Sleep and Biological Rhythms

, Volume 17, Issue 2, pp 191–201 | Cite as

The anxiolytic effects of Bai Le Mian capsule, a traditional Chinese hypnotic in mice

  • Tian-Xiao Wang
  • Yu-Er Wu
  • Wei Xu
  • Wan-Kun Gong
  • Jian Ni
  • Wei-Min Qu
  • Zhi-Li HuangEmail author
Original Article


Bai Le Mian capsule (BLMC), which is composed of fifteen kinds of traditional Chinese Medicine, is a popular traditional Chinese medicine for the treatment of insomnia with anxiety. This study was to investigate the anxiolytic effect of BLMC in mice. BLMC (81, 162, and 325 mg/kg, i.g.) was given once or consecutively for 2 weeks, and anxiety behaviors were tested by the elevated plus maze, open field, and light/dark box, in normal mice and anxious model mice by meta-chlorophenyl-piperazine, a compound with known anxiogenic actions. In normal mice, single administration of BLMC at 325 mg/kg prolonged the time spent in central area by 2.1-fold in open-field test. Repeated administration once a day for 2 weeks, BLMC at 325 mg/kg increased the time spent in central area, open arms and light box by 2.8-, 2.0-, and 1.7-fold, respectively. Similarly, in anxious model mice, single treatment of BLMC at 325 mg/kg increased more time in the open arms by 2.1-fold. Consecutive administration for 2 weeks, BLMC at 325 mg/kg increased the time spent in open arms and light box by 2.3- and 2.1-fold. Immunohistochemical study showed that mCPP increased c-Fos expression in the central nucleus of the amygdala and bed nucleus of stria terminalis by 57% and 60%, and the mCPP-induced c-Fos expression could be reversed by single administration of BLMC. These results indicate that BLMC is an effective treatment for anxiety in mice.


Anxiolytic Bai Le Mian capsule Elevated plus maze Light/dark box Open field 



We are grateful to Huan-Xin Sun for excellent technical support. This study was supported in part by grants-in-aid for scientific research from the National Basic Research Program of China (2015CB856401), and the National Natural Science Foundation of China (81420108015, 31530035, 31671099, 31471064, 31571103, 81671318, and 31421091).

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interest.

Ethical committee permission

Experimental protocols were approved by the Medical Experimental Animal Administrative Committee of Fudan University.


