CNS Drugs

, Volume 17, Issue 8, pp 539–562 | Cite as

Mechanism of Action of St John’s Wort in Depression

What is Known?
  • Veronika ButterweckEmail author
Leading Article


Extracts of Hypericum perforatum L. (St John’s wort) are now successfully competing for status as a standard antidepressant therapy. Because of this, great effort has been devoted to identifying the active antidepressant compounds in the extract. From a phytochemical point of view, St John’s wort is one of the best-investigated medicinal plants. A series of bioactive compounds has been detected in the crude material, namely flavonol derivatives, biflavones, proantho-cyanidines, xanthones, phloroglucinols and naphthodianthrones.

Although St John’s wort has been subjected to extensive scientific studies in the last decade, there are still many open questions about its pharmacology and mechanism of action. Initial biochemical studies reported that St John’s wort is only a weak inhibitor of monoamine oxidase-A and -B activity but that it inhibits the synaptosomal uptake of serotonin, dopamine and noradrenaline (norepinephrine) with approximately equal affinity. However, other in vitro binding assays carried out using St John’s wort extract demonstrated significant affinity for adenosine, GABAa, GABAb and glutamate receptors. In vivo St John’s wort extract leads to a downregulation of β-adrenergic receptors and an upregulation of serotonin 5-HT2 receptors in the rat frontal cortex and causes changes in neurotransmitter concentrations in brain areas that are implicated in depression. In studies using the rat forced swimming test, an animal model of depression, St John’s wort extracts induced a significant reduction of immobility. In other experimental models of depression, including acute and chronic forms of escape deficit induced by Stressors, St John’s wort extract was shown to protect rats from the consequences of unavoidable stress. Recent neuroendocrine studies suggest that St John’s wort is involved in the regulation of genes that control hypothalamic-pituitary-adrenal axis function. With regard to the antidepressant effects of St John’s wort extract, many of the pharmacological activities appear to be attributable to the naphthodianthrone hypericin, the phloroglucinol derivative hyperforin and several flavonoids.

This review integrates new findings of possible mechanisms that may underlie the antidepressant action of St John’s wort and its active constituents with a large body of existing literature.


Imipramine Forced Swimming Test Hypericin Quercitrin Hyperforin 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



The author thanks Dr Miles Herkenham, Professor Dr Adolf Nahrstedt and Professor Dr Hilke Winterhoff for continued enthusiastic support, insightful discussions and thoughtful reading of this manuscript.

No sources of funding were used to assist in the preparation of this manuscript. The author has no conflicts of interest that are directly relevant to the content of this manuscript.


