Journal of Biomedical Science

, Volume 14, Issue 2, pp 285–297 | Cite as

Gamma-aminobutyric acid (GABA) receptor mediates suanzaorentang, a traditional Chinese herb remedy, -induced sleep alteration

  • Pei-Lu Yi
  • Chon-Haw Tsai
  • Ya-Chu Chen
  • Fang-Chia Chang


The sedative-hypnotic medications, including benzodiazepines and non-benzodiazepines, are the most common treatments for insomnia. However, concerns regarding patterns of inappropriate use, dependence and adverse effects have led to caution in prescribing those sedative-hypnotic medications. On the other hand, a traditional Chinese herb remedy, suanzaorentang, has been efficiently and widely used in clinic for insomnia relief without severe side effects in Asia. Although suanzaorentang has been reported to improve sleep disruption in insomniac patients, its mechanism is still unclear. The present study was designed to elucidate the effects of oral administration of suanzaorentang on physiological sleep-wake architectures and its underlying mechanism in rats. We found that oral administration of suanzaorentang at the beginning of the dark onset dose-dependently increased non-rapid eye movement sleep (NREMS) during the dark period, but had no significant effect on rapid eye movement sleep (REMS). Our results also indicated that intracerebroventricular (ICV) administration of γ-aminobutyric acid (GABA) receptor type A antagonist, bicuculline, significantly blocked suanzaorentang-induced enhancement in NREMS during the dark period, but GABAB receptor antagonist, 2-hydroxysaclofen had no effect. These results implicated that this traditional Chinese herb remedy, suanzaorentang increases spontaneous sleep activity and its effects may be mediated through the GABAA receptors, but not GABAB receptors.


GABA non-rapid eye movement sleep (NREMS) rapid eye movement sleep (REMS) suanzaorentang 


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This work was supported by the National Science Council grant NSC94-2320-B-002–126, and China Medical University grants DMR94–058.