  1. 1.
    Mardaga S, Iakimova G. Neurocognitive processing of emotion facial expressions in individuals with self-reported depressive symptoms: the role of personality and anxiety. Neurophysiol Clin. 2014;44(5):447–55.;08.007 CrossRefPubMedGoogle Scholar
  2. 2.
    Weissman MM, Markowitz JS, Ouellette R, Greenwald S, Kahn JP. Panic disorder and cardiovascular/cerebrovascular problems: results from a community survey. Am J Psychiatry. 1990;147(11):1504–8.CrossRefPubMedGoogle Scholar
  3. 3.
    Anderberg J, Bogren M, Mattisson C, Bradvik L. Long-term suicide risk in anxiety—the Lundby study 1947–2011. Arch Suicide Res. 2016;20(3):463–475.CrossRefPubMedGoogle Scholar
  4. 4.
    Olajide D, Lader M. A comparison of buspirone, diazepam, and placebo in patients with chronic anxiety states. J Clin Psychopharmacol. 1987;7(3):148–152.CrossRefPubMedGoogle Scholar
  5. 5.
    Newton RE, Marunycz JD, Alderdice MT, Napoliello MJ. Review of the side-effect profile of buspirone. Am J Med. 1986;80(3B):17–21.CrossRefPubMedGoogle Scholar
  6. 6.
    Huang QL, Gao D, Yue FG, Jiang CG, Zhang T, Lei L. [Efficacy of Bailemian capsule combined with self-help cognitive behavioral therapy in treatment of chronic insomnia]. Zhonghua yi xue za zhi. 2016;96(36):2893–2897.PubMedGoogle Scholar
  7. 7.
    Zhu YH, Tao JQ. Efficacy of Bailemian Capsale in combination with buspirone for generalised anxiety disease of 77 cases. Chin Tradit Pat Med. 2009;32:1102–4.Google Scholar
  8. 8.
    Zhang D, Yu FC, Luo B, Cao W. Bai Le Mian capusle in treating insomnia: a study of 85 cases. J Nanjing Univ Tradit Chin Med. 2015;31:488–90.Google Scholar
  9. 9.
    Li L, Wang L, Wang L. Effect observation on 40 cases of insomnia treated by Bailemian capsules combined with eszopiclone tablets. Clin Med Res Pract. 2017;20:96–7.Google Scholar
  10. 10.
    Kim SY, Adhikari A, Lee SY, Marshel JH, Kim CK, Mallory CS, et al. Diverging neural pathways assemble a behavioural state from separable features in anxiety. Nature. 2013;496(7444):219–223.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Yassa MA, Hazlett RL, Stark CE, Hoehn-Saric R. Functional MRI of the amygdala and bed nucleus of the stria terminalis during conditions of uncertainty in generalized anxiety disorder. J Psychiatr Res. 2012;46(8):1045–52.;04.013 CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Carvalho MC, Moreira CM, Zanoveli JM, Brandao ML. Central, but not basolateral, amygdala involvement in the anxiolytic-like effects of midazolam in rats in the elevated plus maze. J Psychopharmacol. 2012;26(4):543–54.CrossRefPubMedGoogle Scholar
  13. 13.
    Kalin NH, Shelton SE, Davidson RJ. The role of the central nucleus of the amygdala in mediating fear and anxiety in the primate. J Neurosci. 2004;16(24):5506–15.CrossRefGoogle Scholar
  14. 14.
    Zhang Z, Wang HJ, Wang DR, Qu WM, Huang ZL. Red light at intensities above 10 lx alters sleep-wake behavior in mice. Light Sci Appl. 2017;6:e16231CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Lister RG. The use of a plus-maze to measure anxiety in the mouse. Psychopharmacology. 1987;92(2):180–5.CrossRefPubMedGoogle Scholar
  16. 16.
    Nogami A, Sakata Y, Uchida N, Yamaguchi K, Kawasaki C, Shindo T, et al. Effects of yokukansan on anxiety-like behavior in a rat model of cerebrovascular dementia. J Nat Med. 2011;65(2):275–81.CrossRefPubMedGoogle Scholar
  17. 17.
    Wang YQ, Tu ZC, Xu XY, Li R, Qu WM, Urade Y, et al. Acute administration of fluoxetine normalizes rapid eye movement sleep abnormality, but not depressive behaviors in olfactory bulbectomized rats. J Neurochem. 2012;120(2):314–24.CrossRefPubMedGoogle Scholar
  18. 18.
    Liu J, Zhai WM, Yang YX, Shi JL, Liu QT, Liu GL, et al. GABA and 5-HT systems are implicated in the anxiolytic-like effect of spinosin in mice. Pharmacol, Biochem, Behav. 2015;128:41–49.CrossRefGoogle Scholar
  19. 19.
    Wang TX, Yin D, Guo W, Liu YY, Li YD, Qu WM, et al. Antinociceptive and hypnotic activities of pregabalin in a neuropathic pain-like model in mice. Pharmacol, Biochem, Behav. 2015;135:31–39.CrossRefGoogle Scholar
  20. 20.
    Wang YQ, Li R, Wang DR, Cherasse Y, Zhang Z, Zhang MQ, et al. Adenosine A2A receptors in the olfactory bulb suppress rapid eye movement sleep in rodents. Brain Struct Funct. 2017;222(3):1351–66. CrossRefPubMedGoogle Scholar
  21. 21.
    Chen L, Yin D, Wang TX, Guo W, Dong H, Xu Q, et al. Basal forebrain cholinergic neurons primarily contribute to inhibition of electroencephalogram delta activity, rather than inducing behavioral wakefulness in mice. Neuropsychopharmacology. 2016;41(8):2133–46.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Wu YE, Li YD, Luo YJ, Wang TX, Wang HJ, Chen SN, et al. Gelsemine alleviates both neuropathic pain and sleep disturbance in partial sciatic nerve ligation mice. Acta Pharmacol Sin. 2015;36(11):1308–17.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Zhang BJ, Huang ZL, Chen JF, Urade Y, Qu WM. Adenosine A2A receptor deficiency attenuates the somnogenic effect of prostaglandin D2 in mice. Acta Pharmacol Sin. 2017;38(4):469–76.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Belzung C, Griebel G. Measuring normal and pathological anxiety-like behaviour in mice: a review. Behav Brain Res. 2001;125(1–2):141–149.CrossRefPubMedGoogle Scholar
