Involvement of Estrogen Receptors in the Anxiolytic-Like Effect of Phytoestrogen Genistein in Rats with 12-Weeks Postovariectomy


Phytoestrogens are natural compounds found in some vegetables, and they replicate many of the physiochemical and physiological properties of estrogens, including the regulation of mood. The phytoestrogen genistein exerts anxiolytic-like effects in rats with a chronic absence of ovarian hormones, but the mechanism involved in this effect remains to be explored. The present study explored the participation of estrogen receptor-β in the anxiolytic-like effect of genistein (1.0 mg/kg, i.p., for 4 days) in Wistar rats with 12-weeks postovariectomy, considered as experimental model of post-surgical menopause. In the light/dark test, a useful tool for anxiety study and for the screening of anxiolytic drugs, genistein reduced the latency to enter and increased the time spent in the light compartment and significantly increased the frequency and time spent exploring the light compartment compared with the control group, which is considered as an anxiolytic-like effect at experimental level. All behavioral effects produced by genistein in the light/dark test were blocked by previous tamoxifen administration (5.0 mg/kg, s.c., for 6 days), a non selective antagonist for estrogen receptor-β. The effects produced by genistein or tamoxifen in this test were not related to significant changes in general motor activity evaluated in the open field test. In conclusion, the specific contribution of present investigation was identify that estrogen receptor-β is involved in the anxiolytic-like effect produced by phytoestrogen genistein in rats with a long-term absence of ovarian hormones; supporting the hypothesis that estrogen receptor-β participates in the regulation of anxiety associated with low concentration of ovarian hormones and in the anxiolytic-like effects produced by natural estrogenic compounds such as phytoestrogens.

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Rodríguez-Landa, J. , Hernández-López, F. and Saavedra, M. (2012) Involvement of Estrogen Receptors in the Anxiolytic-Like Effect of Phytoestrogen Genistein in Rats with 12-Weeks Postovariectomy. Pharmacology & Pharmacy, 3, 439-446. doi: 10.4236/pp.2012.34059.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] E.D. Lephart, T.W. West, K.S. Weber, R.W. Rhees, K.D.R. Setchell, H. Adlercreutz and D.T. Lund, “Neurobehavioral effects of dietary soy phytoestrogens,” Neurotoxicology Teratology, Vol. 24, No. 1, 2002, pp. 5-16. doi: 10.1016/S0892-0362(01)00197-0
[2] T. Oseni, R. Patel, J. Pyle and V.C. Jordan, “Selective estrogen receptor modulators and phytoestrogens,” Planta Medica, Vol. 74, No. 13, 2008, pp. 1656-1665. doi: 10.1055/s-0028-1088304
[3] L. Pil?áková, I. Riecansky and F. Jagla, “The physiological actions of isoflavone phytoes-trogens,” Physiological Research, Vol. 59, No. 5, 2010, pp. 651-664.
[4] P. Moutsatsou, “The spectrum of phytoestrogens in nature: our knowledge is expanding,” Hormones (Athens), Vol. 6, No. 3, 2007, pp. 173-193.
[5] G. Pisani, L. Facioni, F. Fiorani and G. Pisan, “Psychosexual problems in menopause,” Minerva Ginecologica, Vol. 50, No. 3, 1998, pp. 77-81.
[6] A.M. Paoletti, S. Floris, M. Mannias, M. Orru, D. Crippa, R. Orlandi, M.M. Del Zompo and G.B. Melis, “Evidence that cyproterone acetate improves psychological symptoms and enhances the activity of the dopaminergic system in postmenopause,” Journal of Clinical Endocrinology and Metabolism, Vol. 86, No. 2, 2001, pp. 608-612. doi: 10.1210/jc.86.2.608
[7] T.M.K. Schult, K.E. Ensrud, T. Blackwell, B. Ettinger, R. Wallace and J.A. Tice, “Effect of isoflavones on lipid and bone turnover markers in menopausal women,” Maturitas, Vol. 48, No. 3, 2004, pp. 209-218. doi: org/10.1016/j.maturitas.2003.09.027
[8] R. D'Anna, M.L. Cannata, M. Atteritano, F. Cancellieri, F. Corrado, G. Baviera, O. Triolo, F. Antico, A. Gaudio, N. Frisina, A. Bitto, F. Polito, L. Minutoli, D. Altavilla, H. Marini and F. Squadrito, “Effects of the phytoestrogen genistein on hot flushes, endometrium, and vaginal epithelium in postmenopausal women: a 1-year randomized, double-blind, placebo-controlled study,” Meno-pause, Vol. 14, No. 4, 2007, pp. 648-655. doi: 10.1097/01.gme.0000248708.60698.98
[9] M. Atteritano, F. Pernice, S. Mazzaferro, S. Mantuano, A. Frisina, R. D'Anna, M.L. Cannata, A. Bitto, F. Squadrito, N. Frisina and M. Buemi, “Effects of phytoestrogen genistein on cytogenetic biomarkers in postmenopausal women: 1 year randomized, placebo-controlled study,”. European Journal of Pharmacology, Vol. 589, No. 1-3, 2008, pp. 22-26. doi: org/10.1016/j.ejphar.2008.04.049
[10] A.L. Murkies, C. Lombard, B.J.G. Strauss, G. Wilcox, H.G. Burger and M.S. Morton, “Dietary flour supplementation decreases post-menopausal hot flushes: effect of soy and wheat,” Maturitas, Vol. 61, No. 1-2, 2008, pp. 27-33. doi: org/10.1016/0378-5122(95)00899-V
[11] T.D. Lund and E.D. Lephart, “Dietary soy phytoestrogen produce anxiolytic effects in the elevated plusmaze,” Brain Research, Vol. 913, No. 2, 2001, pp. 180-184. doi: org/10.1016/S0006-8993(01)02793-7
[12] E.D. Lephart, K.D.R. Setchell, R.J. Handa and T.D. Lund, “Behavioral effects of endocrine-disrupting substances: phytoestrogens,” Institute of Laboratory Animals Resources Journal, Vol. 45, No. 4, 2004, pp. 443-454.
