Skip to main content
SpringerLink
Log in

17α-ethinyl estradiol attenuates depressive-like behavior through GABAA receptor activation/nitrergic pathway blockade in ovariectomized mice

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Objectives

This study was performed to investigate the antidepressant-like effect of 17α-ethinyl estradiol (EE2) in ovariectomized (OVX) mice and the possible role of nitrergic and gamma aminobutyric acid (GABA)ergic pathways in this paradigm.

Methods

Bilateral ovariectomy was performed in female mice, and different doses of EE2 were intraperitoneally injected either alone or combined with GABAA agonist, diazepam, GABAA antagonist, flumazenil, non-specific nitric oxide synthase (NOS) inhibitor, Nω-nitro-L-arginine methyl ester (L-NAME), specific nNOS inhibitor, 7-nitroindazole (7-NI), a nitric oxide (NO) precursor, L-arginine, and selective PDE5I, sildenafil. After locomotion assessment, immobility times were recorded in the forced swimming test (FST) and tail suspension test (TST). Moreover, hippocampal nitrite concentrations were measured in the examined groups.

Results

Ten days after ovariectomy, a significant prolonged immobility times were observed. EE2 (0.3 and 1μg/kg and 0.03, 0.1, and 1mg/kg) caused antidepressant-like activity in OVX mice in FST and TST. Diazepam (1 and 5mg/kg), L-NAME (30mg/kg), and 7-NI (100mg/kg) significantly reduced the immobility times. Co-administration of minimal and sub-effective doses of EE2 and diazepam (0.3μg/kg and 0.5mg/kg, respectively) exerted a significant antidepressant-like effect. The same effect was observed in combination of minimal and sub-effective doses of EE2 and either L-NAME or 7-NI. Moreover, combination of minimal and sub-effective doses of EE2, diazepam either L-NAME, or 7-NI emphasized the significant robust antidepressant-like activity.

Conclusions

The study has demonstrated that lowest dose of EE2 exerts a significant antidepressant-like behavior. It is suggested that suppression of NO system, as well as GABAA activation, may be responsible for antidepressant-like activity of EE2 in OVX mice. Moreover, GABAA activation may inhibit nitrergic pathway.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10
Fig. 11

Similar content being viewed by others

Abbreviations

OVX:

Ovariectomized

EE2 :

17α-ethinyl estradiol

GABA:

Gamma aminobutyric acid

NO:

Nitric oxide

cGMP:

Cyclic GMP

L-arg:

L-arginine

L-NAME:

Nω-nitro-L-arginine methyl ester

7-NI:

7-Nitroindazole

NOS:

Nitric oxide synthase

eNOS:

Endothelial NOS

nNOS:

Neuronal NOS

PDE5I:

Phosphodiesterase type 5 inhibitor

FST:

Forced swimming test

TST:

Tail suspension test

NE:

Norepinephrine

References

  • Avis NE, Brambilla D, McKinlay SM, Vass K (1994) A longitudinal analysis of the association between menopause and depression. Results from the Massachusetts Women’s Health Study. Ann Epidemiol 4:214–220

    Article  CAS  PubMed  Google Scholar 

  • Bao AM, Ji YF, Van Someren EJ, Hofman MA, Liu RY, Zhou JN (2004) Diurnal rhythms of free estradiol and cortisol during the normal menstrual cycle in women with major depression. Hormone Behav 45:93–102

    Article  CAS  Google Scholar 

  • Bartholini G (1984) Experimental basis for the antidepressant action of the GABA receptor agonist progabide. Neurosci Lett 47:351–355

    Article  CAS  PubMed  Google Scholar 

  • Bernardi M, Vergoni A, Sandrini M, Tagliavini S, Bertolini A (1989) Influence of ovariectomy, estradiol and progesterone on the behavior of mice in an experimental model of depression. Physiol Behav 45:1067–1068

    Article  CAS  PubMed  Google Scholar 

  • Coker RK, Laurent GJ (1998) Pulmonary fibrosis: cytokines in the balance. Eur Respir J 11:1218–1221

    Article  CAS  PubMed  Google Scholar 

  • da Silva GDL, Matteussi AS, dos Santos ARS, Calixto JB, Rodrigues ALS (2000) Evidence for dual effects of nitric oxide in the forced swimming test and in the tail suspension test in mice. Neurorep 11:3699–3702

    Article  Google Scholar 

  • Daabees TT, Mohy El-Din MM, Zeitoun R, Makar AB (1981) Injectable and oral contraceptive steroids in relation to some neurotransmitters in the rat brain. Biochem Pharmacol 30:1581–1585

    Article  CAS  PubMed  Google Scholar 

  • Delgado PL (2004) Common pathways of depression and pain. J Clin Psych 65(Suppl 12):16–19