  25. 25.
    Shaw D, Annett JM, Doherty B, Leslie JC. Anxiolytic effects of lavender oil inhalation on open-field behaviour in rats. Phytomedicine. 2007;14(9):613–20.CrossRefPubMedGoogle Scholar
  26. 26.
    Prut L, Belzung C. The open field as a paradigm to measure the effects of drugs on anxiety-like behaviors: a review. Eur J Pharmacol. 2003;463(1–3):3–33.CrossRefGoogle Scholar
  27. 27.
    Dawson GR, Tricklebank MD. Use of the elevated plus maze in the search for novel anxiolytic agents. Trends Pharmacol Sci. 1995;16(2):33–36.CrossRefPubMedGoogle Scholar
  28. 28.
    Bourin M, Hascoet M. The mouse light/dark box test. Eur J Pharmacol. 2003;463(1–3):55–65.CrossRefPubMedGoogle Scholar
  29. 29.
    Mora S, Diaz-Veliz G, Millan R, Lungenstrass H, Quiros S, Coto-Morales T, et al. Anxiolytic and antidepressant-like effects of the hydroalcoholic extract from Aloysia polystachya in rats. Pharmacol, Biochem Behav. 2005;82(2):373–378.CrossRefGoogle Scholar
  30. 30.
    Murphy DL, Mueller EA, Hill JL, Tolliver TJ, Jacobsen FM. Comparative anxiogenic, neuroendocrine, and other physiologic effects of m-chlorophenylpiperazine given intravenously or orally to healthy volunteers. Psychopharmacology. 1989;98(2):275–82.CrossRefPubMedGoogle Scholar
  31. 31.
    Bilkei-Gorzo A, Gyertyan I, Levay G. mCPP-induced anxiety in the light-dark box in rats—a new method for screening anxiolytic activity. Psychopharmacology. 1998 Apr;136(3):291–8.CrossRefPubMedGoogle Scholar
  32. 32.
    Wallis CJ, Lal H. A discriminative stimulus produced by 1-(3-chlorophenyl)-piperazine (mCPP) as a putative animal model of anxiety. Prog Neuro-Psychopharmacol Biol Psychiatry. 1998;22(3):547–565.CrossRefGoogle Scholar
  33. 33.
    Kennett GA, Whitton P, Shah K, Curzon G. Anxiogenic-like effects of mCPP and TFMPP in animal models are opposed by 5-HT1C receptor antagonists. Eur J Pharmacol. 1989;164(3):445–454.Google Scholar
  34. 34.
    Altieri SC, Yang H, O’Brien HJ, Redwine HM, Senturk D, Hensler JG, et al. Perinatal vs genetic programming of serotonin states associated with anxiety. Neuropsychopharmacology. 2015;40(6):1456–70.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Akimova E, Lanzenberger R, Kasper S. The serotonin-1A receptor in anxiety disorders. Biol Psychiatry. 2009;66(7):627–35.CrossRefPubMedGoogle Scholar
  36. 36.
    Maron E, Nutt D, Shlik J. Neuroimaging of serotonin system in anxiety disorders. Curr Pharm Des. 2012;18(35):5699–708.CrossRefPubMedGoogle Scholar
  37. 37.
    Jung JW, Cho JH, Ahn NY, Oh HR, Kim SY, Jang CG, et al. Effect of chronic Albizzia julibrissin treatment on 5-hydroxytryptamine1A receptors in rat brain. Pharmacology, biochemistry, and behavior. 2005;81(1):205–210.Google Scholar
  38. 38.
    Qin S, Young CB, Duan X, Chen T, Supekar K, Menon V. Amygdala subregional structure and intrinsic functional connectivity predicts individual differences in anxiety during early childhood. Biol Psychiatry. 2014;75(11):892–900.CrossRefPubMedGoogle Scholar
  39. 39.
    Saiyudthong S, Pongmayteegul S, Marsden CA, Phansuwan-Pujito P. Anxiety-like behaviour and c-fos expression in rats that inhaled vetiver essential oil. Nat Prod Res. 2015;29(22):2141–4.CrossRefPubMedGoogle Scholar
  40. 40.
    Kang-Park MH, Wilson WA, Moore SD. Differential actions of diazepam and zolpidem in basolateral and central amygdala nuclei. Neuropharmacology. 2004;46(1):1–9.CrossRefPubMedGoogle Scholar
  41. 41.
    Tye KM, Prakash R, Kim SY, Fenno LE, Grosenick L, Zarabi H, et al. Amygdala circuitry mediating reversible and bidirectional control of anxiety. Nature. 2011;471(7338):358–362.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Singewald N, Salchner P, Sharp T. Induction of c-Fos expression in specific areas of the fear circuitry in rat forebrain by anxiogenic drugs. Biol Psychiatry. 2003;53(4):275–283.CrossRefPubMedGoogle Scholar

Copyright information

© Japanese Society of Sleep Research 2019

Authors and Affiliations

  • Tian-Xiao Wang
    • 1
  • Yu-Er Wu
    • 1
  • Wei Xu
    • 1
  • Wan-Kun Gong
    • 1
  • Jian Ni
    • 1
  • Wei-Min Qu
    • 1
  • Zhi-Li Huang
    • 1
    Email author
  1. 1.Department of Pharmacology, School of Basic Medical Sciences, State Key Laboratory of Medical NeurobiologyInstitutes of Brain Science and the Collaborative Innovation Center for Brain Science, Fudan UniversityShanghaiChina

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