  1. 1.
    Partinen M. (1994) Epidemiology of sleep disorders. In: Kryger M.H., Roth T., Dement W.C. (Eds) Principles and Practice of Sleep Medicine. Philadelphia: WB Saunders pp 437–452Google Scholar
  2. 2.
    Gillin J.C. (1998) Are sleep disturbances risk factors for anxiety, depressive and addictive disorders? [Review]. Acta Psychiatricia Scandinavica Supplementum. 393: 39–43Google Scholar
  3. 3.
    Chung K.F., Lee C.K.Y. (2002) Over-the-counter sleeping pills: a survey of use in Hong Kong and a review of their constituents. Gen. Hospital Psychiatry. 24: 430–435CrossRefGoogle Scholar
  4. 4.
    Chen H.C., Hsieh M.T. (1985) Clinical trial of suanzaorentang in the treatment of insomnia. Clin. Therapeut.. 7: 334–337Google Scholar
  5. 5.
    Chen H.C., Hsieh M.T., Shibuya T. (1986) Suanzaorentang versus diazepam: a controlled double-blind study in anxiety. Int. J. Clin. Pharmacol, Therapy Toxicol.. 24: 646–650Google Scholar
  6. 6.
    Park J.H., Lee H.J., Koh S.M., Ban J.Y., Seong Y.H. (2004) Protection of NMDA-induced neuronal cell damage by methanol extract of Zizyphi Spinosi Semen in cultured rat cerebellar granule cells. J. Ethnopharmacol. 95: 39–45PubMedCrossRefGoogle Scholar
  7. 7.
    Zheng H.Z., Dong A.H., and She J. (1997) (Eds) Modern Study of Traditional Chinese Medicine (in Chinese), Xue Yuan Press, Beijing, 1997Google Scholar
  8. 8.
    Kanba S., Yamada K., Mizushima H., Murata T., Asai M. (1999) Use of herbal medicine for treating psychiatric disorders in Japan. In: Kanba S., Richelson E. (Eds) Herbal Medicines for Neuropsychiatric Diseases: Current Developments and Research, New York: Brunner/Mazel, p. 3–14Google Scholar
  9. 9.
    Yu S.J., Tseng J. (1996) Fu-ling, a Chinese herbal drug, modulates cytokine secretion by human peripheral blood monocytes. Int. J. Immunopharmacol.. 18: 37–44PubMedCrossRefGoogle Scholar
  10. 10.
    Liao S.L., Kao T.K., Chen W.Y., Lin Y.S., Chen S.Y., Raung S.L., Wu C.W., Lu H.C., Chen C.J. (2004) Tetramethylpyrazine reduces ischemic brain injury in rats. Neurosci. Lett.. 372: 40–45PubMedCrossRefGoogle Scholar
  11. 11.
    Tsukamoto S., Wakana T., Koimaru K., Yoshida T., Sato M., Ohta T. (2005) 7-Hydroxy−3-(4-hydroxybenzyl)chroman and Broussonin B: Neurotrophic compounds, isolated from Anemarrhena asphodeloides Bunge, function as proteasome inhibitors. Biol. Pharmaceut. Bull.. 28: 1798–1800CrossRefGoogle Scholar
  12. 12.
    Tsuda T., Kubota K., Yasuda K., Nishikawa S., Sugaya A., Sugaya E. (1986) Effects of Chinese herbal medicine “kanbaku-taiso-to” on transmembrane ionic currents and its local anesthetic action. J. Ethnopharmacol.. 17: 257–261 PubMedCrossRefGoogle Scholar
  13. 13.
    Liao J.F., Jan Y.M., Huang S.Y., Wang H.H., Yu L.L., Chen C.F. (1995) Evaluation with receptor binding assay on the water extracts of ten CNS-active Chinese herbal drugs. Proc. Natl. Sci. Council, ROC – Part B, Life Sci.. 19: 151–158Google Scholar
  14. 14.
    McGinty D., Szymusiak R. (2003) Hypothalamic regulation of sleep and arousal. Frontier. Biosci.. 8: s1074–s1083CrossRefGoogle Scholar
  15. 15.
    Kukko-Lukjanov T.K., Panula P. (2003) Subcellular distribution of histamine, GABA and galanin in tuberomamillary neurons in vitro. J. Chem. Neuroanatomy. 25: 279–292CrossRefGoogle Scholar
  16. 16.
    Chang F.-C., Opp M.R. (1998) Blockade of corticotropin-releasing hormone receptors reduces spontaneous waking in the rat. Am J Physiol 275: R793-R802PubMedGoogle Scholar
  17. 17.
    Epstein A.M., Fitzsimons J.T., Rolls B.J. (1970) Drinking induced by injection of angiotensin into the brain of the rat. J. Physiol.. 210: 457–474PubMedGoogle Scholar
  18. 18.
    Borbely A.A. (1982) A two process model of sleep regulation. Hum. Neurobiol.. 1: 195–204PubMedGoogle Scholar
  19. 19.
    Yi P.L., Tsai C.H., Lu M.K., Liu H.J., Chen Y.C., and Chang F.C. Interleukin−1β mediates sleep alteration in rotenone-induced parkinsonism rats. Sleep (under review process), 2006Google Scholar
  20. 20.