  1. 1.
    Rosenthal N. St John’s wort: the herbal way to feeling good. New York: Harper Collins Publishers, 1998Google Scholar
  2. 2.
    Bombardelli E, Morazzoni P. Hypericum perforatum. Fitoterapia 1995; 66: 43–68Google Scholar
  3. 3.
    Lohse MJ, Müller-Oerlinghausen B. Psychopharmaka. In: Schwabe U, Paffrath D, editors. Arzneiverordnungreport 2000. Berlin: Springer Verlag, 2000: 581–7Google Scholar
  4. 4.
    Schulz V. Incidence and clinical relevance of the interactions and side effects of Hypericum preparations. Phytomedicine 2001; 8(2): 152–60PubMedGoogle Scholar
  5. 5.
    National Center for Complementary and Alternative Medicine. St John’s wort fact sheet (publication Z-02). Bethesda: National Institutes of Health, 1999Google Scholar
  6. 6.
    Brenner R, Azbel V, Madhusoodanan S, et al. Comparison of an extract of Hypericum (LI 160) and sertraline in the treatment of depression: a double-blind, randomized pilot study. Clin Ther 2000; 22(4): 411–9PubMedGoogle Scholar
  7. 7.
    Harrer G, Schulz V. Clinical investigation of the antidepressant effectiveness of Hypericum. J Geriatr Psychiatry Neurol 1994; 7Suppl. 1: S6–8PubMedGoogle Scholar
  8. 8.
    Philipp M, Kohnen R, Hiller K. Hypericum extract versus imipramine or placebo in patients with moderate depression: randomised multicentre study of treatment for eight weeks. BMJ 1999; 319: 1534–8PubMedGoogle Scholar
  9. 9.
    Schrader E. Equivalence of St John’s wort extract (Ze 117) and fluoxetine: a randomized, controlled study in mild-moderate depression. Int Clin Psychopharmacol 2000; 5(2): 61–8Google Scholar
  10. 10.
    Volz HP. Controlled clinical trials of Hypericum extracts in depressed patients: an overview. Pharmacopsychiatry 1997; 30Suppl. 2: 72–6PubMedGoogle Scholar
  11. 11.
    Woelk H. Comparison of St John’s wort and imipramine for treating depression: randomised controlled trial. BMJ 2000; 321(7260): 536–9PubMedGoogle Scholar
  12. 12.
    Linde K, Ramirez G, Mulrow C. St John’s wort in depression-and overview and meta-analysis of randomised clinical trials. BMJ 1996; 313: 253–8PubMedGoogle Scholar
  13. 13.
    Wheatly D. Hypericum extract: potential in the treatment of depression. CNS Drugs 1998; 9: 431–40Google Scholar
  14. 14.
    Vorbach EU, Arnoldt KH, Hübner WD. Efficacy and tolerability of St John’s wort extract LI 160 versus imipramine in patients with severe depressive episodes according to ICD-10. Pharmacopsychiatry 1997; 30Suppl. 2: 77–80Google Scholar
  15. 15.
    Laakmann G, Schule C, Baghai T, et al. St John’s wort in mild to moderate depression: the relevance of hyperforin for the clinical efficacy. Pharmacopsychiatry 1998; 31Suppl. 1: 54–9PubMedGoogle Scholar
  16. 16.
    Shelton RC, Keller MB, Gelenberg A, et al. Effectiveness of St John’s wort in major depression. JAMA 2001; 285(15): 1978–86PubMedGoogle Scholar
  17. 17.
    Effect of Hypericum perforatum (St John’s wort) in major depressive disorder. JAMA 2002; 287 (14): 1807–14Google Scholar
  18. 18.
    Nahrstedt A. Antidepressant constituents of Hypericum perforatum. In: Chrubasik S, Roufogalis BD, editors. Herbal medicinal products for the treatment of pain. Lismore: Southern Cross University Press, 2000: 144–53Google Scholar
  19. 19.
    Nahrstedt A, Butterweck V. Biologically active and other chemical constituents of the herb of Hypericum perforatum L. Pharmacopsychiatry 1997; 30Suppl. 2: 129–34PubMedGoogle Scholar
  20. 20.
    Butterweck V, Wall A, Lieflaender-Wulf U, et al. Effects of the total extract and fractions of Hypericum perforatum in animal assays for antidepressant activity. Pharmacopsychiatry 1997; 30Suppl. 2: 117–24PubMedGoogle Scholar
  21. 21.
    Jürgenliemk G, Nahrstedt A. Phenolic compounds from Hypericum perforatum. Planta Med 2002; 68: 88–91PubMedGoogle Scholar
  22. 22.
    Chatterjee SS, Bhattacharya S, Wonnemann M, et al. Hyperforin as a possible antidepressant component of Hypericum extracts. Life Sci 1998; 63: 499–510PubMedGoogle Scholar
  23. 23.
    Singer A, Wonnemann M, Müller W. Hyperforin, a major antidepressant constituent of St John’s wort, inhibits serotonin uptake by elevating free intracellular Na+. J Pharmacol Exp Ther 1999; 290: 1363–8PubMedGoogle Scholar
