title: Estradiol reduces depressive-like behavior through inhibiting nitric oxide/cyclic GMP pathway in ovariectomized mice.
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.
authors.affiliation: Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, P.O. Box 13145-784, Tehran, Iran.
authors.forename: Pouria
authors.initials: P
authors.lastname: Heydarpour
authors.forename: Mohammad
authors.initials: M
authors.lastname: Salehi-Sadaghiani
authors.forename: Mehrak
authors.initials: M
authors.lastname: Javadi-Paydar
authors.forename: Reza
authors.initials: R
authors.lastname: Rahimian
authors.forename: Gohar
authors.initials: G
authors.lastname: Fakhfouri
authors.forename: Mohsen
authors.initials: M
authors.lastname: Khosravi
authors.forename: Shayan
authors.initials: S
authors.lastname: Khoshkish
authors.forename: Mohammad Hadi
authors.initials: MH
authors.lastname: Gharedaghi
authors.forename: Mehdi
authors.initials: M
authors.lastname: Ghasemi
authors.forename: Ahmad Reza
authors.initials: AR
authors.lastname: Dehpour
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology / Q000627:therapeutic use; D001522:Behavior, Animal / Q000187:drug effects*; D006152:Cyclic GMP / Q000378:metabolism*; D003863:Depression / Q000188:drug therapy / Q000378:metabolism* / Q000517:prevention & control; D015536:Down-Regulation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004958:Estradiol / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D010052:Ovariectomy; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000928:Antidepressive Agents; D004791:Enzyme Inhibitors; D009569:Nitric Oxide; D004958:Estradiol; D019001:Nitric Oxide Synthase; D006152:Cyclic GMP; D019331:NG-Nitroarginine Methyl Ester