Possible Modulation of the Anexiogenic Effects of Vitex Agnus-castus by the Serotonergic System

Document Type : Original Article


1 Department of Animal Biology, Science and Research Campus, Islamic Azad University, Tehran, Iran

2 Tarbiat Moalem University of Tehran, Tehran, Iran

3 Department of Biology, North Tehran Branch, Islamic Azad University, Tehran, Iran

4 Department of Biology, Karaj Branch, Islamic Azad University, Karaj, Iran


There is well documented evidence for the increase in widespread use of complementary and alternative medicine in the treatment of physical and psychiatric symptoms and disorders within the populations. In the present study, we investigated the influence of Vitex agnus-castus (vitex) on anxiety-like behaviors of rats.
Materials and Methods
Elevated plus maze which is one of the methods used for testing anxiety is used in our present study. Rats were orally administrated with vitex for two week. The anxiety test was carried out after two weeks of oral administration of vitex. For evaluating interaction of vitex and serotonergic systems, rats were anaesthetized with ketamine and special cannulas were inserted stereotaxically into the third ventricle (TV) of brain. After 1 week recovery, the effects of serotonegic agents on anxiety were studied.
Oral administration of vitex (100, 200, 300 mg/kg) for two weeks induced an anxiogenic-like effect which was shown through specific decreases in the percentages of open arm time (OAT %) and open arm entries (OAE %). Intra-TV infusion of 5HT1A receptor agonist, 8-OH-DPAT (5, 10 and 25 ng/rat) increased OAT% and OAE%, indicating anxiolytic–like behavior. However, injection of 5HT1A receptor antagonist NAN190 (0.25, 0.5 and 1 µg/rat) produced anxiogenic-like behavior. The most effective dose of 8-OH-DPAT                (10 ng/rat), when co-administered with vitex (100, 200, 300 mg/kg), attenuated the anxiogenic-like effects of vitex significantly. Injection of the less effective dose of NAN190 (0.5 µg/rat), in combination with vitex (100, 200, 300 mg/kg), potentiate anxiogenic effects of vitex.
These results illustrate that 5HT1A receptor is involved in the anxiogenic effects of vitex.


