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.
Copyright © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Aniline Compounds / pharmacology
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Animals
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Antidepressive Agents / therapeutic use*
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Benzamides / pharmacology
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Cyclic AMP Response Element-Binding Protein / metabolism*
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Depression / drug therapy*
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Depression / genetics
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Disease Models, Animal
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Dose-Response Relationship, Drug
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Enzyme Inhibitors / pharmacology
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Exploratory Behavior / drug effects
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Female
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Gene Expression Regulation / drug effects
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Gene Expression Regulation / genetics
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Immobility Response, Tonic / drug effects
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Oxytocin / metabolism*
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Phosphorylation / drug effects
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Piperazines / therapeutic use*
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Purines / therapeutic use
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Receptors, Oxytocin / deficiency
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Sex Factors
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Sexual Behavior, Animal / drug effects
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Sildenafil Citrate
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Sulfones / therapeutic use*
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Swimming / psychology
Substances
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2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluoro-5-bromobenzamide
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Aniline Compounds
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Antidepressive Agents
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Benzamides
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Cyclic AMP Response Element-Binding Protein
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Enzyme Inhibitors
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Piperazines
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Purines
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Receptors, Oxytocin
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Sulfones
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Oxytocin
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Sildenafil Citrate