[13] D.E. Hartley, J.E. Edwards, C.E. Spiller, N. Alom, S. Tucci, P. Seth, M.L. Forsling and S.E. File, “The soya isoflavone content of rat diet can increase anxiety and stress hormone release in the male rat,” Psychopharmacology (Berl.), Vol. 167, No. 1, 2003, pp. 46-53. DOI: doi: 10.1007/s00213-002-1369-7
[14] K. Almstrup, M.F. Fernández, J.H. Petersen, N. Oleam, N.E. Skakkebaek and H. Leffers, “Dual effects of phytoestrogens result in U-shaped dose-response curves,” Environmental Health Perspectives,Vol. 110, No. 8, 2002, pp. 743-748.
[15] N.S. Sapronov and S.B. Kasakova, “Effects of synthetic and plant-derived selective modulators of estrogen receptors on depression-like behavior of female rats,” Bulletin of Experimental Biology and Medicine, Vol. 146, No. 1, 2008, pp. 73-76.
[16] A. Kageyama, H. Sakakibara, W. Zhou, M. Yoshioka, M. Ohsumi, K. Shimoi and H. Yokogoshi, “Genistein regulated serotonergic activity in the hippocampus of ovariectomized rats under forced swim stress,” Bioscience Biotechnology and Biochemistry, Vol. 74, No. 10, 2010, pp. 2005-2010. Doi: org/10.1271/bbb.100238
[17] J.F. Rodríguez-Landa, J.D. Hernández-Figueroa, B.C. Hernández-Calderón and M. Saavedra, “Anxiolytic-like effect of phytoestrogen genistein in rats with long-term absence of ovarian hormones in the black and white model,” Progress in Neuropsychopharmacology and Biological Psychiatry, Vol. 33, No. 2, 2009, pp. 367-372. doi: org/10.1016/j.pnpbp.2008.12.024
[18] M. Bourin and M. Hascoet, “The mouse light/dark box test,” European Journal of Pharmacology, Vol. 463, No. 1-3, 2003, pp. 55-65. doi: org/10.1016/S0014-2999(03)01274-3,
[19] G.G.J.M. Kuiper, J.G. Lemmen, B. Carlsson, J.C. Corton, S.H. Safe, P.T. van der Saag, B. van der Burg and J.A. Gustafsson, “Interaction of estrogenic chemical and phytoestrogens with estrogen receptor ?,” Endocrinology, Vol. 139, No. 10, 1998, pp. 4252-4263. doi: 10.1210/en.139.10.4252
[20] G.G.J.M. Kuiper, B. Carlsson, K. Grandien, E. Enmark, J. H?ggblad, S. Nilsson and J.A. Gustafsson, “Comparison of the ligand binding specificity and transcript tissue distribution of the estrogen receptors α and β”. Endocrinology, Vol. 138, No. 3, 1997, pp. 863-870. doi: 10.1210/en.138.3.863
[21] A.C.W. Pike, A.M. Brzozowski, R.E. Hubbard, T. Bonn, A.G. Thorsell, O. Engstrom, J. Ljunggren, J.A. Gustafsson and M. Carlquist, “Structure of the ligand-binding domain of oestrogen receptor beta in the presence of a partial agonist and full antagonist,” The EMBO Journal, Vol. 18, No. 17, 1999, pp. 4608-4618. doi:10.1093/emboj/18.17.4608
[22] A.C.W. Pike, A.M. Brzozowski, J. Walton, R.E. Hubbard, T. Bonn, J.A. Gustafsson and M. Carlquist, “Structural aspects of agonism and antagonism in the oestrogen receptor,” Biochemical Society Transactions, Vol. 28, No. 4, 2000, pp. 396-400. doi:10.1042/bst0280396
[23] T.D. Lund, T. Rovis, W.C.J. Chung and R.J. Handa, “Novel actions of estrogen receptor-on anxiety-related behaviors,” Endocrinology, Vol. 146, No. 2, 2005, pp. 797-807. doi: 10.1210/en.2004-1158
[24] A.A. Walf and C.A. Frye, “ERβ-Selective estrogen receptor modulators produce antianxiety behavior when administered systemically to ovariectomized rats,” Neuropsychopharmacology, Vol. 30, No. 9, 2005, pp. 1598-1609. doi:10.1038/sj.npp.1300713
[25] A.A. Walf and C.A. Frye, “Estradiol reduces anxiety- and depression-like behavior of aged female mice,” Physiology and Behavior, Vol. 99, No. 2, 2010, 169-174. doi: org/10.1016/j.physbeh.2009.09.017
[26] National Research Council, “Guide for the care and use of laboratory animals: a report of the Institute of Laboratory Animal Resource Committee on the Care and Use of Laboratory Animals,” NIH Publication No. 85-23, revised, Department of Health and Human Services, Washington, DC, 1996.