    Hsieh M.T., Chen H.C., Kao H.C., Shibuya T. (1986) Suanzaorentang and anxiolytic Chinese medicine, affects the central adrenergic and serotonergic systems in rats. Proc. Natl. Sci. Council, ROC –Part B, Life Sci.. 10: 263–268Google Scholar
  21. 21.
    Li Y., Wang R., Chen M., Wang Z., Bi K. (2001) Pharmacodynamics study of suanzaoren decoction extracted by different technological process Zhong Yao Cai 24: 884–885PubMedGoogle Scholar
  22. 22.
    Hansen M.K., Kapas L., Fang J., Krueger J.M. (1998) Cafeteria diet-induced sleep is blocked by subdiaphragmatic vagotomy in rats. Am. J. Physiol.. 274: R168-R174PubMedGoogle Scholar
  23. 23.
    Jenkins J.B., Omori T., Guan Z., Vgontzas A.N., Bixler E.O., Fang J. (2006) Sleep is increased in mice with obesity induced by high-fat food. Physiol. Behav.. 87: 255–262PubMedCrossRefGoogle Scholar
  24. 24.
    Roky R., Kapas L., Taishi P., Fang J., Krueger J.M. (1999) Food restriction alters the diurnal distribution of sleep in rats. Physiol. Behav. 67: 697–703PubMedCrossRefGoogle Scholar
  25. 25.
    Rizzo P., Beelke M., De Carli F., Canovaro P., Nobili L., Robert A., Fornaro P., Tanganelli P., Regesta G., Ferrillo F. (2004) Modifications of sleep EEG induced by chronic vagus nerve stimulation in patients affected by refractory epilepsy. Clin. Neurophysiol. 115: 658–664PubMedCrossRefGoogle Scholar
  26. 26.
    Valdes-Cruz A., Magdaleno-Madrigal V.M., Martinez-Vargas D., Fernandez-Mas R., Almazan-Alvarado S., Martinez A., Fernandez-Guardiola A. (2002) Chronic stimulation of the cat vagus nerve: effect on sleep and behavior Prog. Neuro-Psychopharmacol. Biol. Psychiatry. 26: 113–118CrossRefGoogle Scholar
  27. 27.
    Vgontzas A.N., Papanicolaou D.A., Bixler E.O., Chrousos G.P. (1997) Elevation of plasma cytokines in disorders of excessive daytime sleepiness: Role of sleep disturbance and obesity. J. Clin. Endocrinol. Metab.. 82: 1313–1316PubMedCrossRefGoogle Scholar
  28. 28.
    Kubota T., Fang J., Guan Z., Brown R.A., Krueger J.M. (2001) Vagotomy attenuates tumor necrosis factor-alpha-induced sleep and EEG delta-activity in rats. Am. J. Physiol. – Regulat. Integr. Comp. Physiol.. 280: R1213-R1220Google Scholar
  29. 29.
    Graeff F.G., Netto C.F., Jr. Zangrossi H. (1998) The elevated T-maze as an experimental model of anxiety Neurosci. Biobehav. Rev. 23: 237–246PubMedCrossRefGoogle Scholar
  30. 30.
    Ripoll N., Hascoet M., Bourin M. (2006) Implication of 5-HT2 A  subtype receptors in DOI activity in the four-plates test-retest paradigm in mice. Behav Brain Res. 166: 131–139PubMedCrossRefGoogle Scholar
  31. 31.
    Hilakivi I., Kovala T., Lappavuori A., Shvaloff A. (1987) Effects of serotonin and noradrenaline uptake blockers on wakefulness and sleep in cats. Pharmacol. Toxicol.. 60: 161–166PubMedCrossRefGoogle Scholar
  32. 32.
    Nicholson A.N., Pascoe P.A. (1986) 5-Hydroxytryptamine and noradrenaline uptake inhibition: studies on sleep in man. Neuropharmacology.25: 1079–1083PubMedCrossRefGoogle Scholar
  33. 33.
    Monti J.M., Jantos H. (2004) Effects of the 5-HT1 A  receptor ligands flesinoxan and WAY 100635 given systemically or microinjected into the laterodorsal tegmental nucleus on REM sleep in the rat. Behav. Brain Res.. 151: 159–166PubMedCrossRefGoogle Scholar
  34. 34.
    Popa D., Lena C., Fabre V., Prenat C., Gingrich J., Escourrou P., Hamon M., Adrien J. (2005) Contribution of 5-HT2 receptor subtypes to sleep-wakefulness and respiratory control, and functional adaptations in knock-out mice lacking 5-HT2 A receptors. J. Neurosci.. 25: 11231–11238PubMedCrossRefGoogle Scholar
  35. 35.
    Mendelson W.B. (1985) GABA-benzodiazepin-receptor chloride ionophore complex: Implications for the pharmacology of sleep. In: Wauquier A., Monti J.M., Gaillard J.M. (eds) Sleep Neurotransmitters and Neuromodulators, New York: Raven Press, p. 229Google Scholar
  36. 36.
    Gottesmann C. (2002) GABA mechanisms and sleep. Neuroscience. 111: 231–239PubMedCrossRefGoogle Scholar
  37. 37.
    Faulhaber J., Steiger A., Lancel M. (1997) The GABAA agonist THIP produces slow wave sleep and reduces spindling activity in NREM sleep in humans. Psychopharmacology. 130: 285–291PubMedCrossRefGoogle Scholar