  24. 24.
    Müller WE, Singer A, Wonnemann M. Hyperforin-antidepressant activity by a novel mechanism of action. Pharmacopsychiatry 2001; 34Suppl. 1: S98–S102PubMedGoogle Scholar
  25. 25.
    Wonnemann M, Singer A, Siebert B, et al. Evaluation of synaptosomal uptake inhibition of most relevant constituents of St John’s wort. Pharmacopsychiatry 2001; 41Suppl. 1: S148–S51Google Scholar
  26. 26.
    Butterweck V, Petereit F, Winterhoff H, et al. Solubilized hypericin and pseudohypericin from Hypericum perforatum exert antidepressant activity in the forced swimming test. Planta Med 1998; 64: 291–4PubMedGoogle Scholar
  27. 27.
    Butterweck V, Winterhoff H, Herkenham M. St John’s wort, hypericin, and imipramine: a comparative analysis of mRNA levels in brain areas involved in HPA axis control following short-term and long-term administration in normal and stressed rats. Mol Psychiatry 2001; 6: 547–64PubMedGoogle Scholar
  28. 28.
    Butterweck V, Nahrstedt A, Evans J, et al. In vitro receptor screening of pure constituents of St John’s wort reveals novel interaction with a number of GPCR’s. Psychopharmacology 2002; 162: 193–202PubMedGoogle Scholar
  29. 29.
    Butterweck V, Jürgenliemk G, Nahrstedt A, et al. Flavonoids from Hypericum perforatum show antidepressant activity in the forced swimming test. Planta Med 2000; 66: 3–6PubMedGoogle Scholar
  30. 30.
    Calapai G, Crupi A, Firenzuoli F, et al. Effects of Hypericum perforatum on levels of 5-hydroxytryptamine, noradrenaline and dopamine in the cortex, diencephalon and brainstem of the rat. J Pharm Pharmacol 1999; 51: 723–8PubMedGoogle Scholar
  31. 31.
    Suzuki O, Katsumata Y, Oya M. Inhibition of monoamine oxidase by hypericin. Planta Med 1984; 50: 272–4PubMedGoogle Scholar
  32. 32.
    Demisch L, Hölzl J, Gollnik B. Identification of selective MAO-type-A inhibitors in Hypericum perforatum L. Pharmacopsychiatry 1989; 22: 194–6Google Scholar
  33. 33.
    Sparenberg BL, Demisch J, Hölzl J. Untersuchungen über die antidepressiven Wirkstoffe von Johanniskraut. Pharm Ztg Wiss 1993; 138: 239–54Google Scholar
  34. 34.
    Bladt S, Wagner H. Inhibition of MAO by fractions and constituents of Hypericum extract. J Geriatr Psychiatry 1994; 154: 125–34Google Scholar
  35. 35.
    Thiede HM, Walper A. Inhibition of MAO and COMT by Hypericum extracts and hypericin. J Geriatr Psychiatry Neurol 1994; 7: S54–S6PubMedGoogle Scholar
  36. 36.
    Cott JM. In vitro binding and enzyme inhibition by Hypericum perforatum extract. Pharmacopsychiatry 1997; 30Suppl. 2: 108–12PubMedGoogle Scholar
  37. 37.
    Müller W, Rolli M, Schäfer C, et al. Effects of Hypericum extract (LI 160) in biochemical models of antidepressant activity. Pharmacopsychiatry 1997; 30Suppl. 2: 102–7PubMedGoogle Scholar
  38. 38.
    Cracchiolo C. Pharmacology of St John’s wort: botanical and chemical aspects. Sci Rev Alt Med 1998; 2: 29–35Google Scholar
  39. 39.
    Müller WE, Schäfer C. Johanniskraut: in-vitro Studie über Hypericum-extrakt (LI 160), hypericin und kämpferol als antidepressiva. Dtsch Apoth Ztg 1996; 136: 17–24Google Scholar
  40. 40.
    Amara SG, Kuhar MJ. Neurotransmitter transporters: recent progress. Annu Rev Neurosci 1993; 16: 73–93PubMedGoogle Scholar
  41. 41.
    Shaskan EG, Snyder SH. Kinetics of serotonin accumulation into slices from rat brain: relationship to catecholamine uptake. J Pharmacol Exp Ther 1970; 175: 404–18PubMedGoogle Scholar
  42. 42.
    Snyder SH. Putative neurotransmitters in the brain: selective neuronal uptake, subcellular localization, and interactions with centrally acting drugs. Biol Psychiatry 1970; 2: 367–89PubMedGoogle Scholar
  43. 43.
    Fuller RW, Wong DT. Serotonin uptake and serotonin uptake inhibition. Ann N Y Acad Sci 1990; 600: 68–78PubMedGoogle Scholar
  44. 44.
    Horn AS, Coyle JT, Snyder SH. Catecholamine uptake by synaptosomes from rat brain: structure-activity relationships of drugs with differential effects on dopamine and norepinephrine neurons. Mol Pharmacol 1971; 7: 66–80PubMedGoogle Scholar
