Abstract
Anxiety disorders are highly prevalent and considered a major public health concern worldwide. Current anxiolytics are of limited efficacy and associated with various side effects. Our novel herbal treatment (NHT), composed of four constituents, was shown to reduce anxiety-like behavior while precluding a common side effect caused by current anxiolytics, i.e., sexual dysfunction. Nevertheless, NHT’s mechanism of action is yet to be determined. There is evidence that some medicinal herbs interact with the GABAergic system. Therefore, we aimed to examine whether NHT’s anxiolytic-like effect is exerted by alterations in GABAA receptor density in the hippocampus, prefrontal cortex, and hypothalamus. The effects of 3-weeks treatment with NHT on anxiety-like behavior and locomotion were assessed using the elevated plus maze (EPM) and the open field test (OFT), respectively. Regional GABAA receptor levels were analyzed using [3H] RO15-1788 high-affinity binding assays. In stressed mice, NHT reduced anxiety-like behavior similarly to the benzodiazepine, clonazepam, while locomotion remained intact. Lack of changes or minor changes in regional GABAA receptor density in the brain were induced by NHT or clonazepam. In naive mice, performance in the EPM, locomotion and GABAA receptor densities were not altered by treatment with NHT or clonazepam. These findings support NHT as an efficacious and safe anxiolytic, although the GABAergic involvement remains to be further elucidated.
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References
Avital A, Richter-Levin G (2005) Exposure to juvenile stress exacerbates the behavioural consequences of exposure to stress in the adult rat. Int J Neuropsychopharmacol 8:163–173. https://doi.org/10.1017/S1461145704004808
Avnimelech-Gigus N, Feldon J, Tanne Z, Gavish M (1986) The effects of prenatal chlordiazepoxide administration on avoidance behavior and benzodiazepine receptor density in adult albino rats. Eur J Pharmacol 129:185–188. https://doi.org/10.1016/0014-2999(86)90352-3
Baxter AJ, Scott KM, Vos T, Whiteford HA (2013) Global prevalence of anxiety disorders: a systematic review and meta-regression. Psychol Med 43:897–910. https://doi.org/10.1017/S003329171200147X
Benavides J, Peny B, Ruano D, Vitorica J, Scatton B (1993) Comparative autoradiographic distribution of central ω (benzodiazepine) modulatory site subtypes with high, intermediate and low affinity for zolpidem and alpidem. Brain Res 604:240–250. https://doi.org/10.1016/0006-8993(93)90375-W
Bremner JD, Innis RB, Southwick SM, Staib L, Zoghbi S, Charney DS (2000) Decreased benzodiazepine receptor binding in prefrontal cortex in combat-related posttraumatic stress disorder. Am J Psychiatry 157:1120–1126. https://doi.org/10.1176/appi.ajp.157.7.1120
Britten N (1994) Patients’ ideas about medicines: a qualitative study in a general practice population. Br J Gen Pract 44:465–468. https://doi.org/10.1186/1471-2296-6-20
Burstein O, Franko M, Gale E, Handelsman A, Barak S, Motsan S, Shamir A, Toledano R, Simhon O, Hirshler Y, Chen G, DoronR (2017) Escitalopram and NHT normalized stress-induced anhedonia and molecular neuroadaptations in a mouse model of depression. PLoS One 12. https://doi.org/10.1371/journal.pone.0188043
Butterweck V, Hegger M, Winterhoff H (2004) Flavonoids of St. John’s Wort reduce HPA axis function in the rat. Planta Med 70:1008–1011. https://doi.org/10.1055/s-2004-832631
Carobrez AP, Bertoglio LJ (2005) Ethological and temporal analyses of anxiety-like behavior: the elevated plus-maze model 20 years on. In: Neuroscience and Biobehavioral Reviews. pp 1193–1205. https://doi.org/10.1016/j.neubiorev.2005.04.017