  38. 38.
    Von Krosigk M., Bal T., McCormick D.A. (1993) Cellular mechanisms of a synchronized oscillation in thalamus. Science. 261: 361–364CrossRefGoogle Scholar
  39. 39.
    Borbely A.A., Mattmann P., Loepfe M., Strauch I., Lehmann D. (1985) Effects of benzodiazepine hypnotics on all-night sleep EEG spectra. Hum. Neurobiol.. 4: 189–194PubMedGoogle Scholar
  40. 40.
    Gaillard J.M., Schultz P., Tissot R. (1973) Effects of three benzodiazepines (nitrazepam, flunitrazepam and bromazepam) on sleep of normal subjects, studied with an automatic scoring system. Pharmakopsychiatrie. 6: 207–217CrossRefGoogle Scholar
  41. 41.
    Lancel M., Gronlein T.A.M., Faulhaber J. (1996) Role of GABAA receptors in sleep regulation. Differential effects of muscimol and midazolam on sleep in rat. Neuropsychopharmacology. 15: 63–74PubMedCrossRefGoogle Scholar
  42. 42.
    Mendelson W.B, Martin J.V. (1990) Effects of muscimol and flurazepam on the sleep EEG in the rat. Life. Sci.. 47: 99–101CrossRefGoogle Scholar
  43. 43.
    Monti J.M., Altier H. (1973) Flunitrazepam (Ro 5–4200) and sleep cycle in normal subjects. Psychopharmacologia. 32: 343–349PubMedCrossRefGoogle Scholar
  44. 44.
    Gandolfo G., Scherschlicht R., Gottesmann C. (1994) Benzodiazepines promote the intermediate stage at the expense of paradoxical sleep in the rat. Pharmacol. Biochem. Behav.. 49: 921–927PubMedCrossRefGoogle Scholar
  45. 45.
    Borbely A.A., Achermann P. (1991) Ultradian dynamics of sleep after a single dose of benzodiazepine hypnotics Eur. J. Pharmacol. 195: 11–18PubMedCrossRefGoogle Scholar
  46. 46.
    Tobler I., Kopp C., Deboer T., Rudolph U. (2001) Diazepam-induced changes in sleep: role of the alpha 1 G ABAA receptor subtype. Proc. Natl. Acad. Sci. USA. 98: 6464–6469PubMedCrossRefGoogle Scholar
  47. 47.
    Declerck A.C., Ruwe F., O’Hanlon J.F., Wauquier A. (1992) Effects of zolpidem and flunitrazepam on nocturnal sleep of women subjectively complaining of insomnia. Psychopharmacology. 106: 497–501PubMedCrossRefGoogle Scholar
  48. 48.
    Depoortere H., Francon D., Van Luijtelaar E.L.J.M., Drinkenburg W.H.I.M., Coenen A.M.L. (1995) Differential effects of midazolam and zolpidem on sleep-wake states and epileptic activity in WAG/Rij rats. J. Pharmacol. Exp. Ther.. 237: 649–658Google Scholar
  49. 49.
    Gottesmann C., Trefouret S., Depoortere H. (1994) Influence of Zolpidem, a novel hypnotic, on the intermediate stage and paradoxical sleep in rat. Pharmacol. Biochem. Behav.. 47: 359–362PubMedCrossRefGoogle Scholar
  50. 50.
    Juhasz G., Emri Z., Kekesi K.A., Salfay O., Crunelli V. (2004) Blockade of thalamic GABAB receptors decreases EEG synchronization. Neurosci. Lett.. 172: 155–158CrossRefGoogle Scholar
  51. 51.
    Johnston G.A.R. (1986) Multiplicity of GABA receptors. In: Olsen R.W., Venter J.C. (Eds) Benzodiazepine/GABA Receptors and Chloride Channels: Structural and Functional Properties. New York: Alan R. Liss, Inc., p. 57–71Google Scholar
  52. 52.
    Enz R., Brandstatter J.H., Hartveit E., Wassle H., Bormann J. (1995) Expression of GABA receptor rho 1 and rho 2 subunits in the retina and brain of rat. Eur. J. Neurosci.. 7: 1495–1501PubMedCrossRefGoogle Scholar
  53. 53.
    Boue-Grabot E., Taupignon A., Tramu G., Garret M. (2000) Molecular and electrophysiological evidence for a GABAC receptor in thyrotropin-secreting cells. Endocrinology. 141: 1627–1632PubMedCrossRefGoogle Scholar
  54. 54.
    Arnaud C., Gauthier P., Gottesmann C. (2001) Study of GABAC receptor antagonist on sleep-wake behavior in rats. Psychopharmacology. 154: 415–419PubMedCrossRefGoogle Scholar

Copyright information

© National Science Council Taipei 2006

Authors and Affiliations

  • Pei-Lu Yi
    • 1
  • Chon-Haw Tsai
    • 2
  • Ya-Chu Chen
    • 2
  • Fang-Chia Chang
    • 2
  1. 1.Department of Medical TechnologyJen-Teh Junior College of Medicine, Nursing and ManagementMiaoliTaiwan
  2. 2.Neuroscience Laboratory, Department of NeurologyChina Medical University HospitalTaichungTaiwan

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