  45. 45.
    Bourin M, Baker GB. The future of antidepressants. Biomed Pharmacother 1996; 50: 7–12PubMedGoogle Scholar
  46. 46.
    Richelson E. Synaptic effects of antidepressants. J Clin Psychopharmacol 1996; 16Suppl. 2: 1S–7SPubMedGoogle Scholar
  47. 47.
    Gobbi M, Dalla Valle F, Ciapparelli C, et al. Hypericum perforatum L. extract does not inhibit 5-HT transporter in rat brain cortex. Naunyn Schmiedebergs Arch Pharmacol 1999; 360: 262–9PubMedGoogle Scholar
  48. 48.
    Müller WE, Singer A, Wonnemann M, et al. Hyperforin represents the neurotransmitter reuptake inhibiting constituent of Hypericum extract. Pharmacopsychiatry 1998; 31Suppl. 1: 16–21PubMedGoogle Scholar
  49. 49.
    Neary JT, Whittemore SR, Bu Y, et al. Biochemical mechanisms of action of Hypericum LI 160 in glial and neuronal cells: inhibition of neurotransmitter uptake and stimulation of extracellular signal regulated protein kinase. Pharmacopsychiatry 2001; 34Suppl. 1: S103–S7PubMedGoogle Scholar
  50. 50.
    Perovic S, Müller WE. Pharmacological profile of Hypericum extract. Arzneimittel Forschung 1995; 45: 1145–8PubMedGoogle Scholar
  51. 51.
    Kientsch U, Bürgi S, Ruedeberg C, et al. St John’s wort extract ZE 117 (Hypericum perforatum) inhibits norepinephrine and serotonin uptake into rat brain slices and reduces β-adrenoceptor numbers on cultured rat brain cells. Pharmacopsychiatry 2001; 34Suppl. 1: S56–60PubMedGoogle Scholar
  52. 52.
    Jensen AG, Hansen SH, Nielsen EO. Adhyperforin as a contributor to the effect of Hypericum perforatum L. in biochemical models of antidepressant activity. Life Sci 2001; 68: 1593–605PubMedGoogle Scholar
  53. 53.
    Raffa RB. Screen of receptor and uptake-site activity of hypericin component of St John’s wort reveals S-receptor binding. Life Sci 1998; 62(16): 265–70Google Scholar
  54. 54.
    Haslam E. Natural polyphenols (vegetable tannins) as drugs: possible modes of action. J Nat Prod 1996; 59: 205–15PubMedGoogle Scholar
  55. 55.
    Buchholzer ML, Dvorak C, Chatterjee SS, et al. Dual modulation of striatal acetylcholine release by hyperforin, a constituent of St John’s wort. J Pharmacol Exp Ther 2002; 301(2): 714–9PubMedGoogle Scholar
  56. 56.
    Wonnemann M, Singer A, Müller WE. Inhibition of synaptosomal uptake of 3H-L-glutamate and 3H-GABA by hyperforin, a major constituent of St John’s wort: the role of amiloride sensitive sodium conductive pathways. Neuropsy-chopharmacology 2000; 23(2): 188–97Google Scholar
  57. 57.
    Fisunov A, Lozovaya N, Tsintsadze T, et al. Hyperforin modulates gating of P-type Ca2+ current in cerebellar Purkinje neurons. Eur J Physiol 2000; 440: 427–34Google Scholar
  58. 58.
    Krishtal O, Lozovaya N, Fisunov A, et al. Modulation of ion channels in rat neurons by the constituents of Hypericum perforatum. Pharmacopsychiatry 2001; 34Suppl. 1: S74–82PubMedGoogle Scholar
  59. 59.
    Chatterjee S, Filippov V, Lishko P, et al. Hyperforin attenuates various ionic conductance mechanisms in the isolated hippocampal neurons of the rat. Life Sci 1999; 65(22): 2395–405PubMedGoogle Scholar
  60. 60.
    Biber A, Fischer H, Römer A, et al. Oral bioavailability of hyperforin from Hypericum extracts in rats and human volunteers. Pharmacopsychiatry 1998; 31Suppl. 1: 36–43PubMedGoogle Scholar
  61. 61.
    Yu PH. Effect of the Hypericum perforatum extract on serotonin turnover in the mouse brain. Pharmacopsychiatry 2000; 33: 60–5PubMedGoogle Scholar
  62. 62.
    Serdarevic N, Eckert GP, Müller WE. The effects of extracts of St John’s wort and kava kava on brain neurotransmitter levels in the mouse. Pharmacopsychiatry 2001; 34Suppl. 1: S134–S6PubMedGoogle Scholar
  63. 63.
    Fornal CA, Metzler CW, Mirescu C, et al. Effects of standardized extracts of St John’s wort on the single-unit activity of serotonergic dorsal raphe neurons in awake cats: comparisons with fluoxetine and sertraline. Neuropsychopharmacology 2001; 25(6): 858–70PubMedGoogle Scholar
  64. 64.
    Di Matteo V, Di Giovanni G, Di Mascio M, et al. Effect of acute administration of Hypericum-CO2 extract on dopamine and serotonin release in the rat central nervous system. Pharmacopsychiatry 2000; 33: 14–8PubMedGoogle Scholar