Chouinard G (2004) Issues in the clinical use of benzodiazepines: potency, withdrawal, and rebound. J Clin Psychiatry 277:301–306. https://doi.org/10.1001/jama.1997.03540280039031
Crestani F, Lorez M, Baer K, Essrich C, Benke D, Laurent JP, Belzung C, Fritschy JM, Lüscher B, Mohler H (1999) Decreased GABAA-receptor clustering results in enhanced anxiety and a bias for threat cues. Nat Neurosci 2:833–839. https://doi.org/10.1038/12207
Doron R, Lotan D, Rak-Rabl A, Raskin-Ramot A, Lavi K, Rehavi M (2012) Anxiolytic effects of a novel herbal treatment in mice models of anxiety. Life Sci 90:995–1000. https://doi.org/10.1016/j.lfs.2012.05.014
Doron R, Lotan D, Einat N, Yaffe R, Winer A, Marom I, Meron G, Kately N, Rehavi M (2014a) A novel herbal treatment reduces depressive-like behaviors and increases BDNF levels in the brain of stressed mice. Life Sci 94:151–157. https://doi.org/10.1016/j.lfs.2013.10.025
Doron R, Lotan D, Versano Z, Benatav L, Franko M, Armoza S, Kately N, Rehavi M (2014b) Escitalopram or novel herbal mixture treatments during or following exposure to stress reduce anxiety-like behavior through corticosterone and BDNF modifications. PLoS One 9:e91455. https://doi.org/10.1371/journal.pone.0091455
Dube SR, Anda RF, Felitti VJ, Chapman DP, Williamson DF, Giles WH (2001) Childhood abuse, household dysfunction, and the risk of attempted suicide throughout the life span: findings from the adverse childhood experiences study. JAMA 286:3089–3096. https://doi.org/10.1001/jama.286.24.3089
Ducottet C, Belzung C (2004) Behaviour in the elevated plus-maze predicts coping after subchronic mild stress in mice. Physiol Behav 81:417–426. https://doi.org/10.1016/j.physbeh.2004.01.013
Duval ER, Javanbakht A, Liberzon I (2015) Neural circuits in anxiety and stress disorders: a focused review. Ther Clin Risk Manag. https://doi.org/10.2147/TCRM.S48528
Earnheart JC, Schweizer C, Crestani F, Iwasato T, Itohara S, Mohler H, Luscher B (2007) GABAergic control of adult hippocampal neurogenesis in relation to behavior indicative of trait anxiety and depression states. J Neurosci 27:3845–3854. https://doi.org/10.1523/JNEUROSCI.3609-06.2007
Farach FJ, Pruitt LD, Jun JJ, Jerud AB, Zoellner LA, Roy-Byrne PP (2012) Pharmacological treatment of anxiety disorders: current treatments and future directions. J Anxiety Disord 26:833–843. https://doi.org/10.1016/j.janxdis.2012.07.009
Gallager DW, Lakoski JM, Gonsalves Rauch SFSL (1984) Chronic benzodiazepine treatment decreases postsynaptic GABA sensitivity. Nature 308:74–77. https://doi.org/10.1038/308074a0
Galpern WR, Lumpkin M, Greenblatt DJ, Shader RI, Miller LG (1991) Chronic benzodiazepine administration. Psychopharmacology 104:225–230
Hasler G, Nugent AC, Carlson PJ, Carson RE, Geraci M, Drevets WC (2008) Altered cerebral γ-aminobutyric acid type A-benzodiazepine receptor binding in panic disorder determined by [11C]flumazenil positron emission tomography. Arch Gen Psychiatry 65:1166–1175. https://doi.org/10.1001/archpsyc.65.10.1166
Katzman MA (2009) Current considerations in the treatment of generalized anxiety disorder. CNS Drugs 23:103–120. https://doi.org/10.2165/00023210-200923020-00002
Kaufman J, Charney D (2000) Comorbidity of mood and anxiety disorders. Depress Anxiety 12:69–76. https://doi.org/10.1002/1520-6394(2000)12:1+<69::AID-DA9>3.0.CO;2-K
Kessler RC, Ruscio AM, Shear K, Wittchen H-U (2009) Epidemiology of anxiety disorders. In: Behavioral neurobiology of anxiety and its treatment. Springer, pp 21–35
Lin RD, Hou WC, Yen KY, Lee MH (2003) Inhibition of monoamine oxidase B (MAO-B) by Chinese herbal medicines. Phytomedicine 10:650–656. https://doi.org/10.1078/0944-7113-00324
Lydiard RB (2003) The role of GABA in anxiety disorders. J Clin Psychiatry 64(Suppl 3):21–27
