1. ¹The Mina & Everard Goodman Faculty of Life Sciences and The Leslie and Susan Gonda (Goldschmied) Multidisciplinary Brain Research Center, Bar-Ilan University, Ramat-Gan, Israel
2. ²Biological Psychiatry, Felsenstein Medical Research Center, Beilinson Campus, Petah-Tikva, Israel
3. ³Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel

Correspondence: Dr G Yadid, Multidisciplinary Brain Research Center, Bar-Ilan University, Ramat-Gan 52900, Israel, Tel: +972 3 531 8123; Fax: +972 3 635 4965; E-mail: yadidg@mail.biu.ac.il

Received 16 May 2007; Revised 26 February 2008; Accepted 27 February 2008; Published online 21 May 2008.

Abstract

Alterations in the levels of dehydroepiandrosterone (DHEA) in the brain can allosterically modulate -aminobutyric-acid-type-A (GABA_AR), N-methyl-D-aspartate (NMDAR), and Sigma-1 (1R) receptors. In humans, DHEA has antidepressive effects; however, the mechanism is unknown. We examined whether alterations in DHEA also occur in an animal model of depression, the Flinders-sensitive-line (FSL) rats, with the intention of determining the brain site of DHEA action and its antidepressant mechanism. We discovered that DHEA levels were lower in some brain regions involved with depression of FSL rats compared to Sprague–Dawley (SD) controls. Moreover, DHEA (1 mg/kg IP for 14 days)-treated FSL rats were more mobile in the forced swim test than FSL controls. In the NAc and VTA, significant changes were observed in the levels of the -subunit of GABA_A, but not of 1R mRNA, in FSL rats compared to SD rats. The -subunit controls the sensitivity of the GABA_AR to the neurosteroid. Indeed, treatment (14 days) of FSL rats with the GABA_A agonist muscimol (0.5 mg/kg), together with DHEA (a negative modulator of GABA_A), reversed the effect of DHEA on immobility in the swim test. Perfusion of DHEA sulfate (DHEAS) (3 nM and 30 nM for 14 days) into the VTA and NAc of FSL rats improved their performance in the swim test for at least 3 weeks post-treatment. Our results imply that alterations in DHEA are involved in the pathophysiology of depression and that the antidepressant action of DHEA is mediated via GABA_ARs in the NAc and VTA.