Abstract
Rationale
Several reports suggest that estrogens possess antidepressant effects and could facilitate the action of some antidepressants.
Objective
To analyze the interaction between three different types of estrogens, 17β-estradiol (E2), ethinylestradiol (EE2) or diethyl-stilbestrol (DES) and the antidepressants, fluoxetine (FLX) or desipramine (DMI) in ovariectomized female rats subjected to an animal model for the study of antidepressant compounds, the forced swimming test (FST).
Methods
The effect of the combination of a sub-optimal dose of FLX (2.5 mg/kg) or DMI (2.5 mg/kg) with a sub-active dose of E2 (10 μg/kg), EE2, (2.5 or 5 μg/kg) or DES (1 mg/kg) was analyzed in both the FST and the open field paradigm.
Results
The combination of a sub-optimal dose of E2 or DES with that of the antidepressant DMI resulted in a clear antidepressant-like effect, evidenced by a significant decrease in immobility accompanied by an increase in climbing behavior. Sub-optimal doses of either E2 or DES also facilitated the antidepressant-like effect of a sub-optimal dose of FLX. In this case, a decrease in immobility with a concomitant increase in swimming behavior was observed. Finally, the combination of EE2 with either DMI or FLX decreased immobility and induced an increase in both swimming and climbing behaviors. All combinations decreased rats’ locomotor activity when evaluated in the open field test.
Conclusion
In the FST estrogens were able to facilitate the action of two different kinds of antidepressants; however, these effects were dependent on the type of estrogen used.
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References
Amsterdam J, García-España F, Fawett J, Quitkin F, Reimherr F, Rosenbaum J, Beasley C (1999) Fluoxetine efficacy in menopausal women with and without estrogen replacement. J Affec Disord 55:11–17
Berlanga C (1988) Potentiating effect of estrogen in patient with treatment-resistant depression. J Clin Psychiatry 42:12
Bernardi M, Vergoni A, Sandrini M, Tagliavini S, Bertolini A (1989) Influence of ovariectomy, estradiol and progesterone on the behavior of mice in experimental model of depression. Physiol Behav 45:1067–1068
Bethea CL, Pecins-Thompson M, Schutzer W, Gundlah C, Lu Z (1998) Ovarian steroids and serotonin neural function. Mol Neurobiol 18:87–122
Biegon A, Reches A, Snyder L, McEwen B (1983) Serotonergic and noradrenergic receptors in the rat brain: modulation by chronic exposure to ovarian hormones. Life Sci 32:2015–2021
Birzniece V, Johansson I-M, Wang M-D, Bäckström T, Olsson T (2002) Ovarian hormone effects on 5-hydroxytryptamine2A and 5-hydroxytryptamine2C receptor mRNA expression in the ventral hippocampus and frontal cortex of female rats. Neurosci Lett 319:157–161
Blier P (2001) Possible neurobiological mechanisms underlying faster onset of antidepressant action. J Clin Psychiatry 62:7–11
Borsini F, Meli A (1988) Is the forced swimming test a suitable model for revealing antidepressant activity? Psychopharmacology 94:147–160
Chang A, Chang S (1999) Nongenomic steroidal modulation of high-affinity serotonin transport. Biochem Biophys Acta 1417:157–166
Chaput Y, Montigny C, Blier P (1991) Presynaptic and post-synaptic modifications of serotonin system by long-term administration of antidepressant treatments. An in vivo electrophysiologic study in the rat. Neuropsychopharmacology 5:219–229
Cryan J, Lucki I (2000) Antidepressant-like behavioral effects mediated by 5-hydroxytryptamine2C receptors. J Pharmacol Exp Ther 295:1120–1126