    Google Scholar 

  • Dhingra D, Goyal PK (2008) Inhibition of MAO and GABA: probable mechanisms for antidepressant-like activity of Nardostachys jatamansi DC. in mice. Ind J Exp Biol 46:212

    Google Scholar 

  • Dwason G, Jue S, Brogden R (1984) Alprazolam: a review of its pharmacodynamic properties and efficacy in the treatment of anxiety and depression. Drug 27:132–147

    Article  Google Scholar 

  • Earley C, Leonard B (1978) GABA and gonadal hormones. Brain Res 155:27–34

    Article  CAS  PubMed  Google Scholar 

  • Esplugues JV (2002) NO as a signalling molecule in the nervous system. Br J Pharmacol 135:1079–1095

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fleischmann A, Makman MH, Etgen AM (1990) Ovarian steroids increase veratridine-induced release of amino acid neurotransmitters in preoptic area synaptosomes. Brain Res 507:161–163

    Article  CAS  PubMed  Google Scholar 

  • Fragata IR, Ribeiro JA, Sebastião AM (2006) Nitric oxide mediates interactions between GABAA receptors and adenosine A1 receptors in the rat hippocampus. Eur J Pharmacol 543:32–39

    Article  CAS  PubMed  Google Scholar 

  • Ghasemi M, Montaser-Kouhsari L, Shafaroodi H, Nezami BG, Ebrahimi F, Dehpour AR (2009a) NMDA receptor/nitrergic system blockage augments antidepressant-like effects of paroxetine in the mouse forced swimming test. Psychopharmacol 206:325–333

    Article  CAS  Google Scholar 

  • Ghasemi M, Sadeghipour H, Mosleh A, Sadeghipour HR, Mani AR, Dehpour AR (2008) Nitric oxide involvement in the antidepressant-like effects of acute lithium administration in the mouse forced swimming test. Eur Neuropsychopharmacol 18:323–332

    Article  CAS  PubMed  Google Scholar 

  • Ghasemi M, Sadeghipour H, Poorheidari G, Dehpour AR (2009b) A role for nitrergic system in the antidepressant-like effects of chronic lithium treatment in the mouse forced swimming test. Behav Brain Res 200:76–82

    Article  CAS  PubMed  Google Scholar 

  • Gingerich S, Krukoff TL (2005) Estrogen modulates endothelial and neuronal nitric oxide synthase expression via an estrogen receptor β-dependent mechanism in hypothalamic slice cultures. Endocrinol 146:2933–2941

    Article  CAS  Google Scholar 

  • Gotti S, Martini M, Pradotto M, Viglietti-Panzica C, Panzica G (2009) Rapid changes on nitrinergic system in female mouse hippocampus during the ovarian cycle. J Chem Neuroanat 38:117–123

    Article  CAS  PubMed  Google Scholar 

  • Harkin AJ, Bruce KH, Craft B, Paul IA (1999) Nitric oxide synthase inhibitors have antidepressant-like properties in mice: 1. Acute treatments are active in the forced swim test. Eur J Pharmacol 372:207–213

    Article  CAS  PubMed  Google Scholar 

  • Harvey BH, Duvenhage I, Viljoen F, Scheepers N, Malan SF, Wegener G et al (2010) Role of monoamine oxidase, nitric oxide synthase and regional brain monoamines in the antidepressant-like effects of methylene blue and selected structural analogues. Biochem Pharmacol 80:1580–1591

    Article  CAS  PubMed  Google Scholar 

  • Heydarpour P, Salehi-Sadaghiani M, Javadi-Paydar M, Rahimian R, Fakhfouri G, Khosravi M et al (2013) Estradiol reduces depressive-like behavior through inhibiting nitric oxide/cyclic GMP pathway in ovariectomized mice. Hormone Behav 63:361–369

    Article  CAS  Google Scholar 

  • Hu Y, Wu DL, Luo CX, Zhu LJ, Zhang J, Wu HY et al (2012) Hippocampal nitric oxide contributes to sex difference in affective behaviors. Proc Natl Acad Sci U S A 109:14224–14229

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kessler RC, Merikangas KR, Wang PS (2007) Prevalence, comorbidity, and service utilization for mood disorders in the United States at the beginning of the twenty-first century. Ann Rev Clin Psychol 3:137–158

    Article  Google Scholar 

  • Lam RW, Wan D, Cohen NL, Kennedy SH (2002) Combining antidepressants for treatment-resistant depression: a review. J Clin Psych 63:685–693

    Article  CAS  Google Scholar 

  • López-Jaramillo P, Terán E, Molina G, Rivera J, Lozano A (1996) Oestrogens and depression. Lancet 348:135–136