  65. 65.
    Rommelspacher H, Siemanowitz B, Mannel M. Acute and chronic actions of a dry methanolic extract of Hypericum perforatum and a hyperforin-rich extract on dopaminergic and serotonergic neurons in rat nucleus accumbens. Pharmacopsychiatry 2001; 34Suppl. 1: S119–S26PubMedGoogle Scholar
  66. 66.
    Franklin M, Chi JD, Mannel M, et al. Acute effects of LI 160 (extract of Hypericum perforatum, St John’s wort) and two of its constituents on neuroendocrine responses in the rat. J Psychopharmacol 2000; 14(4): 360–3PubMedGoogle Scholar
  67. 67.
    Kaehler ST, Sinner C, Chatterjee SS, et al. Hyperforin enhances the extracellular concentrations of catecholamines, serotonin and glutamate in the rat locus coeruleus. Neurosci Lett 1999; 262: 199–202PubMedGoogle Scholar
  68. 68.
    Philippu A. In vivo neurotransmitter release in the locus coeruleus-effects of hyperforin, inescapable shock and fear. Pharmacopsychiatry 2001; 34Suppl. 1: S111–S5PubMedGoogle Scholar
  69. 69.
    Brady LS, Whitfield HJ, Fox RJ, et al. Long-term antidepressant administration alters corticotropin-releasing hormone, tyrosine hydroxylase and mineralocorticoid receptor gene expression in rat brain. J Clin Invest 1991; 87: 831–7PubMedGoogle Scholar
  70. 70.
    Brady LS, Gold PW, Herkenham M, et al. The antidepressant fluoxetine, idazoxan and phenelzine alter corticotropin-releasing hormone and tyrosine hydroxylase mRNA levels in rat brain: therapeutic implications. Brain Res 1992; 572: 117–25PubMedGoogle Scholar
  71. 71.
    Butterweck V, Böckers T, Körte B, et al. Long-term effects of St John’s wort and hypericin on monoamine levels in rat hypothalamus and hippocampus. Brain Res 2002; 930: 21–9PubMedGoogle Scholar
  72. 72.
    Franklin M, Cowen PJ. Researching the antidepressant actions of Hypericum perforatum (St John’s wort) in animals and man. Pharmacopsychiatry 2001; 34Suppl. 1: S29–37PubMedGoogle Scholar
  73. 73.
    Winterhoff H, Butterweck V, Nahrstedt A, et al. Pharmakologische Untersuchungen zur antidepressiven Wirkung von Hypericum perforatum L. In: Loew D, Rietbrock N, editors. Phytopharmaka in forschung und klinischer anwendung. Darmstadt: Steinkopff Verlag, 1995: 39–56Google Scholar
  74. 74.
    Butterweck V, Korte B, Winterhoff H. Pharmacological and endocrine effects of Hypericum perforatum and hypericin after repeated treatment. Pharmacospsychiatry 2001; 34Suppl. 1: S2–7Google Scholar
  75. 75.
    Franklin M, Chi J, McGavin C, et al. Neuroendocrine evidence for dopaminergic actions of Hypericum extract (LI 160) in healthy volunteers. Biol Psychiatry 1999; 46: 581–4PubMedGoogle Scholar
  76. 76.
    Tuomisto J, Mannisto P. Neurotransmitter regulation of anterior pituitary hormones. Pharmacol Rev 1985; 37(3): 249–311PubMedGoogle Scholar
  77. 77.
    Charney DS, Menkes DB, Heninger GR. Receptor sensitivity and the mechanism of action of antidepressant treatment: implications for the etiology and therapy of depression. Arch Gen Psychiatry 1981; 38: 1160–80PubMedGoogle Scholar
  78. 78.
    Heninger GR, Charney DS. Mechanism of action of antidepressant treatments: implications for the etiology and treatment of depressive disorders. In: Meltzer H, editor. Psychopharmacology: the third generation in progress. New York: Raven Press, 1987: 535–44Google Scholar
  79. 79.
    Sulser F, Vetulani J, Mobley P. Mode of action of antidepressant drugs. Biochem Pharmacol 1978; 27: 257–61PubMedGoogle Scholar
  80. 80.
    Banerjee SP, Kung LS, Riggi SJ, et al. Development of β-adrenergic receptor subsensitivity by antidepressants. Nature 1977; 268: 455–6PubMedGoogle Scholar
  81. 81.
    Vetulani J, Sulser F. Action of antidepressant treatments reduces reactivity of noradrenergic cAMP-generating system in limbic forebrain. Nature 1975; 257: 495–6PubMedGoogle Scholar
  82. 82.
    Meltzer HY. Role of serotonin in depression. Ann N Y Acad Sci 1990; 600: 486–99PubMedGoogle Scholar
  83. 83.