[27] Secretaría de Agricultura, Ganadería, Desarrollo Rural, Pesca y Alimentación, “Norma Oficial Mexicana NOM-062-ZOO-1999, Especificaciones técnicas para la producción, cuidado y uso de los animales de laboratorio,” México, DF, 1999.
[28] L. Martínez-Mota, C.M. Contreras and M. Saavedra, “Progesterone reduces immobility in rats forced to swim,” Archives of Medical Research, Vol. 30, No. 4, 1999, pp. 286-289. doi: org/10.1016/S0188-0128(99)00024-X,
[29] O. Picazo, E. Estrada-Camarena and A. Hernández-Aragón, “Influence of the post-ovariectomy time frame on the experimental anxiety and the behavioural actions of some anxiolytic agents,” European Journal of Pharmacology, Vol. 530, No. 1-2, 2006, pp. 88-94. doi: org/10.1016/j.ejphar.2005.11.024
[30] A.G. Gutiérrez-García, C.M. Contreras. D.I. Vásquez-Hernández, T. Molina-Jiménez and E. Jácome-Jácome, “Testosterone reduces cumulative burying in female Wistar rats with minimal partici-pation of estradiol,” Pharmacology, Biochemistry, and Behavior, Vol. 93, No. 4, 2009, pp. 406-412. doi: org/10.1016/j.pbb.2009.06.002
[31] M.J. Zuluaga, D. Agrati, M. Pereira, N. Uriarte, A. Fernández-Guasti and A. Ferreira, “Experimental anxiety in the black and white model in cycling, pregnant and lactating rats,” Physiology and Behavior, Vol. 84, No. 2, 2005, pp. 279-286. doi: org/10.1016/j.physbeh.2004.12.004
[32] B. Costall, B.J. Jones, M.E. Kelly, R.J. Naylor and D.M. Tomkins, “Exploration of mice in a black and white test box: validation as a model of anxiety,” Pharmacology, Biochemistry, and Behavior, Vol. 32, No. 3, 1989, pp. 777-785. doi: org/10.1016/0091-3057(89)90033-6,
[33] [A.G. Gutiérrez-García, C.M. Contreras, M.R. Mendoza-López, S. Cruz-Sánchez, O. García-Barradas, J.F. Rodríguez-Landa and B. Bernal-Morales, “A single session of emotional stress produces anxiety in Wistar rats,” Behavioral Brain Research, Vol. 167, No. 1, 2006, pp. 30-35. doi: org/10.1016/j.bbr.2005.08.011
[34] E.S. Onaivi and B.R. Martin, “Neuropharmacological and physiological validation of a computer-controlled two-compartment black and white box for the assessment of anxiety,” Progress in Neuropsychophar-macology and Biological Psychiatry, Vol. 13, No. 6, 1989, pp. 963-976. doi: org/10.1016/0278-5846(89)90047-X
[35] M. Imaizumi, S. Miyazaki and K. Onodera, “Effects of xanthine derivatives in a light/dark test in mice and the contribution of adenosine receptors,” Methods and Findings in Experimental and Clinical Pharmacology, Vol. 16, No. 9, 1994, pp. 639-644.