Cyr M, Landry M, Di Paolo T (2000) Modulation by estrogen-receptor directed drugs of 5-hydroxytryptamine-2A receptors in rat brain. Neuropsychopharmacology 23:69–78
Detke M, Rickels M, Lucki I (1995) Active behaviors in the rat forced swimming test differentially activated by serotonergic and noradrenergic antidepressants. Psychopharmacology 121:66–72
Duman R (1999) The neurochemistry of mood disorders: preclinical studies. In: Charney D, Nestler E, Bunney B (eds). Neurobiology of mental Illness, 1st edn. Oxford University Press, Oxford, pp 333–347
Epperson C, Wisner K, Yamamoto B (1999) Gonadal steroids in the treatment of mood disorders. Psychosom Med 61:676–697
Espejo E, Minano F (1999) Prefrontocortical dopamine depletion induces antidepressant-like effects in rats and alters the profile of desipramine during Porsolt’s test. Neuroscience 88:609–615
Estrada-Camarena E, Contreras CM, Saavedra M, Luna-Baltazar I, López-Rubalcava C (2002) Participation of the lateral septal nuclei (LSN) in the antidepressant-like actions of progesterone in the forced swimming test (FST). Behav Brain Res 134:175–183
Estrada-Camarena E, Fernández-Guasti A, López-Rubalcava L (2003) Antidepressant-like effect of different estrogenic compounds in the forced swimming test. Neuropsychopharmacology 28:830–838
Galea L, Wide J, Barr A (2001) Estradiol alleviates depressive-like symptoms in a novel animal model of post-partum depression. Behav Brain Res 122:1–9
Genazzani A, Spinetti A, Gallo R, Bernardi F (1999) Menopause and the central nervous system: intervention options. Maturitas 31:103–110
Ghraf R, Michel M, Hiemke C, Knuppen R (1983) Competition by monophenolic estrogens and catecholestrogens for high-affinity uptake of [3H] (−)-norepinephrine into synaptosomes from rat cerebral cortex and hypothalamus. Brain Res 277:163–168
Halbreich U, Kahn L (2001) Role of estrogen in the aetiology and treatment of mood disorders. CNS Drugs 15:797–817
Harkin A, Kelly JP, McNamara M, Connor TJ, Dredge K, Redmond A, Leonard BE (1999) Activity and onset of action of reboxetine and effect of combination with sertraline in an animal model of depression. Eur J Pharmacol 8:123–132
Heal D, Bristow L, De Souza R, Bloomfield J, Hurst E, Elliot J (1988) The influence of injection of estradiol to female rats on changes in α2- and β-adrenoceptor function induced by repeated administration of desipramine or electroconvulsive shock. Neuropharmacology 27:1151–1159
Hendrick V, Altshuler L, Suri R (1998) Hormonal changes in the post-partum and implications for post-partum depression. Psychosomatics 39:93–101
Hiemke C, Bruder D, Poetz B, Ghraf R (1985) Sex-specific effects of estradiol on hypothalamic noradrenaline turnover in gonadectomized rats. Exp Brain Res 59:68–72
Holschneider D, Kumazawa T, Chen K, Shih J (1998) Tissue-specific effects of estrogen on monoamino oxidase A and B in the rat. Life Sci 63:155–160
Jensvold M (1996) Non-pregnant reproductive-age women. Part II: exogenous sex steroid hormones and psychopharmacology. In: Jensvold M, Halbreich U, Hamilton J (eds) Psychopharmacology and woman: sex, gender and hormones. American Psychiatric Press, Arlington, Va., pp 170–190
Karkarnias G, Li C-S, Etgen M (1997) Estradiol reduction of α2-adrenoceptor binding in female rat cortex is correlated with decreases in α2A/D-adrenoceptor messenger RNA. Neuroscience 81:593–597
Kitada Y, Miyauchi T, Satoh A, Satoh S (1981) Effects of antidepressants in the rat forced swimming test. Eur J Pharmacol 72:146–152
Klaiber E, Broverman D, Vogel W, Kobayashi T (1979) Estrogen therapy for severe persistent depressions in women. Arch Gen Psychiatry 36:550–554