    Teufel-Mayer R, Gleitz J. Effects of long-term administration of Hypericum extracts on the affinity and density of the central serotonergic 5-HTia and 5-HT2A receptors. Pharmacopsychiatry 1997; 30Suppl. 2: 113–6PubMedGoogle Scholar
  84. 84.
    Butterweck V. Beitrag zur pharmakologie und wirkstofffindung von Hypericum perforatum L. Münster: Institut für pharmazeutische Biologie und Phytochemie, Westfälische Wilhelms-Universität, 1997Google Scholar
  85. 85.
    Baker G, Greenshaw A. Effects of long-term administration of antidepressants and neuroleptics on receptors in the central nervous system. Cell Mol Neurobiol 1989; 9: 1–44PubMedGoogle Scholar
  86. 86.
    Leonard BE. Mechanisms of action of antidepressants. CNS Drugs 1995; 4Suppl. 1: 1–12Google Scholar
  87. 87.
    Leonard BE. The comparative pharmacological properties of selective serotonin re-uptake inhibitors in animals. In: Feigh-ner JP, Boyer WF, editors. Selective serotonin re-uptake inhib-itors: advances in basic research and clinical practice. Chiches-ter: John Wiley and Sons, 1996: 35–62Google Scholar
  88. 88.
    Watanabe Y, Sakai R, McEwen B, et al. Stress and antidepressant effects on hippocampal and cortical 5-HTIA and 5-HT2 receptors and transport sites for serotonin. Brain Res 1993; 615: 87–94PubMedGoogle Scholar
  89. 89.
    Lopez J, Chalmers D, Little K, et al. Regulation of serotoninl A, glucocorticoid and mineralocorticoid receptor in rat brain and human hippocampus: implications for the neurobiology of depression. Biol Psychiatry 1998; 43: 547–73PubMedGoogle Scholar
  90. 90.
    Briley M, Moret C. Neurobiological mechanisms involved in antidepressant therapies. Clin Neuropharmacol 1993; 16: 387–400PubMedGoogle Scholar
  91. 91.
    Blier P, de Montigny C. Current advances and trends in the treatment of depression. Trends Pharmacol Sci 1994; 15: 220–6PubMedGoogle Scholar
  92. 92.
    Eison A, Yocca FD, Gianutsos G. Effect of chronic administration of antidepressant drugs on 5-HT2 mediated behaviour in the rat following noradrenergic or serotonergic denervation. J Neural Trans 1991; 84: 19–32Google Scholar
  93. 93.
    Goodnough DB, Baker GB. 5-hydroxytryptamine 2 and β-adrenergic receptor regulation in rat brain following chronic treatment with desipramine and fluoxetine alone and in combination. J Neurochem 1994; 62: 2262–8PubMedGoogle Scholar
  94. 94.
    Hrdina PD, Vu TB. Chronic fluoxetine treatment upregulates 5-HT uptake sites and 5-HT2 receptors in the rat brain: an autoradiographic study. Synapse 1993; 14: 324–31PubMedGoogle Scholar
  95. 95.
    Stahl S. 5HT1A receptors and pharmacotherapy: is serotonin receptor down-regulation linked to the mechanism of action of antidepressant drugs? Psychopharmacol Bull 1994; 30: 39–43PubMedGoogle Scholar
  96. 96.
    Simmen U, Burkard W, Berger K, et al. Extracts and constituents of Hypericum perforatum inhibit the binding of various ligands to recombinant receptors expressed with the Semliki Forest virus system. J Recept Signal Transduct Res 1999; 19: 59–74PubMedGoogle Scholar
  97. 97.
    Simmen U, Higelin J, Berger-Büter K, et al. Neurochemical studies with St John’s wort in vitro. Pharmacopsychiatry 2001; 34Suppl. 1: S137–S42PubMedGoogle Scholar
  98. 98.
    Gobbi M, Moia M, Pirona L, et al. In vitro binding studies with two Hypericum perforatum extracts - hyperforin, hypericin and biapigenin - on 5-HT6, 5-HT7, GABAA/benzodiazepine, sigma, NPY-Y1/Y2 receptors and dopamine transporters. Pharmacopsychiatry 2001; 34Suppl. 1: S45–S8PubMedGoogle Scholar
  99. 99.
    Chatterjee SS, Nöldner M, Koch E, et al. Antidepressant activity of Hypericum perforatum and hyperforin: the neglected possibility. Pharmacopsychiatry 1998; 31Suppl. 1: 7–15PubMedGoogle Scholar
  100. 100.
    Baureithel KH, Buter KB, Engesser A, et al. Inhibition of benzodiazepine binding in vitro by amentoflavone, a constituent of various species of Hypericum. Pharm Acta Helv 1997; 72(3): 153–7PubMedGoogle Scholar
  101. 101.
    Nielsen M, Frokjaer S, Braestrup C. High affinity of the naturally-occurring biflavonoid, amentoflavon, to brain benzodiazepine receptors in vitro. Biochem Pharmacol 1988; 37(17): 3285–7PubMedGoogle Scholar
  102. 102.