Masand PS, Gupta S (2002) Long-term side effects of newer-generation antidepressants: SSRIS, venlafaxine, nefazodone, bupropion, and mirtazapine. Ann Clin Psychiatry 14:175–182. https://doi.org/10.1023/A:1021141404535
Medina JH, Novas ML, De Robertis E (1983a) Changes in benzodiazepine receptors by acute stress: different effect of chronic diazepam or Ro 15-1788 treatment. Eur J Pharmacol 96:181–185. https://doi.org/10.1016/0014-2999(83)90306-0
Medina JH, Novas ML, De Robertis E (1983b) Chronic RO 15-1788 treatment increases the number of benzodiazepine receptors in rat cerebral cortex and hippocampus. Eur J Pharmacol 90:125–128. https://doi.org/10.1016/0014-2999(83)90223-6
Miller LG, Woolverton S, Greenblatt DJ, Lopez F, Roy RB, Shader RI (1989) Chronic benzodiazepine administration. IV. Rapid development of tolerance and receptor downregulation associated with alprazolam administration. Biochem Pharmacol 38:3773–3777. https://doi.org/10.1016/0006-2952(89)90584-4
Möhler H (2012) The GABA system in anxiety and depression and its therapeutic potential. In: Neuropharmacology. pp 42–53. https://doi.org/10.1016/j.neuropharm.2011.08.040
Möhler H, Okada T, Enna SJ (1978) Benzodiasepine and neurotransmitter receptor bunding in rat brain after chronic administration of diazepam or phenobarbital. Brain Res 156:391–395. https://doi.org/10.1016/0006-8993(78)90526-7
Montpied P, Martin BM, Cottingham SL, Stubblefield BK, Ginns EI, Paul SM (1988) Regional distribution of the GABAA/benzodiazepine receptor ($α$ subunit) mRNA in rat brain. J Neurochem 51:1651–1654
Nemeroff CB (2003) The role of GABA in the pathophysiology and treatment of anxiety disorders. Psychopharmacol Bull 37:133–146
Nikolaus S, Antke C, Beu M, Müller H-W (2010) Cortical GABA, striatal dopamine and midbrain serotonin as the key players in compulsive and anxiety disorders—results from in vivo imaging studies. Rev Neurosci 21. https://doi.org/10.1515/REVNEURO.2010.21.2.119
Nuss P (2015) Anxiety disorders and GABA neurotransmission: a disturbance of modulation. Neuropsychiatr Dis Treat 11:165–175. https://doi.org/10.2147/NDT.S58841
Nutt DJ, Malizia AL (2001) New insights into the role of the GABAA-benzodiazepine receptor in psychiatric disorder. Br J Psychiatry 179:390–396. https://doi.org/10.1192/bjp.179.5.390
Nutt DJ, Malizia AL (2004) Structural and functional brain changes in posttraumatic stress disorder. J Clin Psychiatry 65(Suppl 1):11–17. https://doi.org/10.1016/j.neuroimage.2010.03.037
Peng WH, Hsieh MT, Lee YS, Lin YC, Liao J (2000) Anxiolytic effect of seed of Ziziphus jujuba in mouse models of anxiety. J Ethnopharmacol 72:435–441. https://doi.org/10.1016/S0378-8741(00)00255-5
Penza KM, Heim C, Nemeroff CB (2003) Neurobiological effects of childhood abuse: implications for the pathophysiology of depression and anxiety. In: Archives of Women’s Mental Health. pp 15–22. https://doi.org/10.1007/s00737-002-0159-x
Ravindran LN, Stein MB (2010) The pharmacologic treatment of anxiety disorders: a review of progress. J Clin Psychiatry 71:839–854. https://doi.org/10.4088/JCP.10r06218blu
Rogers A, Pilgrim D (1993) Service users’ views of psychiatric treatments. Sociol Health Illn 15:612–631. https://doi.org/10.1111/1467-9566.ep11433593
Roy-Byrne PP, Davidson KW, Kessler RC, Asmundson GJG, Goodwin RD, Kubzansky L, Lydiard RB, Massie MJ, Katon W, Laden SK, Stein MB (2008) Anxiety disorders and comorbid medical illness. Gen Hosp Psychiatry 30:208–225. https://doi.org/10.1016/j.genhosppsych.2007.12.006
Sankar R (2012) GABAA receptor physiology and its relationship to the mechanism of action of the 1,5-benzodiazepine clobazam. CNS Drugs 26:229–244
Sarris J, McIntyre E, Camfield DA (2013) Plant-based medicines for anxiety disorders, part 1: a review of preclinical studies. CNS Drugs 27:207–219. https://doi.org/10.1007/s40263-013-0044-3