    Article  PubMed  Google Scholar 

  • Ludka FK, Zomkowski AD, Cunha MP, Dal-Cim T, Zeni AL, Rodrigues AL, Tasca CI (2012) Acute atorvastatin treatment exerts antidepressant-like effect in mice via the L-arginine-nitric oxide-cyclic guanosine monophosphate pathway and increases BDNF levels. Eur Neuropsychopharmacol 23(5):400–412

    Article  PubMed  Google Scholar 

  • Luine VN, Grattan DR, Selmanoff M (1997) Gonadal hormones alter hypothalamic GABA and glutamate levels. Brain Res 747:165–168

    Article  CAS  PubMed  Google Scholar 

  • Maggi A, Perez J (1986) Estrogen induced up-regulation of γ-aminobutyric acid receptors in the CNS of rodents. J Neurochem 47:1793–1797

    Article  CAS  PubMed  Google Scholar 

  • Mantovani M, Pértile R, Calixto JB, Santos AR, Rodrigues ALS (2003) Melatonin exerts an antidepressant-like effect in the tail suspension test in mice: evidence for involvement of N-methyl-d-aspartate receptors and the L-arginine-nitric oxide pathway. Neurosci Lett 343:1–4

    Article  CAS  PubMed  Google Scholar 

  • Mirbaha H, Tabaeizadeh M, Shaterian-Mohammadi H, Tahsili-Fahadan P, Dehpour AR (2009) Estrogen pretreatment modulates morphine-induced conditioned place preference in ovariectomized mice. Pharmacol Biochem Behav 92:399–403

    Article  CAS  PubMed  Google Scholar 

  • Mombereau C, Kaupmann K, Froestl W, Sansig G, van der Putten H, Cryan JF (2004) Genetic and pharmacological evidence of a role for GABAB receptors in the modulation of anxiety- and antidepressant-like behavior. Neuropsychopharmacol 29:1050–1062

    Article  CAS  Google Scholar 

  • Murphy DD, Cole NB, Greenberger V, Segal M (1998) Estradiol increases dendritic spine density by reducing GABA neurotransmission in hippocampal neurons. J Neurosci 18:2550–2559

    CAS  PubMed  Google Scholar 

  • Nicoletti F, Patti F, Ferrara N, Canonico PL, Giammona G, Condorelli DF et al (1982) Comparative effects of estrogens and prolactin on nigral and striatal GAD activity. Brain Res 232:238–241

    Article  CAS  PubMed  Google Scholar 

  • Pajolla GP, Accorsi-Mendonca D, Rodrigues GJ, Bendhack LM, Machado BH, Lunardi CN (2009) Fluorescent indication that nitric oxide formation in NTS neurons is modulated by glutamate and GABA. Nitric Oxide 20:207–216

    Article  CAS  PubMed  Google Scholar 

  • Porsolt R, Bertin A, Jalfre M (1977) Behavioral despair in mice: a primary screening test for antidepressants. Arch Int Pharmacodyn Ther 229:327–336

    CAS  PubMed  Google Scholar 

  • Prange AJ, Wilson IC, Alltop LB (1972) Estrogen may well affect response to antidepressant. J Am Med Assoc 219(2):143–144

    Article  Google Scholar 

  • Puzzo D, Sapienza S, Arancio O, Palmeri A (2008) Role of phosphodiesterase 5 in synaptic plasticity and memory. Neuropsyc Dis Treat 4:371

    Article  CAS  Google Scholar 

  • Rocha BA, Fleischer R, Schaeffer JM, Rohrer SP, Hickey GJ (2005) 17β-estradiol-induced antidepressant-like effect in the forced swim test is absent in estrogen receptor-β knockout (BERKO) mice. Psychopharmacol 179:637–643

    Article  CAS  Google Scholar 

  • Rosa AO, Lin J, Calixto JB, Santos ARS, Rodrigues ALS (2003) Involvement of NMDA receptors and L-arginine-nitric oxide pathway in the antidepressant-like effects of zinc in mice. Behav. Brain Res 144:87–93

    CAS  Google Scholar 

  • Sadaghiani MS, Javadi-Paydar M, Gharedaghi MH, Fard YY, Dehpour AR (2011) Antidepressant-like effect of pioglitazone in the forced swimming test in mice: the role of PPAR-gamma receptor and nitric oxide pathway. Behav Brain Res 224:336–343

    Article  CAS  PubMed  Google Scholar 

  • Sadeghi M, Sianati S, Anaraki DK, Ghasemi M, Paydar MJ, Sharif B et al (2009) Study of morphine-induced dependence in gonadectomized male and female mice. Pharmacol Biochem Behav 91:604–609

    Article  CAS  PubMed  Google Scholar 

  • Saeedi Saravi SS, Dehpour AR (2015a) Potential role of organochlorine pesticides in the pathogenesis of neurodevelopmental, neurodegenerative and neurobehavioral disorders: a review. Life Sci, in press. doi.org/10.1016/j.lfs.2015.11.006.

