological analogue of rapid eye movement (REM) sleep atonia. Experiments have shown that prazosin, an alpha 1 antagonist, dramatically aggravates canine narcolepsy-cataplexy through a central mechanism, and that [3H]prazosin binding sites are increased in the amygdala of narcoleptic dogs. However, the corresponding Scatchard plots were curvilinear and best fit was obtained with a two-site model, suggesting the existence of two [3H]prazosin binding sites. These two sites (high and low affinity [3H]prazosin binding sites) met the criteria for authentic receptors and were respectively very similar to the alpha 1a and alpha 1b (high and low affinity for WB4101, respectively) subtypes recently described in the rat and rabbit. Our results of in vivo pharmacology and in vitro [3H]prazosin binding in canine narcolepsy now clearly implicate the low affinity [3H]prazosin binding site (alpha 1b) in canine narcolepsy: (1) Prazosin, an alpha 1 antagonist with similar affinity for both subtypes, was much more potent in increasing cataplexy than WB4101, a compound with more affinity for the alpha 1a receptor. (2) Chlorethylclonidine and phenoxybenzamine, two irreversible blockers of the alpha 1 receptors with more affinity for the alpha 1b receptors, aggravate cataplexy for up to two weeks. (3) The alpha 1 receptor upregulation previously reported by our group in the amygdala of narcoleptic dogs was due to a selective increase in the low affinity [3H]prazosin binding sites. A role for noradrenaline in REM sleep regulation has been suspected for many years, but has never been clearly elucidated.(ABSTRACT TRUNCATED AT 250 WORDS)
Mignot
E
E
Sleep Disorders Center, Stanford University School of Medicine, Palo Alto, CA 94304.
Guilleminault
C
C
Bowersox
S
S
Frusthofer
B
B
Nishino
S
S
Maddaluno
J
J
Ciaranello
R
R
Dement
W C
WC
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology; D002385:Cataplexy / Q000378:metabolism*; D003000:Clonidine / Q000031:analogs & derivatives / Q000494:pharmacology; D004146:Dioxanes / Q000494:pharmacology; D004285:Dogs; D009290:Narcolepsy / Q000378:metabolism*; D010643:Phenoxybenzamine / Q000494:pharmacology; D011224:Prazosin / Q000494:pharmacology*; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects / Q000502:physiology*; D012895:Sleep, REM
D000317:Adrenergic alpha-Antagonists; D004146:Dioxanes; D011942:Receptors, Adrenergic, alpha; D010643:Phenoxybenzamine; C051731:chlorethylclonidine; C010654:(2-(2',6'-dimethoxy)phenoxyethylamino)methylbenzo-1,4-dioxane; D003000:Clonidine; D011224:Prazosin