title: Extracellular signal-regulated kinase 2 signaling in the hippocampal dentate gyrus mediates the antidepressant effects of testosterone.
abstract: BACKGROUND
  Human and animal studies suggest that testosterone may have antidepressant effects. In this study, we sought to investigate the molecular mechanisms underlying the antidepressant effects of testosterone within the hippocampus, an area that is fundamental in the etiology of depression.
  
  
  METHODS
  The effects of testosterone replacements in gonadectomized adult male rats were investigated using the sucrose preference and forced swim tests. We explored possible effects of testosterone on hippocampal neurogenesis and gene expression of stress-related molecules. Through the use of viral vectors, we pursued the antidepressant molecular mechanism(s) of testosterone in mediating anhedonia and manipulated extracellular signal-regulated kinase 2 (ERK2) expression in the dentate gyrus in gonadectomized rats with testosterone replacements.
  
  
  RESULTS
  Testosterone had antidepressant effects, likely mediated by aromatization to estrogen metabolites, in the sucrose preference and forced swim tests despite having no effects on hippocampal cell proliferation or survival. We found a testosterone-dependent regulation of hippocampal ERK2 expression. Functionally, reducing ERK2 activity within the dentate gyrus induced anhedonia in gonadectomized rats receiving testosterone supplementation, whereas the overexpression of ERK2 rescued this behavior in gonadectomized rats.
  
  
  CONCLUSIONS
  These results implicate a role for ERK2 signaling within the dentate gyrus area of the hippocampus as a key mediator of the antidepressant effects of testosterone.
authors.affiliation: Department of Biomedical Sciences, Program in Neurosciences, College of Medicine, Florida State University, USA.
authors.forename: Nicole
authors.initials: N
authors.lastname: Carrier
authors.forename: Mohamed
authors.initials: M
authors.lastname: Kabbaj
mesh_terms: D059445:Anhedonia / Q000187:drug effects*; D000818:Animals; D000928:Antidepressive Agents / Q000378:metabolism / Q000494:pharmacology; D019208:Brain-Derived Neurotrophic Factor / Q000096:biosynthesis; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002755:Choice Behavior / Q000187:drug effects; D018891:Dentate Gyrus / Q000187:drug effects / Q000378:metabolism*; D004195:Disease Models, Animal; D015870:Gene Expression / Q000187:drug effects; D046353:Immobility Response, Tonic / Q000187:drug effects; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism*; D009043:Motor Activity / Q000187:drug effects; D055495:Neurogenesis / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D011965:Receptors, Glucocorticoid / Q000096:biosynthesis; D013739:Testosterone / Q000031:analogs & derivatives / Q000097:blood / Q000494:pharmacology*
chemical_list: D000928:Antidepressive Agents; D019208:Brain-Derived Neurotrophic Factor; D011965:Receptors, Glucocorticoid; D013739:Testosterone; D019950:Mitogen-Activated Protein Kinase 1