title: Testosterone has antidepressant-like efficacy and facilitates imipramine-induced neuroplasticity in male rats exposed to chronic unpredictable stress.
abstract: Hypogonadal men are more likely to develop depression, while testosterone supplementation shows antidepressant-like effects in hypogonadal men and facilitates antidepressant efficacy. Depression is associated with hypothalamic-pituitary-adrenal (HPA) axis hyperactivity and testosterone exerts suppressive effects on the HPA axis. The hippocampus also plays a role in the feedback regulation of the HPA axis, and depressed patients show reduced hippocampal neuroplasticity. We assessed the antidepressant-like effects of testosterone with, or without, imipramine on behavioral and neural endophenotypes of depression in a chronic unpredictable stress (CUS) model of depression. A 21-day CUS protocol was used on gonadectomized male Sprague-Dawley rats treated with vehicle, 1mg of testosterone propionate, 10mg/kg of imipramine, or testosterone and imipramine in tandem. Testosterone treatment reduced novelty-induced hypophagia following CUS exposure, but not under non-stress conditions, representing state-dependent effects. Further, testosterone increased the latency to immobility in the forced swim test (FST), reduced basal corticosterone, and reduced adrenal mass in CUS-exposed rats. Testosterone also facilitated the effects of imipramine by reducing the latency to immobility in the FST and increasing sucrose preference. Testosterone treatment had no significant effect on neurogenesis, though the combination of testosterone and imipramine increased PSA-NCAM expression in the ventral dentate gyrus. These findings demonstrate the antidepressant- and anxiolytic-like effects of testosterone within a CUS model of depression, and provide insight into the mechanism of action, which appears to be independent of enhanced hippocampal neurogenesis.
authors.affiliation: Graduate Program in Neuroscience, University of British Columbia, Canada.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Wainwright
authors.affiliation: Department of Psychology, University of British Columbia, Canada.
authors.forename: Joanna L
authors.initials: JL
authors.lastname: Workman
authors.affiliation: Department of Psychology, University of British Columbia, Canada.
authors.forename: Amir
authors.initials: A
authors.lastname: Tehrani
authors.affiliation: Department of Psychology, University of British Columbia, Canada.
authors.forename: Dwayne K
authors.initials: DK
authors.lastname: Hamson
authors.affiliation: Department of Psychology, University of British Columbia, Canada; Centre for Brain Health, University of British Columbia, Canada.
authors.forename: Carmen
authors.initials: C
authors.lastname: Chow
authors.affiliation: Department of Psychology, University of British Columbia, Canada; Centre for Brain Health, University of British Columbia, Canada.
authors.forename: Stephanie E
authors.initials: SE
authors.lastname: Lieblich
authors.affiliation: Graduate Program in Neuroscience, University of British Columbia, Canada; Department of Psychology, University of British Columbia, Canada; Centre for Brain Health, University of British Columbia, Canada. Electronic address: lgalea@psych.ubc.ca.
authors.forename: Liisa A M
authors.initials: LA
authors.lastname: Galea
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D002908:Chronic Disease; D003345:Corticosterone / Q000378:metabolism; D018891:Dentate Gyrus / Q000187:drug effects / Q000378:metabolism; D003863:Depression / Q000473:pathology / Q000517:prevention & control; D004195:Disease Models, Animal; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000378:metabolism; D007099:Imipramine / Q000494:pharmacology*; D008297:Male; D055495:Neurogenesis / Q000187:drug effects; D009473:Neuronal Plasticity / Q000187:drug effects*; D010913:Pituitary-Adrenal System / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013315:Stress, Psychological / Q000188:drug therapy / Q000473:pathology / Q000523:psychology*; D013739:Testosterone / Q000494:pharmacology*
chemical_list: D000928:Antidepressive Agents; D013739:Testosterone; D007099:Imipramine; D003345:Corticosterone
keywords: Androgens; Antidepressant; Chronic unpredictable stress; Depression; Hippocampus; Neurogenesis; Neuroplasticity; PSA-NCAM; Testosterone