Silvia Giatti, Silvia Diviccaro, Lucia Cioffi, Eva Falvo, Donatella Caruso, Roberto C. Melcangi
Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, Italy
• Brain neuroactive steroid levels are altered by paroxetine treatment.
•Brain neuroactive steroid levels are altered after one-month withdrawal.
•Paroxetine treatment and withdrawal did not affect steroid plasma levels.
•Brain expression of steroidogenic enzymes is affected by paroxetine treatment.
•Brain expression of steroidogenic enzymes is affected after one-month withdrawal.
Selective serotonin reuptake inhibitors (SSRI) show high efficacy in treating depression, however during treatment side effects, like for instance sexual dysfunction, may appear, decreasing compliance. In some cases, this condition will last after drug discontinuation, leading to the so-called post-SSRI sexual dysfunction (PSSD). The etiology of PSSD is still unknown, however a role for neuroactive steroids may be hypothesized. Indeed, these molecules are key physiological regulators of the nervous system, and their alteration has been associated with several neuropathological conditions, including depression. Additionally, neuroactive steroids are also involved in the control of sexual function. Interestingly, sexual dysfunction induced by SSRI treatment has been also observed in animal models. On this basis, we have here evaluated whether a subchronic treatment with paroxetine for two weeks and/or its withdrawal (i.e., a month) may affect the levels of neuroactive steroids in brain areas (i.e., hippocampus, hypothalamus, and cerebral cortex) and/or in plasma and cerebrospinal fluid of male rats. Data obtained indicate that the SSRI treatment alters neuroactive steroid levels and the expression of key enzymes of the steroidogenesis in a brain tissue- and time-dependent manner. Indeed, these observations with the finding that plasma levels of neuroactive steroids are not affected suggest that the effect of paroxetine treatment is directly on neurosteroidogenesis. In particular, a negative impact on the expression of steroidogenic enzymes was observed at the withdrawal. Therefore, it is possible to hypothesize that altered neurosteroidogenesis may also occur in PSSD and consequently it may represent a possible pharmacological target for this disorder.