D(1)/D(2) receptor-targeting L-stepholidine, an active ingredient of the Chinese herb Stephonia, induces non-rapid eye movement sleep in mice.
L-stepholidine, an active ingredient of the Chinese herb Stephonia, is the first compound known to have mixed dopamine D(1) receptor agonist/D(2) antagonist properties and to be a potential treatment medication for schizophrenia. In schizophrenic patients insomnia is a common symptom and could be partly related to the presumed over-activity of the dopaminergic system. To elucidate whether stepholidine modulates sleep behaviors, we observed its effects on sleep-wake profiles in mice. The results showed that stepholidine administered i.p. at doses of 20, 40 or 80 mg/kg significantly shortened the sleep latency to non-rapid eye movement (non-REM, NREM) sleep, increased the amount of NREM sleep, and prolonged the duration of NREM sleep episodes, with a concomitant reduction in the amount of wakefulness. Stepholidine at doses of 40 and 80 mg/kg increased the number of state transitions from wakefulness to NREM sleep and subsequently from NREM sleep to wakefulness. However, stepholidine had no effect on either the amount of REM sleep or electroencephalogram power density of either NREM or REM sleep. Immunohistochemistry study showed that stepholidine dose-dependently increased c-Fos expression in neurons of the ventrolateral preoptic area, a sleep center in the anterior hypothalamus, as compared with the vehicle control. These results indicate that stepholidine initiates and maintains NREM sleep with activation of the sleep center in mice, suggesting its potential application for the treatment of insomnia.
Qiu
Mei-Hong
MH
State Key Laboratory of Medical Neurobiology, Shanghai Medical College, Fudan University, Shanghai, 200032, PR China.
Qu
Wei-Min
WM
Xu
Xin-Hong
XH
Yan
Ming-Ming
MM
Urade
Yoshihiro
Y
Huang
Zhi-Li
ZL
D000818:Animals; D001599:Berberine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D018491:Dopamine Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D065127:Dopamine D2 Receptor Antagonists; D004305:Dose-Response Relationship, Drug; D004365:Drugs, Chinese Herbal / Q000008:administration & dosage / Q000494:pharmacology*; D004569:Electroencephalography / Q000187:drug effects; D004576:Electromyography / Q000187:drug effects; D007274:Injections, Intraperitoneal; D051379:Mice; D008810:Mice, Inbred C57BL; D017286:Polysomnography / Q000187:drug effects; D011301:Preoptic Area / Q000166:cytology / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D011930:Reaction Time; D017447:Receptors, Dopamine D1 / Q000819:agonists; D012815:Signal Processing, Computer-Assisted; D007319:Sleep Initiation and Maintenance Disorders / Q000188:drug therapy; D012894:Sleep Stages / Q000187:drug effects*
D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D004365:Drugs, Chinese Herbal; D016760:Proto-Oncogene Proteins c-fos; D017447:Receptors, Dopamine D1; D001599:Berberine; C010513:stepholidine