Specificity of direct transition from wake to REM sleep in orexin/ataxin-3 transgenic narcoleptic mice.
To create operational criteria for polygraphic assessments of direct transitions from wake to REM sleep (DREM), as a murine analog of human cataplexy, we have analyzed DREM episodes in congenic lines of orexin/ataxin-3 transgenic [TG] mice and wild-type littermates. The sleep stage of each 10-second epoch was visually scored using our standard criteria. Specificity of DREM for narcoleptic TG mice and sensitivity to detect DREM was evaluated using different DREM criteria. We found that DREM transitions by 10-second epoch scoring are not specific for narcoleptic TG mice and also occur in WT mice during light period. These wake-to-REM transitions in WT mice (also seen in TG mice during light period) were characteristically different from DREM transitions in TG mice during dark period; they tended to occur as brief bouts of wakefulness interrupting extended episodes of REM sleep, suggesting that these transitions do not represent abnormal manifestations of REM sleep. We therefore defined the DREM transitions by requiring a minimum number of preceding wake epochs. Requiring no fewer than four consecutive epochs of wakefulness produced the best combination of specificity (95.9%) and sensitivity (66.0%). By definition, DREM in dark-period is 100% specific to narcolepsy and was 95.9% specific overall. In addition, we found that desipramine, a trycyclic anticataplectic, potently reduces DREM, while two wake-promoting compounds have moderate (D-amphetamine) and no (modafinil) effect on DREM; the effects mirror the anticataplectic effects of these compounds reported in canine and human narcolepsy. Our definition of DREM in murine narcolepsy may provide good electrophysiological measures for cataplexy-equivalent episodes.
Stanford University Center for Narcolepsy, Palo Alto, CA 94035, USA.
Nobuhiro
N
Fujiki
Timothy
T
Cheng
Fuyumi
F
Yoshino
Seiji
S
Nishino
D000704:Analysis of Variance; D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology; D000067699:Ataxin-3; D001559:Benzhydryl Compounds / Q000494:pharmacology; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D003891:Desipramine / Q000494:pharmacology; D003913:Dextroamphetamine / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography / Q000379:methods; D004576:Electromyography / Q000379:methods; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D000077408:Modafinil; D009290:Narcolepsy / Q000235:genetics* / Q000503:physiopathology*; D009479:Neuropeptides / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D000068797:Orexins; D012680:Sensitivity and Specificity; D012895:Sleep, REM / Q000187:drug effects / Q000502:physiology*; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics*; D014851:Wakefulness / Q000502:physiology*
D000929:Antidepressive Agents, Tricyclic; D001559:Benzhydryl Compounds; D000697:Central Nervous System Stimulants; D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; D009687:Nuclear Proteins; D000068797:Orexins; D014157:Transcription Factors; D000067699:Ataxin-3; C511594:Atxn3 protein, mouse; D000077408:Modafinil; D003891:Desipramine; D003913:Dextroamphetamine