DHEA lessens depressive-like behavior via GABA-ergic modulation of the mesolimbic system

Alterations in the levels of dehydroepiandrosterone (DHEA) in the brain can allosterically modulate γ-aminobutyric-acid-type-A (GABA_AR), N-methyl-D-aspartate (NMDAR), and Sigma-1 (σ1R) 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 δ-subunit of GABA_A, but not of σ1R mRNA, in FSL rats compared to SD rats. The δ-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.