Research Article: Inhibition by fluoxetine of LH-stimulated cyclic AMP synthesis in tumor Leydig cells partly involves AMPK activation

Date Published: June 4, 2019

Publisher: Public Library of Science

Author(s): Thi Mong Diep Nguyen, Danièle Klett, Laura Filliatreau, Yves Combarnous, Ping Song.


Fluoxetine (FLX), a widely used antidepressant primarily acting as a selective serotonin reuptake inhibitor (SSRI), has been shown to exhibit other mechanisms of action in various cell types. Consequently, it might have unexpected adverse effects not related to its intended use, possibly in the endocrine regulation of reproduction. We show in the present report that after a 1-hour preincubation of MLTC-1 Leydig cells with FLX, the intracellular cyclic adenosine monophosphate (cAMP) responses to Luteinizing Hormone (LH) and forskolin (FSK) are reduced through AMPK-dependent and -independent pathways respectively. FLX at low concentrations (12.5μM and 25μM) induced this inhibition without triggering AMPK phosphorylation, while higher FLX concentrations (50μM and 100μM) induced AMPK phosphorylation and lowered ATP concentration similarly to Metformin. Pretreatment with the specific AMPK inhibitor Compound C (CpdC), significantly diminished the inhibition of cAMP synthesis caused by high concentration of FLX. Moreover, as expected FLX also caused a decline of steroidogenesis which is under the control of cAMP. Taken together, these findings demonstrate that the inhibition of cAMP synthesis by FLX is dose-dependent and occurs in MLTC-1 cells through two mechanisms, AMPK-independent and AMPK-dependent, at low and high concentrations, respectively. FLX also inhibited hormone-induced steroidogenesis in MLTC-1 cells and mouse testicular Leydig cells, suggesting similar mechanisms in both cell types.

Partial Text

Fluoxetine (FLX), the active molecule in Prozac, is a drug used to fight symptoms of conditions such as major depression, obsessive-compulsive disorder, bulimia nervosa and panic disorder, dysautonomia, postpartum depression, premature ejaculation, fibromyalgia or trichotillomania [1–2]. It primarily acts as a selective serotonin reuptake inhibitor [3], but also inhibits various ion channels [4–8] as well as the respiratory chain in mitochondria [9]. Consequently, it is expected to lower ATP production and thus to stimulate 5’-AMP activated protein kinase (AMPK) activity.

The present report shows that the antidepressant fluoxetine (FLX), at μM concentrations, exerts a strong inhibition on LH-stimulated cyclic AMP synthesis and progesterone secretion in MLTC-1 cells, at least partly mediated by AMPK activation.