Sartorius N, Gaebel W, Cleveland HR, Stuart H, Akiyama T, Arboleda-Flórez J, Baumann AE, Gureje O, Jorge MR, Kastrup M, Suzuki Y, Tasman A (2010) WPA guidance on how to combat stigmatization of psychiatry and psychiatrists. World Psychiatry 9:131–144. https://doi.org/10.1002/j.2051-5545.2010.tb00296.x
Scheid V, Bensky D, Ellis A, Barolet R (2009) Chinese herbal medicine: formulas and strategies, 2nd edn. Eastland Press, Seattle
Schimmenti A, Bifulco A (2015) Linking lack of care in childhood to anxiety disorders in emerging adulthood: the role of attachment styles. Child Adolesc Ment Health 20:41–48. https://doi.org/10.1111/camh.12051
Shekhar A, Hingtgen JN, DiMicco JA (1990) GABA receptors in the posterior hypothalamus regulate experimental anxiety in rats. Brain Res 512:81–88. https://doi.org/10.1016/0006-8993(90)91173-E
Simon NM, Otto MW, Worthington JJ, Hoge EA, Thompson EH, LeBeau RT, Moshier SJ, Zalta AK, Pollack MH (2009) Next-step strategies for panic disorder refractory to initial pharmacotherapy: a 3-phase randomized clinical trial. J Clin Psychiatry 70:1563–1570. https://doi.org/10.4088/JCP.08m04485blu
Singhuber J, Baburin I, Kählig H, Urban E, Kopp B, Hering S (2012) GABAA receptor modulators from Chinese herbal medicines traditionally applied against insomnia and anxiety. Phytomedicine 19:334–340. https://doi.org/10.1016/j.phymed.2011.10.009
Smith KS, Engin E, Meloni EG, Rudolph U (2012) Benzodiazepine-induced anxiolysis and reduction of conditioned fear are mediated by distinct GABAAreceptor subtypes in mice. Neuropharmacology 63:250–258. https://doi.org/10.1016/j.neuropharm.2012.03.001
Tan KR, Rudolph U, Lu C (2011) Hooked on benzodiazepines: GABAA receptor subtypes and addiction. Cell Press, pp 1–10. https://doi.org/10.1016/j.tins.2011.01.004
Thase ME (2006) Managing depressive and anxiety disorders with escitalopram. Expert Opin Pharmacother 7:429–440. https://doi.org/10.1517/14656566.7.4.429
Whiskey E, Taylor D (2013) A review of the adverse effects and safety of noradrenergic antidepressants. J Psychopharmacol 27:732–739. https://doi.org/10.1177/0269881113492027
Wildmann J (1988) Increase of natural benzodiazepines in wheat and potato during germination. Biochem Biophys Res Commun 157:1436–1443. https://doi.org/10.1016/S0006-291X(88)81036-2
Willner P, Muscat R, Papp M (1992) Chronic mild stress-induced anhedonia: a realistic animal model of depression. Neurosci Biobehav Rev 16:525–534. https://doi.org/10.1016/S0149-7634(05)80194-0
You Z, Xia Q, Liang F, Tang Y, Xu C, Huang J, Zhao L, Zhang W, He J (2010) Effects on the expression of GABAA receptor subunits by jujuboside A treatment in rat hippocampal neurons. J Ethnopharmacol 128:419–423. https://doi.org/10.1016/j.jep.2010.01.034
Zezula J, Cortés R, Probst A, Palacios JM (1988) Benzodiazepine receptor sites in the human brain: autoradiographic mapping. Neuroscience 25:771–795. https://doi.org/10.1016/0306-4522(88)90036-X
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The authors would like to thank Nadav Kately for inventing and developing the NHT herbal formula.
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All experiments were approved by the Academic College Tel Aviv Yaffo committee for animal care and use. Methods were carried out in accordance with the NIH guidelines.
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Doron, R., Sever, A., Handelsman, A. et al. GABAA Receptor Density Is Not Altered by a Novel Herbal Anxiolytic Treatment. J Mol Neurosci 65, 110–117 (2018). https://doi.org/10.1007/s12031-018-1078-2
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DOI: https://doi.org/10.1007/s12031-018-1078-2