Li Q, Muma A, Van de Kar L (1996) Chronic fluoxetine induces a gradual desensitization of 5-HT1A receptors: reductions in hypothalamic and midbrain Gi and G0 proteins and in neuroendocrine responses to 5-HT1A agonist. J Pharmacol Exp Ther 279:1035–1042
Li Q, Muma A, Battaglia G, Van de Kar L (1997) Fluoxetine gradually increases [125I]DOI-label 5-HT2A/2C receptors in the hypothalamus with changing the levels of Gq- and G11-proteins. Brain Res 775:225–228
López-Rubalcava C, Lucki I (2000) Strain differences in the behavioral effects of antidepressant drugs in the rat forced swimming test. Neuropsychopharmacology 22:191–199
Lucki I (1997) The forced swimming test as a model for core and component behavioral effects of antidepressant drugs. Behav Pharmacol 8:523–532
Ma Z-Q, Violani E, Villa F, Picotti G, Maggi A (1995) Estrogenic control of monoamine oxidase A activity in human neuroblastoma cells expressing physiological concentrations of estrogen receptor. Eur J Pharmacol 284:171–176
Martínez-Mota L, Estrada-Camarena E, López-Rubalcava C, Contreras CM, Fernández-Guasti A (2000) Interaction of desipramine with steroid hormones on experimental anxiety. Psychoneuroendocrinology 25:109–120
Martínez-Mota L, Estrada-Camarena E, López-Rubalcava C (2003) Indorenate produces antidepressant-like actions in the rat forced swimming test via 5-HT1A receptors. Psychopharmacology 165:60–66
McEwen B, Alves S (1999) Estrogen actions in the central nervous system. Endocrine Rev 20:279–307
McEwen B, Akama K, Alves S, Brake W, Bulloch K, Lee S et al. (2001) Tracking the estrogen receptor in neurons: implications for estrogen-induced synapse formation. Proc Natl Acad Sci USA 98:7093–7100
Mendelson S, McKittrick C, McEwen B (1993) Autoradiographic analyses of the effects of estradiol benzoate on [3H]paroxetine binding in the cerebral cortex and dorsal hippocampus of gonadectomized male and female rats. Brain Res 601:299–302
Michel M, Rother A, Hiemke C, Ghraf R (1987) Inhibition of synaptosomal high-affinity uptake of dopamine and serotonin by estrogen agonists and antagonists. Biochem Pharmacol 36:3175–3180
Mize A, Alper R (2000) Acute and long-term effects of 17β-estradiol on Gi/0 coupled neurotransmitter receptor function in female rat brain as assessed by agonist-stimulated [35S] GTPγS binding. Brain Res 859:326–333
Mize A, Poisner A, Alper R (2001) Estrogens act in rat hippocampus and frontal cortex to produce rapid, receptor-mediated decreases in serotonin 5-HT1A receptor function. Neuroendocrinology 73:166–174
Mongeau R, Blier P, Montigny C (1997) The serotonergic and noradrenergic systems of the hippocampus: their interactions and the effects of antidepressant treatments. Brain Res Rev 23:145–195
Okada M, Hayashi n, Kometani M, Nakao K, Inukai T (1997) Influences of ovariectomy and continuous replacement of 17 β-estradiol on the tail skin temperature and behavior in the forced swimming test in rats. Jpn J Pharmacol 73:93–96
Oppenheim G (1983) Estrogen in the treatment of depression: neuropharmacological mechanisms. Biol Psychiatry 18:721–725
Page M, Detke M, Dalvi A, Kirby L, Lucki I (1999) Serotonergic mediation of the effects of fluoxetine, but not desipramine, in the rat forced swimming test. Psychopharmacology 147:162–167
Piñeyro G, Blier P (1999) Autoregulation of serotonin neurons: role in antidepressant drug action. Pharmacol Rev 51:533–591
Prange A (1972) Estrogen may well affect response to antidepressant. JAMA 219:143–144
Porsolt R, Le Pichon M, Jalfre M (1977) Depression: a new animal model sensitive to antidepressant treatments. Nature 266:730–732