  • Saeedi Saravi SS, Moosavi SE, Saeedi Saravi SS, Dehpour AR (2015b) Minocycline attenuates depressive-like behavior induced by rat model of testicular torsion/detorsion: involvement of nitric oxide/cyclic guanosine monophosphate pathway. Basic Clin Pharmacol Toxicol, in press. doi: 10.1111/bcpt.12489.

  • Saeedi Saravi SS, Amirkhanloo R, Arefidoust A, Yaftian R, Dehpour AR, Shokrzadeh M (2015c) On the effect of minocycline on the depressive-like behavior of mice exposed to sub-acute malathion: interaction of nitric oxide with cholinergic system. Metab Brain Dis, in press. doi 10.1007/s11011-015-9764-z.

  • Saleh TM, Connell BJ, McQuaid T, Cribb AE (2003) Estrogen-induced neurochemical and electrophysiological changes in the parabrachial nucleus of the male rat. Brain Res 990:58–65

    Article  CAS  PubMed  Google Scholar 

  • Scatton B, Zivkovic B, Dedek J, Lloyd KG, Constantinidis J, Tissot R et al (1982) Gamma-aminobutyric acid (GABA) receptor stimulation. III. Effect of progabide (SL 76002) on norepinephrine, dopamine and 5-hydroxytryptamine turnover in rat brain areas. J Pharmacol Exp Ther 220:678–688

    CAS  PubMed  Google Scholar 

  • Schulz R, Drayer RA, Rollman BL (2002) Depression as a risk factor for non-suicide mortality in the elderly. Biol Psyc 52:205–225

    Article  Google Scholar 

  • Steru L, Chermat R, Thierry B, Simon P (1985) The tail suspension test: a new method for screening antidepressants in mice. Psychopharmacol 85:367–370

    Article  CAS  Google Scholar 

  • Trullas R, Folio T, Young A, Miller R, Boje K, Skolnick P (1991) 1-Aminocyclopropanecarboxylates exhibit antidepressant and anxiolytic actions in animal models. Eur J Pharmacol 203:379–385

    Article  CAS  PubMed  Google Scholar 

  • Weiland NG, Orchinik M (1995) Specific subunit mRNAs of the GABAA receptor are regulated by progesterone in subfields of the hippocampus. Mol Brain Res 32:271–278

    Article  CAS  PubMed  Google Scholar 

  • Wójtowicz T, Lebida K, Mozrzymas JW (2008) 17β-estradiol affects GABAergic transmission in developing hippocampus. Brain Res 1241:7–17

    Article  PubMed  Google Scholar 

  • Yu D, Eldered WD (2005) Glycine and GABA interact to regulate the nitric oxide/cGMP signaling pathway in the turtle retina. Vis Neurosci 22:825–838

    Article  PubMed  PubMed Central  Google Scholar 

  • Zabel U, Kleinschnitz C, Oh P, Nedvetsky P, Smolenski A, Müller H et al (2002) Calcium-dependent membrane association sensitizes soluble guanylyl cyclase to nitric oxide. Nat Cell Biol 4:307–311

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, 13145-784, Tehran, Iran

    Seyed Soheil Saeedi Saravi, Alireza Arefidoust, Rahele Yaftian & Ahmad Reza Dehpour

  2. Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran

    Seyed Soheil Saeedi Saravi, Alireza Arefidoust, Rahele Yaftian & Ahmad Reza Dehpour

  3. Department of Toxicology-Pharmacology, Faculty of Pharmacy, Guilan University of Medical Sciences, Rasht, Iran

    Seyed Soheil Saeedi Saravi

  4. Department of Toxicology-Pharmacology, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran

    Seyed Sobhan Saeedi Saravi

Authors
  1. Seyed Soheil Saeedi Saravi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alireza Arefidoust
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rahele Yaftian
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Seyed Sobhan Saeedi Saravi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ahmad Reza Dehpour
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ahmad Reza Dehpour.

Ethics declarations

Conflict of interest

The authors declare that there are no conflicts of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Saeedi Saravi, S.S., Arefidoust, A., Yaftian, R. et al. 17α-ethinyl estradiol attenuates depressive-like behavior through GABAA receptor activation/nitrergic pathway blockade in ovariectomized mice. Psychopharmacology 233, 1467–1485 (2016). https://doi.org/10.1007/s00213-016-4242-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-016-4242-9

Keywords

Search

Navigation