title: The 3beta-hydroxysteroid dehydrogenase inhibitor trilostane shows antidepressant properties in mice.
abstract: Changes in neuro(active)steroid levels are involved in depressive states and mood disorders. For instance, dehydroepiandrosterone or pregnenolone sulfate showed anti-stress and antidepressant activity in rodents and regulation of allopregnanolone levels appeared to be one of the consequence of an effective antidepressant therapy in patients. 4alpha,5-Epoxy-17beta-hydroxy-3-oxo-5alpha-androstane-2alpha-carbonitrile (trilostane) inhibits the activity of 3beta-hydroxysteroid dehydrogenase (3beta-HSD) that, in particular, converts pregnenolone into progesterone. We examined whether systemic administration of trilostane affects the response to stress and depression. An acute treatment with trilostane (6.3-50mg/kg SC injected twice -16 and -2h before the measure) increased 3beta-HSD mRNA levels in the hippocampus and adrenals, but had little effect on protein levels. The trilostane treatment failed to affect open-field, locomotor or exploratory behaviors, but significantly reduced the immobility duration in the forced swimming test, measuring antidepressant-like activity, and increased the time spent in open arm in the elevated plus-maze, measuring anxiety response. The antidepressant-like effect of trilostane was effective after a repeated treatment (2.5-20mg/kgSC twice-a-day during 7 days) or in mice submitted to a restraint stress during 21 days and showing several behavioral and physiological parameters of depression (decreased body weight, increased adrenal glands weight and anhaedonia). Trilostane also reduced stress-induced increase in plasma corticosterone and ACTH levels, showing direct effect on HPA axis activity. These observations suggest that the 3beta-HSD inhibitor trilostane present antidepressant-like activity, putatively by regulating brain and peripheral levels of neuroactive steroids.
authors.affiliation: Université de Montpellier II, 34095 Montpellier, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Espallergues
authors.forename: Laurent
authors.initials: L
authors.lastname: Givalois
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: D015096:3-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology; D001007:Anxiety / Q000517:prevention & control; D001522:Behavior, Animal / Q000187:drug effects; D003863:Depression / Q000517:prevention & control*; D013196:Dihydrotestosterone / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D004353:Drug Evaluation, Preclinical; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D008297:Male; D051379:Mice; D008954:Models, Biological; D009043:Motor Activity / Q000187:drug effects; D011581:Psychological Tests; D012333:RNA, Messenger / Q000378:metabolism; D013550:Swimming
chemical_list: D000928:Antidepressive Agents; D012333:RNA, Messenger; D013196:Dihydrotestosterone; D015096:3-Hydroxysteroid Dehydrogenases; C009954:trilostane