    Kroeze WK, Roth BL. The molecular biology of serotonin receptors: therapeutic implications for the interface of mood and psychosis. Biol Psychiatry 1998; 44: 1128–42PubMedGoogle Scholar
  103. 103.
    Roth BL, Meltzer HY, Khan N. Binding of typical and atypical antipsychotic drugs to multiple neurotransmitter receptors. Adv Pharmacol 1998; 42: 482–5PubMedGoogle Scholar
  104. 104.
    Thiebot MH, Martin P, Puech AJ. Animal behavioural studies in the evaluation of antidepressant drugs. Br J Psychiatry Suppl 1992; 160(15): 44–50Google Scholar
  105. 105.
    Porsolt R, Le Pichon M, Jalfre M. Depression: a new animal model sensitive to antidepressant treatments. Nature 1977; 266: 730–2PubMedGoogle Scholar
  106. 106.
    Overmier JB, Seligman MEP. Effects of inescapable shock upon subsequent escape and avoidance learning. J Comp Physiol Psychol 1967; 78: 340–3Google Scholar
  107. 107.
    Porsolt RD. Behavioural despair. In: Enna SJ, Malick JB, Richelson E, editors. Antidepressants: neurochemical, behavioural and clinical perspectives. New York: Raven Press, 1981: 121–39Google Scholar
  108. 108.
    Betin C, De Feudis FV, Blavet N, etal. Further characterization of the behavioural despair in mice: positive effects of convulsants. Physiol Behav 1982; 28: 307–11PubMedGoogle Scholar
  109. 109.
    Browne RG. Effects of antidepressants and anticholinergics in a mouse “behavioural despair” test. Eur J Pharmacol 1979; 58: 331–4PubMedGoogle Scholar
  110. 110.
    Schlechter MD, Chance WT. Non-specificity of “behavioural despair” as an animal model of depression. Eur J Pharmacol 1979; 60: 139–42Google Scholar
  111. 111.
    Wallach MD, Hedley LR. The effects of antihistamines in a modified behavioural despair test. Commun Psychopharmacol 1979; 3: 35–9PubMedGoogle Scholar
  112. 112.
    Kitada Y, Miyauchi T, Satoh A, et al. Effects of antidepressants in the rat forced swimming test. Eur J Pharmacol 1981; 72: 145–52PubMedGoogle Scholar
  113. 113.
    Porsolt R, Anton G, Blavet N, et al. Behavioural despair in rats: a new model sensitive to antidepressant treatments. Eur J Pharmacol 1978; 47: 379–91PubMedGoogle Scholar
  114. 114.
    Cryan JF, Markou A, Lucki I. Assessing antidepressant activity in rodents: recent developments and future needs. Trends Pharmacol Sci 2002; 23(5): 238–45PubMedGoogle Scholar
  115. 115.
    De Vry J, Maurel S, Schreiber R, et al. Comparison of Hypericum extracts with imipramine and fluoxetine in animal models of depression and alcoholism. Eur Neuropsychopharmacol 1999; 9: 461–8Google Scholar
  116. 116.
    Özturk Y. Testing the antidepressant effects of Hypericum species on animal models. Pharmacopsychiatry 1997; 30Suppl. 2: 125–8PubMedGoogle Scholar
  117. 117.
    Panocka I, Perfumi M, Angeletti S, et al. Effects of Hypericum perforatum extract on ethanol intake, and on behavioural despair: a search for the neurochemical systems involved. Pharmacol Biochem Behav 2000; 66(1): 105–11PubMedGoogle Scholar
  118. 118.
    Maier SF, Seligman MEP. Learned helplessness: theory and evidence. J Exp Psychol 1976; 1: 3–46Google Scholar
  119. 119.
    Garber J, Miller WR, Seaman SF. Learned helpless, stress and the depressive disorders. In: Depue RA, editor. The psychobiology of depressive disorders: implications for the effects of stress. New York: Academic Press, 1979: 335–63Google Scholar
  120. 120.
    Dorworthy TR, Overmeier JB. On “learned helplessness”: the therapeutic effects of electroconvulsive shock. Physiol Behav 1977; 4: 355–8Google Scholar
  121. 121.
    Martin P, Soubrie P, Simon P. The effect of monoamine oxidase inhibitors compared with classical tricyclic antidepressants on learned helplessness paradigm. Prog Neuropsychopharmacol Biol Psychiatry 1987; 11: 1–7PubMedGoogle Scholar
  122. 122.
    Martin P, Soubrie P, Puech AJ. Reversal of helpless behaviour by serotonin uptake blockers in rats. Psychopharmacology 1990; 101: 403–7PubMedGoogle Scholar
  123. 123.
    Sherman AD, Sacquinte JL, Petty F. Specificity of the learned helplessness model of depression. Pharmacol Biochem Behav 1982; 16: 449–54PubMedGoogle Scholar
  124. 124.
