title: The antidepressant-like effects of the 3β-hydroxysteroid dehydrogenase inhibitor trilostane in mice is related to changes in neuroactive steroid and monoamine levels.
abstract: In the present study, we analyzed the effects of a systemic treatment with the competitive 3β-hydroxysteroid dehydrogenase (3β-HSD) inhibitor trilostane on: (i) neurosteroid and monoamine levels in the brain, and (ii) the antidepressant activity of steroids and antidepressants in the forced swimming test (FST). 3β-HSD converts pregnenolone (PREG) into progesterone (PROG) or dehydroepiandrosterone (DHEA) into androstenedione. These neuroactive steroids are known to regulate neurotransmitters effects in the brain, particularly glutamate, γ-aminobutyric acid (GABA) and serotonin (5-HT), with consequences on mood and depression. We previously reported that trilostane showed antidepressant-like properties in the FST and concomitantly regulated plasma adrenocorticotropin (ACTH) and corticosterone levels, markers of the stress-induced hypothalamus-pituitary-adrenal (HPA) axis activation. We here observed that adrenalectomy/castration blocked the trilostane effect, outlining the importance of peripheral steroid levels. Trilostane (25 mg/kg) decreased hippocampus PROG contents and paradoxically increased circulating PROG levels. It also increased PREG levels in the hippocampus and frontal cortex. In the FST, a co-treatment with trilostane facilitated DHEAS (5-20 mg/kg) antidepressant activity, but showed only an additive, not facilitative, effect with PREGS (10-40 mg/kg), PROG (10-40 mg/kg) or allopregnanolone (ALLO, 1-8 mg/kg). Trilostane (25 mg/kg) treatment significantly increased 5-HT and (-)-norepinephrine (NE) turnovers in the hippocampus, an effect likely related to its antidepressant action. In co-administration studies, trilostane further decreased immobility following fluoxetine (30-60 mg/kg), sertraline (20-40 mg/kg) and imipramine (20-40 mg/kg), but not desipramine (20-40 mg/kg), treatments. A significant additive effect was observed for the selective 5-HT reuptake inhibitors (SSRI) at their highest dose. This study confirmed that a systemic administration of trilostane directly affected peripheral and brain levels in neuroactive steroids and monoamine turnover, resulting in antidepressant activity. The drug could be proposed as a co-treatment with SSRI. This article is part of a Special Issue entitled 'Anxiety and Depression'.
authors.affiliation: Université de Montpellier II, 34095 Montpellier, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Espallergues
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Mamiya
authors.forename: Monique
authors.initials: M
authors.lastname: Vallée
authors.forename: Takenao
authors.initials: T
authors.lastname: Koseki
authors.forename: Toshitaka
authors.initials: T
authors.lastname: Nabeshima
authors.forename: Jamal
authors.initials: J
authors.lastname: Temsamani
authors.forename: Claude
authors.initials: C
authors.lastname: Laruelle
authors.forename: Tangui
authors.initials: T
authors.lastname: Maurice
mesh_terms: D000315:Adrenalectomy; D000704:Analysis of Variance; D000818:Animals; D001009:Anxiety, Castration; D015306:Biogenic Monoamines / Q000378:metabolism*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D003863:Depression / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D013196:Dihydrotestosterone / Q000031:analogs & derivatives* / Q000097:blood / Q000627:therapeutic use; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000097:blood / Q000627:therapeutic use*; D008401:Gas Chromatography-Mass Spectrometry / Q000379:methods; D008297:Male; D051379:Mice; D011863:Radioimmunoassay; D013256:Steroids / Q000378:metabolism*; D013550:Swimming / Q000523:psychology; D013997:Time Factors
chemical_list: D015306:Biogenic Monoamines; D004791:Enzyme Inhibitors; D013256:Steroids; D013196:Dihydrotestosterone; C009954:trilostane