The antidepressant-like effects of the 3b-hydroxysteroid dehydrogenase inhibitor trilostane in mice is related to changes in neuroactive steroid and monoamine levels Julie Espallergues a, b, c, g , Takayoshi Mamiya d , Monique Vallée e, f , Takenao Koseki d , Toshitaka Nabeshima d , Jamal Temsamani g , Claude Laruelle e , Tangui Maurice a, b, c, * a Université de Montpellier II, 34095 Montpellier, France b Inserm U. 710, 34095 Montpellier cedex 5, France c E.P.H.E., 75017 Paris, France d Department of Chemical Pharmacology, Graduate School of Pharmaceutical Science, Meijo University, Nagoya 468-8503, Japan e Inserm U. 862, Neurocentre Magendie, Physiopathology of Addiction Group, 33000 Bordeaux, France f Université de Bordeaux, 33000 Bordeaux, France g CLL Pharma, 06200 Nice, France article info Article history: Received 25 February 2011 Received in revised form 30 August 2011 Accepted 6 September 2011 Keywords: Trilostane 3b-hydroxysteroid dehydrogenase Neurosteroids Monoamines Forced swimming test Depression abstract In the present study, we analyzed the effects of a systemic treatment with the competitive 3b-hydroxysteroid dehydrogenase (3b-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). 3b-HSD converts pregnenolone (PREG) into progesterone (PROG) or dehy- droepiandrosterone (DHEA) into androstenedione. These neuroactive steroids are known to regulate neurotransmitters effects in the brain, particularly glutamate, g-aminobutyric acid (GABA) and sero- tonin (5-HT), with consequences on mood and depression. We previously reported that trilostane showed antidepressant-like properties in the FST and concomitantly regulated plasma adrenocortico- tropin (ACTH) and corticosterone levels, markers of the stress-induced hypothalamusepituitarye 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 hippo- campus 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 (5e20 mg/kg) antidepressant activity, but showed only an additive, not facilitative, effect with PREGS (10e40 mg/kg), PROG (10e40 mg/kg) or allopregnanolone (ALLO, 1e8 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, trilos- tane further decreased immobility following fluoxetine (30e60 mg/kg), sertraline (20e40 mg/kg) and imipramine (20e40 mg/kg), but not desipramine (20e40 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’. Ó 2011 Elsevier Ltd. All rights reserved. Abbreviations: ALLO, 5a-pregnan-3a-ol,20-one, allopregnanolone; 3a-HSOR, 3a-hydroxysteroid oxydoreductase; 3a/3b-HSD, 3a/3b-hydroxysteroid dehydrogenase; 5b-DHP, 5b-dihydroprogesterone; 5-HIAA, 5-hydroxyindole-3-acetic acid; 5-HT, serotonin; ACTH, adrenocorticotropin; AdX/CX, adrenalectomized/castrated; BDNF, brain- derived neurotrophic factor; CSF, cerebrospinal fluid; DA, dopamine; DHEA, dehydroepiandrosterone; DHEAS, dehydroepiandrosterone sulfate ester; DOC, deoxy- corticosterone; DOPAC, 3,4-dihydroxyphenylacetic acid; Epi, (-)-epinephrine; EPIALLO, 3b-hydroxy-5a-pregnan-ol-20-one, epiallopregnanolone; HVA, homovanillic acid; i.p., intraperitoneally; MHPG, 4-hydroxy-3-methoxyphenylglycol (MHPG); NE, (-)-norepinephrine; PREG, pregnenolone; PREGS, pregnenolone sulfate ester; PROG, progesterone; s.c., subcutaneously; SSRI, selective serotonin reuptake inhibitor; THDOC, 3a,5a-tetrahydrodeoxycorticosterone. * Corresponding author. University of Montpellier 2, Inserm U. 710, cc 105, PL E Bataillon, 34095 Montpellier cedex 5, France. E-mail address: Tangui.Maurice@univ-montp2.fr (T. Maurice). Contents lists available at SciVerse ScienceDirect Neuropharmacology journal homepage: www.elsevier.com/locate/neuropharm 0028-3908/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.neuropharm.2011.09.005 Neuropharmacology 62 (2012) 492e502