Porsolt R, Anton G, Blavet N, Jalfre M (1978) Behavioral despair in rats: a new model sensitive to antidepressant treatments. Eur J Pharmacol 47:379–391
Raap D, Van de Kar L (1999) Selective serotonin reuptake inhibitors and neuroendocrine function. Life Sci 65:1217–1235
Raap D, DonCarlos L,García F, Muma N, Wolf W, Battaglia A, Van de Kar L (2000) Estrogen desensitizes 5-HT1A receptors and reduces levels of Gz,Gi1 and Gi3 proteins in the hypothalamus. Neuropharmacology 39:1823–1832
Rachman I, Unnerstall J, Pfaff D, Cohen R (1998) Estrogen alters behavior and forebrain c-fos expression in ovariectomized rats subjected to the forced swim test. Proc Natl Acad Sci USA 95:13941–13946
Richardson T, Robinson R (2000) Menopause and depression: a review of psychologic function and sex steroid neurobiology during the menopause. Prim Care Update Obstet/Gynecol 7:215–223
Robinson G (2001) Psychotic and mood disorders associated with the perimenopausal period. Epidemiology, aetiology and management. CNS Drugs 15:175–184
Schneider M, Small G, Hamilton S, Bystrisky A, Nemeroff C, Meyers B (1997) Estrogen replacement and response to fluoxetine in surgically menopausal women. Am J Geriatr Psychiatr 5:97–106
Schneider L, Small G, Clary CM (2001) Estrogen replacement therapy and antidepressant response to sertraline in older depressed women. Am J Geriatr Psychiatr 9:393–399
Shapira B, Oppenheim G, Zohar J, Segal M, Malach D, Belmaker R (1985) Lack of efficacy of estrogen supplementation to imipramine in resistant female depressives. Biol Psychiatry 20:570–583
Sherwin B (1988) Affective changes with estrogen and androgen replacement therapy in surgically menopausal women. J Affect Disord 14:177–187
Somani S, Khurana R (1973) Mechanism of estrogen-imipramine interaction. JAMA 23:560
Stahl S (1997) Sex therapy in psychiatry treatment has a new partner: reproductive hormones. J Clin Psychiatry 58:468–469
Stahl S (1998a) Basic psychopharmacology of antidepressants. Part 2: estrogen as an adjunct to antidepressant treatment. J Clin Psychiatry 59:15–24
Stahl S (1998b) Augmentation of antidepressants by estrogen. Psychopharmacol Bull 34:319–321
Stahl S (1998c) Basic psychopharmacology of antidepressants. Part 1: antidepressants have seven distinct mechanisms of action. J Clin Psychiatry 59:5–14
Sumner B, Fink G (1995) Estrogen increases the density of 5-hydroxytryptamine2A receptors in cerebral cortex and nucleus accumbens in female rat . J Steroid Biochem 54:15–20
Uphouse L (2000) Female gonadal hormones, serotonin and sexual receptivity. Brain Res Rev 33:242–257
Wilkinson M, Herdon H (1982) Diethylstilbestrol regulates the number of α- and β-adrenergic binding sites in incubated hypothalamus and amygdala. Brain Res 248:79–85
Wilson M, Dwyer K, Roy E (1988) Direct effects of ovarian hormones on antidepressant binding sites. Brain Res 22:181–185
Acknowledgements
Authors wish to thank to Dr. Gabriela Rodríguez-Manzo for her comments on the manuscript, to Isabel Beltrán-Villalobos and José Manuel Pérez-Luna for technical assistance and Eli-Lilly Company (México) for their kind donation of FLX. The present work was partially supported by CONACyT grant 40895; EE-C received a doctoral fellowship from CONACyT (96 338).
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Estrada-Camarena, E., Fernández-Guasti, A. & López-Rubalcava, C. Interaction between estrogens and antidepressants in the forced swimming test in rats. Psychopharmacology 173, 139–145 (2004). https://doi.org/10.1007/s00213-003-1707-4
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DOI: https://doi.org/10.1007/s00213-003-1707-4