The antidepressant-like effects of the 3β-hydroxysteroid dehydrogenase inhibitor trilostane in mice is related to changes in neuroactive steroid and monoamine levels
Neuropharmacology. 2012-01-01; 62(1): 492-502
DOI: 10.1016/j.neuropharm.2011.09.005
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1. Neuropharmacology. 2012 Jan;62(1):492-502. doi:
10.1016/j.neuropharm.2011.09.005. Epub 2011 Sep 22.
The antidepressant-like effects of the 3β-hydroxysteroid dehydrogenase inhibitor
trilostane in mice is related to changes in neuroactive steroid and monoamine
levels.
Espallergues J(1), Mamiya T, Vallée M, Koseki T, Nabeshima T, Temsamani J, Laruelle C, Maurice T.
Author information:
(1)Université de Montpellier II, 34095 Montpellier, France.
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’.
Copyright © 2011 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.neuropharm.2011.09.005
PMID: 21945799 [Indexed for MEDLINE]