Antidepressant-like effect of sildenafil through oxytocin-dependent cyclic AMP response element-binding protein phosphorylation

Neuroscience. 2012 Jan 3:200:13-8. doi: 10.1016/j.neuroscience.2011.11.001. Epub 2011 Nov 9.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aniline Compounds / pharmacology
  • Animals
  • Antidepressive Agents / therapeutic use*
  • Benzamides / pharmacology
  • Cyclic AMP Response Element-Binding Protein / metabolism*
  • Depression / drug therapy*
  • Depression / genetics
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / pharmacology
  • Exploratory Behavior / drug effects
  • Female
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / genetics
  • Immobility Response, Tonic / drug effects
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Oxytocin / metabolism*
  • Phosphorylation / drug effects
  • Piperazines / therapeutic use*
  • Purines / therapeutic use
  • Receptors, Oxytocin / deficiency
  • Sex Factors
  • Sexual Behavior, Animal / drug effects
  • Sildenafil Citrate
  • Sulfones / therapeutic use*
  • Swimming / psychology

Substances

  • 2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluoro-5-bromobenzamide
  • Aniline Compounds
  • Antidepressive Agents
  • Benzamides
  • Cyclic AMP Response Element-Binding Protein
  • Enzyme Inhibitors
  • Piperazines
  • Purines
  • Receptors, Oxytocin
  • Sulfones
  • Oxytocin
  • Sildenafil Citrate