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Updated: May 15, 2026
Ovariectomy and 17β-estradiol Replacement in Rats and Mice: A Visual Demonstration
Published on: June 7, 2012
Estradiol reduces depressive-like behavior through inhibiting nitric oxide/cyclic GMP pathway in ovariectomized mice
Pouria Heydarpour1, Mohammad Salehi-Sadaghiani, Mehrak Javadi-Paydar
1Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, P.O. Box 13145-784, Tehran, Iran.
Abstract:
Estradiol decline has been associated with depressive-like behavior in female mice and NO has been suggested to play a major role in the pathogenesis of major depression. This study was conducted to investigate the antidepressant-like effects of acute estradiol administration in female ovariectomized (OVX) mice and the possible role of nitric oxide (NO)/cyclic GMP (cGMP) pathway. To this end, bilateral ovariectomy was performed in female mice and different doses of estradiol were injected alone or in combination with non-specific NO synthase (NOS) inhibitor (L-NAME), selective neural NOS (nNOS) inhibitor (7-NI), an NO precursor (L-arginine) or selective phosphodiesterase type 5 inhibitor (sildenafil). The duration of immobility was recorded in the forced swimming test (FST) to assess the depressive behavior. Moreover, hippocampal levels of NO were determined in select groups. 10 days following the procedure, OVX mice showed significantly prolonged immobility time in comparison with the sham group. Estradiol (3, 10, and 30 μg/kg, s.c.), when injected 1 h prior to FST, exerted antidepressant-like effects in OVX mice. Both L-NAME (30 mg/kg, i.p.), and 7-NI (50 mg/kg, i.p.) significantly reduced the immobility times of OVX mice. Administration of a sub-effective dose of L-NAME (10mg/kg), 15 min after a sub-effective dose of estradiol (1 μg/kg, s.c.) had a robust antidepressant-like effect in OVX mice. Also a sub-effective dose of 7-NI (25 mg/kg), 30 min after a sub-effective dose of estradiol (1 μg/kg, s.c.) showed antidepressant-like effect in OVX mice. Both the NO precursor L-arginine (750 mg/kg, i.p.) and the cGMP-specific phosphodiesterase type 5 inhibitor sildenafil (5 mg/kg, i.p.), 30 min before estradiol treatment, prevented the antidepressant-like effect of a potent dose of estradiol (10 μg/kg, s.c.) in OVX mice. The present findings suggest that suppression of the NO synthase/NO/cGMP pathway may be involved in the antidepressant-like effects of estradiol in OVX mice.
Insights
Estradiol administration shows antidepressant-like effects in ovariectomized mice, suggesting a role for the nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) pathway. This pathway
Area of Science:
- Neuroscience
- Endocrinology
- Pharmacology
Background:
- Declining estradiol levels are linked to depressive behaviors in female mice.
- Nitric oxide (NO) is implicated in the pathogenesis of major depression.
Purpose of the Study:
- To investigate the antidepressant-like effects of estradiol in ovariectomized (OVX) mice.
- To explore the involvement of the nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) pathway in these effects.
Main Methods:
- Ovariectomy was performed in female mice.
- Estradiol was administered alone or with NO synthase inhibitors (L-NAME, 7-NI), an NO precursor (L-arginine), or a cGMP-specific phosphodiesterase type 5 inhibitor (sildenafil).
- Depressive behavior was assessed using the forced swimming test (FST), and hippocampal NO levels were measured.
Main Results:
- OVX mice exhibited increased immobility time, indicating depressive behavior.
- Estradiol administration reduced immobility time in OVX mice.
- Inhibition of NO synthase pathways (using L-NAME or 7-NI) and co-administration of sub-effective doses of estradiol and NOS inhibitors demonstrated antidepressant-like effects. Conversely, L-arginine and sildenafil blocked estradiol's antidepressant effects.
Conclusions:
- Estradiol exerts antidepressant-like effects in OVX mice.
- The NO/cGMP pathway is involved in mediating these antidepressant effects of estradiol.