    Willner P. The validity of animal models of depression. Psychopharmacology 1984; 83: 1–16PubMedGoogle Scholar
  125. 125.
    Willner P. Animal models of depression: an overview. Pharmacol Ther 1990; 45: 425–55PubMedGoogle Scholar
  126. 126.
    Gambrana C, Ghiglieri O, Tolu P, et al. Efficacy of an Hypericum perforatum (St John’s wort) extract in preventing and reverting a condition of escape deficit in rats. Neuropsycho-pharmacology 1999; 21(2): 247–54Google Scholar
  127. 127.
    Gambrana C, Tolu PL, Masi F, et al. A study of the antidepressant activity of Hypericum perforatum on animal models. Pharmacopsychiatry 2001; 34Suppl. 1: S42–S4Google Scholar
  128. 128.
    Holsboer F, Spengler D, Heuser I. The role of corticotropin-releasing hormone in the pathogenesis of Cushing’s disease, anorexia nervosa, alcoholism, affective disorders and dementia. Prog Brain Res 1992; 93: 385–417PubMedGoogle Scholar
  129. 129.
    Holsboer F, Barden N. Antidepressants and hypothalamic-pituitary-adrenocortical regulation. Endocr Rev 1996; 17: 187–205PubMedGoogle Scholar
  130. 130.
    Ansseau M. Hormonal disturbances in depression. In: Honig A, Van Praag HM, editors. Depression: neurobiological, psycho-pathological and therapeutic advances. Chichester: John Wiley & Sons, 1997: 235–50Google Scholar
  131. 131.
    Vetulani J, Nalepa I. Antidepressants: past, present and future. Eur J Pharmacol 2000; 405: 351–63PubMedGoogle Scholar
  132. 132.
    Gold P, Goodwin F, Chrousos G. Clinical and biochemical manifestations of depression: relation to the neurobiology of stress. N Engl J Med 1988; 319: 348–53PubMedGoogle Scholar
  133. 133.
    Raadsher F, Hoogendijk W, Stam F, et al. Increased numbers of corticotropin-releasing hormone expressing neurons in the hypothalamic paraventricular nucleus of depressed patients. Neuroendocrinology 1994; 60: 436–44Google Scholar
  134. 134.
    Barden N, Reul J, Holsboer F. Do antidepressants stabilize mood through actions on the hypothalamic-pituitary-adrenal axis? Trends Neurosci 1995; 18: 6–11PubMedGoogle Scholar
  135. 135.
    Pepin M, Govindan M, Barden N. Increased glucocorticoid receptor gene promoter activity after antidepressant treatment. Mol Pharmacol 1992; 41: 1016–22PubMedGoogle Scholar
  136. 136.
    Herman J. In situ hybridization analysis of vasopressin gene transcription in the paraventricular and supraoptic nuclei of the rat: regulation by stress and glucocorticoids. J Comp Neurol 1995; 363: 15–27PubMedGoogle Scholar
  137. 137.
    Mamalaki E, Kvetnansky R, Brady L, et al. Repeated immobilization stress alters tyrosine hydroxylase, corticotropin-releasing hormone and corticosteroid receptor messenger ribonucleic acid levels in rat brain. J Neuroendocrinol 1992; 4(6): 690–5Google Scholar
  138. 138.
    Sawchenko P, Brown E, Chan R, et al. The paraventricular nucleus of the hypothalamus and the functional neuroanatomy of visceromotor responses to stress. Prog Brain Res 1996; 107: 201–22PubMedGoogle Scholar
  139. 139.
    Fuchs E, Kramer M, Hermes B, et al. Psychological stress in tree shrews: clomipramine counteracts behavioural and endocrine changes. Pharmacol Biochem Behav 1996; 54(1): 219–28PubMedGoogle Scholar
  140. 140.
    Plaznik A, Palejko W, Stefanski R, et al. Open field behaviour of rats reared in different social conditions: the effects of stress and imipramine. Pol J Pharmacol 1993; 45(3): 243–52PubMedGoogle Scholar
  141. 141.
    Thiele B, Brink I, Ploch M. Modulation of cytokine expression by Hypericum extract. J Geriatr Psychiatry Neurol 1994; 7: S60–S2PubMedGoogle Scholar
  142. 142.
    Fiebich BL, Höllig A, Lieb K. Inhibition of substance P-induced cytokine synthesis by St John’s wort extracts. Pharmacopsychiatry 2001; 34Suppl. 1: S26–S8PubMedGoogle Scholar
  143. 143.
    Maubach KA, Ruoniak NM, Kramer MS, et al. Novel strategies for pharmacotherapy of depression. Curr Opin Chem Biol 1999; 3: 481–8PubMedGoogle Scholar

Copyright information

© Adis Data Information BV 2003

Authors and Affiliations

  1. 1.Institute of Pharmacology and ToxicologyUniversitätsklinikum MünsterMünsterGermany

Personalised recommendations