[36] C.J. Auger and R.M. Forber-Lorman, “Progestin receptor-mediated reduction of anxiety-like behavior in male rats,” PLoS One, Vol. 3, No. 11, 2008, pp. e3606. doi: 10.1371/journal.pone.0003606
[37] A.A. Walf and C.A. Frye, “Estradiol reduces anxiety- and depression-like behavior of aged female mice,” Physiology and Behavior, Vol. 99, No. 2, 2010, pp. 169-174. doi: org/10.1016/j.physbeh.2009.09.017,
[38] T. Shimada, K. Matsumoto, M. Osanai, H. Matsuda, K. Terasawa and H. Watanabe, “The modified light/dark transition test in mice: evaluation of classic and putative anxiolytic and anxiogenic drugs,” General Pharmacology, Vol. 26, No. 1, 1995, pp. 205-210. doi: org/10.1016/0306-3623(94)00148-G,
[39] M.A. Birkett, N.M. Shinday, E.J. Kessler, J.S. Meyer, S. Ritchie and J.K. Rowlett, “Acute anxiogenic-like effects of selective serotonin reuptake inhibitors are attenuated by the benzodiazepine diaze-pam in BALB/c mice,” Pharmacology, Biochemistry, and Be-havior, Vol. 98, No. 4, 2011, pp. 544-551. doi: org/10.1016/j.pbb.2011.03.006,
[40] E.T. Venancio, N.F. Rocha, E.R. Rios, M.L. Feitosa, M.I. Linhares, F.H. Melo, M.S. Matias, F.M. Fonseca, F.C. Sousa, L.K. Leal and M.M. Fonteles, “Anxiolytic-like effect of standardized extract of Justicia pectoralis (SEJP) in mice: involvement of GA-BA/benzodiazepine receptor,” Phytotherapy Research, Vol. 25, No. 3, 2001, pp. 444-450. doi: 10.1002/ptr.3274
[41] B.F. Bradley, N.J. Starkey, S.L. Brown and R.W. Lea, “The effects of prolonged rose odor inhalation in two animal models of anxiety,” Physiology and Behavior, Vol. 92, No. 5, 2007, pp. 931-938. doi: org/10.1016/j.physbeh.2007.06.023,
[42] T. Barkhem, B. Carlsson, Y. Nilsson, E. Enmark, J. Gustafsson and S. Nilsson, “Differential response of estrogen receptor ? and estrogen re-ceptor ? to partial estrogen agonist/antagonists,” Molecular Pharmacology, Vol. 54, No. 1, 1998, pp. 105-112.
[43] E.M. McInerney, K.E. Weis, J. Sun, S. Mosselman and B.S. Katze-nellenbogen, “Transcription activation by the human estrogen receptor subtype β (ERβ) studied with ERβ and ER? receptor chimeras,” Endocrinology, Vol. 139, No. 11, 1998,pp. 4513-4522. doi: 10.1210/en.139.11.4513
[44] T. Watanabe, S. Inoue, S. Ogawa, Y. Ishii, H. Hiroi, K. Ikeda, A. Orimo and M. Muramatsu, “Agonistic effect of tamoxifen is dependent on cell type, ERE-promoter context, and estrogen receptor subtype: functional difference between estrogen receptors α and β,” Biochemical and Biophysical Research Communication, Vol. 236, No. 1, 1997, pp. 140-145. doi: org/10.1006/bbrc.1997.6915
[45] F. Clénet, M. Hascoet, G. Fillion, H. Galons and M Bourin, “Anxiolytic profile of HG1, a 5-HT-moduline antagonist, in three mouse models of anxiety,” European Neuropsychopharmacology, Vol. 14, No. 6, 2004, pp. 449-456. doi: 10.1016/j.euroneuro.2003.12.004
[46] W.H. Peng, C.R. Wu, C.S. Chen, C.F. Chen, Z.C. Leu and M.T. Hsieh, “Anxiolytic effect of berberine on exploratory activity of the mouse in two experimental anxiety models: interaction with drugs acting at 5-HT receptors,” Life Sciences, vol. 75, No. 20, 2004, pp. 2451-2462. doi: org/10.1016/j.lfs.2004.04.032
[47] M. Canonico and P.Y. Scarabin, “Hormone therapy and risk of venous thromboembolism among postmenopausal women,” Climateric, vol. 12, No. 1, 2009, pp. 76-80. doi: 10.1080/13697130903006837
[48] L.J. Martin, S. Minkin and N.F. Boyd, “Hormone therapy, mammographic density, and breast cancer risk,” Maturitas, Vol. 64, No. 1, 2009, pp. 20-26. doi: org/10.1016/j.maturitas.2009.07.009
[49] J.L. Shifren and I. Schiff, “Role of hormone therapy in the management of menopause,” Obstetrics Gynecology, Vol. 115, No. 4, 2010, pp. 839-855. doi: 10.1097/AOG.0b013e3181d41191
[50] M.P. Warren, “Hormone therapy for menopausal symptoms: putting benefits and risks into perspective,” Journal of Family Practice, Vol. 59, No. 12, 2010, pp. E1-7.

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