title: Antidepressant-like effect of sildenafil through oxytocin-dependent cyclic AMP response element-binding protein phosphorylation.
abstract: Oxytocin (OT) levels in plasma increase during sexual response and are significantly lower in patients with depression. A drug for the treatment of sexual dysfunction, sildenafil, enhances the electrically evoked release of OT from the posterior pituitary. In this study, we showed that sildenafil had an antidepressant-like effect through activation of an OT signaling pathway. Application of sildenafil reduced depression-related behavior in male mice. The antidepressant-like effect was blocked by an OT receptor (OTR) antagonist and was absent in OTR knockout (KO) mice. Sildenafil increased the phosphorylation of cAMP response element-binding protein (CREB) in the hippocampus. The OTR antagonist inhibited sildenafil-induced CREB phosphorylation and sildenafil had no effect on CREB phosphorylation in OTR KO mice. These results suggest sildenafil to have an antidepressant-like effect through the activation of OT signaling and to be a promising drug for the treatment of depression.
authors.affiliation: Department of Physiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Matsushita
authors.forename: M
authors.initials: M
authors.lastname: Matsuzaki
authors.forename: X-J
authors.initials: XJ
authors.lastname: Han
authors.forename: T-I
authors.initials: TI
authors.lastname: Nishiki
authors.forename: I
authors.initials: I
authors.lastname: Ohmori
authors.forename: H
authors.initials: H
authors.lastname: Michiue
authors.forename: H
authors.initials: H
authors.lastname: Matsui
authors.forename: K
authors.initials: K
authors.lastname: Tomizawa
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology; D000818:Animals; D000928:Antidepressive Agents / Q000627:therapeutic use*; D001549:Benzamides / Q000494:pharmacology; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D003863:Depression / Q000188:drug therapy* / Q000235:genetics; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005106:Exploratory Behavior / Q000187:drug effects; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D046353:Immobility Response, Tonic / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010121:Oxytocin / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000627:therapeutic use*; D011687:Purines / Q000627:therapeutic use; D018045:Receptors, Oxytocin / Q000172:deficiency; D012737:Sex Factors; D012726:Sexual Behavior, Animal / Q000187:drug effects; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000627:therapeutic use*; D013550:Swimming / Q000523:psychology
chemical_list: C488185:2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluoro-5-bromobenzamide; D000814:Aniline Compounds; D000928:Antidepressive Agents; D001549:Benzamides; D017362:Cyclic AMP Response Element-Binding Protein; D004791:Enzyme Inhibitors; D010879:Piperazines; D011687:Purines; D018045:Receptors, Oxytocin; D013450:Sulfones; D010121:Oxytocin; D000068677:Sildenafil Citrate