1. Bennett J, Brown C. Use of herbal remedies by patients in a health maintenance organization. J Am Pharm Assoc 2000; 40:353-358.
2. Eisenberg D, Davis R, Ettner S, Appel S, Wilkey S, Van Rompay M, et al. Trends in alternative medicine use in the United States, 1990-1997: results of a follow-up national survey. JAMA 1998; 280:1569.
3. Niggemann B, Grüber C. Side effects of complementary and alternative medicine. Allergy 2003; 58:707-716.
4. Wong A, Smith M, Boon H. Herbal remedies in psychiatric practice. Arch Gen Psychiatry 1998; 55:1033.
5. MacGregor F, Abernethy V, Dahabra S, Cobden I, Hayes P. Hepatotoxicity of herbal remedies. Brit Med J 1989; 299:1156.
6. Cossuta D, Simándi B, Vági E, Hohmann J, Prechl A, Lemberkovics É, et al. Supercritical fluid extraction of Vitex agnus- castus fruit.  J Supercrit Fluids 2008; 47:188-194.
7. Wuttke W, Jarry H, Christoffel V, Spengler B, Seidlova-Wuttke D. Chaste tree (Vitex agnus-castus)-pharmacology and clinical indications. Phytomedicine 2003; 10:348-357.
8. Webster D, Lu J, Chen S, Farnsworth N, Wang Z. Activation of the [mu]-opiate receptor by Vitex agnus-castus methanol extracts: Implication for its use in PMS. J ethnopharmacol  2006; 106:216-221.
9. Van Die M, Burger H, Bone K, Cohen M, Teede H. Hypericum perforatum with Vitex agnus-castus in menopausal symptoms: a randomized, controlled trial. Menopause 2009; 16:156.
10. Kessler R, Chiu W, Demler O, Walters E. Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the national comorbidity survey replication. Arch Gen Psychiatry 2005; 62:617.
11. Deacon B, Lickel J and Abramowitz JS.  Medical utilization across the anxiety disorders. . J Anxiety Disorders 2008; 22: 344-350
12. Kessler R, Soukup J, Davis R, Foster D, Wilkey S, Van Rompay M, et al. The use of complementary and alternative therapies to treat anxiety and depression in the United States. Am J Psychiatry 2001; 158:289.
13. Ernst E. Herbal remedies for anxiety-a systematic review of controlled clinical trials. Phytomedicine 2006; 13:205.
14. Zarrindast M, Babapoor-Farrokhran S, Rezayof A. Involvement of opioidergic system of the ventral hippocampus, the nucleus accumbens or the central amygdala in anxiety-related behavior. Life sciences 2008; 82:1175-1181.
15. Lesch K, Bengel D, Heils A, Sabol S, Greenberg B, Petri S, et al. Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science 1996; 274:1527.
16. Simon P, Dupuis R, Costentin J. Thigmotaxis as an index of anxiety in mice. Influence of dopaminergic transmissions. Behav Brain Res 1994; 61:59-64.
17. Paxinos G. The Rat Brain in Stereotaxic Coordinates. 6th ed. San Diego: Elsevier Academic Press; 2007.
18. Degroot A, Kashluba S, Treit D. Septal GABAergic and hippocampal cholinergic systems modulate anxiety in the plus-maze and shock-probe tests. Pharmacol Biochem Behav 2001; 69:391-399.
19. Pellow S, Chopin P, File SE, Briley M. Validation of open:closed arm entries in an elevated plus-maze as a measure of anxiety in the rat. J Neurosci Methods 1985; 14:149-167.
20. Pellow S. Anxiolytic and anxiogenic drug effects in a novel test of anxiety: are exploratory models of anxiety in rodents valid? Methods Find Exp Clin Pharmacol 1986; 8:557-565.
21. Rodgers RJ, Johnson NJ. Factor analysis of spatiotemporal and ethological measures in the murine elevated plus-maze test of anxiety. Pharmacol Biochem Behav 1995; 52:297-303.
22. Zarrindast MR, Solati J, Oryan S, Parivar K. Effect of intra-amygdala injection of nicotine and GABA receptor agents on anxiety-like behaviour in rats. Pharmacology 2008; 82:276-284.
23. Thomas K, Coleman P. Use of complementary or alternative medicine in a general population in Great Britain. Results from the National Omnibus survey. J Public Health  2004; 26:152.
24. Lengacher C, Bennett M, Kip K, Keller R, LaVance M, Smith L, et al. Frequency of use of complementary and alternative medicine in women with breast cancer. Onc Nurs Society 2002;29:1445-1452.
25. van der Watt G, Laugharne J, Janca A. Complementary and alternative medicine in the treatment of anxiety and depression. Curr Opin Psychiatry 2008; 21:37.
26. Barnes P, Powell-Griner E, McFann K, Nahin R. Complementary and alternative medicine use among adults: United States: Elsevier; 2004.p.54-71.
27. Angell M, Kassirer J. Alternative medicine--the risks of untested and unregulated remedies. N Engl J Med 1998 ;339:839.
28. Kozyrskyj A. Herbal products in Canada. How safe are they? Can Fam Physician 1997; 43:697.
29. Ernst E. Herbal medicines: balancing bene ts and risks. Dietary supplements and health 2007; 29:154.
30. Akimova E, Lanzenberger R, Kasper S. The serotonin-1A receptor in anxiety disorders. Biol Psychiatry 2009; 66:627-635.
31. Lanzenberger R, Mitterhauser M, Spindelegger C, Wadsak W, Klein N, Mien L, et al. Reduced serotonin-1A receptor binding in social anxiety disorder. Biol Psychiatry 2007; 61:1081-1089.
32. Goldberg H, Finnerty R. The comparative efficacy of buspirone and diazepam in the treatment of anxiety. Am J Psychiatry 1979; 136:1184.
33. Gammans R, Stringfellow J, Hvizdos A, Seidehamel R, Cohn J, Wilcox C, et al. Use of buspirone in patients with generalized anxiety disorder and coexisting depressive symptoms. Neuropsychobiology 1992; 25:193-201.
34. Artigas F, Romero L, de Montigny C, Blier P. Acceleration of the effect of selected antidepressant drugs in major depression by 5-HT1A antagonists. Trends Neurosci 1996; 19:378-383.
35. Heisler L, Chu H, Brennan T, Danao J, Bajwa P, Parsons L, et al. Elevated anxiety and antidepressant-like responses in serotonin 5-HT1A receptor mutant mice. Proc Natl Acad Sci 1998; 95:15049.
36. Belcheva I, Belcheva S, Petkov V, Hadjiivanova C, Petkov V. Behavorial responses to the 5-HT1A receptor antagonist NAN190 injected into rat CA1 hippocampal area. Gen Pharmacol 1997; 28:435.
37. File S, Gonzalez L, Andrews N. Comparative study of pre-and postsynaptic 5-HT1A receptor modulation of anxiety in two ethological animal tests. J Neurosci 1996; 16:4810.
38. Kennett G, Marcou M, Dourish C, Curzon G. Single administration of 5-HT1A agonists decreases 5-HT1A presynaptic, but not postsynaptic receptor-mediated responses: relationship to antidepressant-like action. Eur J Pharmacol 1987; 138:53-60.
39. Jolas T, Schreiber R, Laporte A, Chastanet M, De Vry J, Glaser T, et al. Are postsynaptic 5-HT1A receptors involved in the anxiolytic effects of 5-HT1A receptor agonists and in their inhibitory effects on the firing of serotonergic neurons in the rat? J Pharmacol Exp Ther 1995; 272:920.
40. Chua P, Krams M, Toni I, Passingham R, Dolan R. A functional anatomy of anticipatory anxiety. NeuroImage 1999; 9:563-571.
41. Kazer J, Sharkey A. The septo-hippocampal system and anxiety:  Artificial Neural Networks 1999; 1: 389 - 394.
42. Davis M. The role of the amygdala in fear and anxiety. Ann Rev Neurosci 1992; 15:353-375.