(166) Paroxetine-Induced Alterations in Neurosteroidogenic Gene Expression in the Female Nucleus Accumbens: Insights into Post-SSRI Sexual Dysfunction

Introduction Post-SSRI sexual dysfunction (PSSD) is a long-lasting condition occurring after the discontinuation of selective serotonin reuptake inhibitors (SSRIs). Even though women represent the majority of SSRI users, the study of this condition in the female sex is highly neglected. Previous studies in male animal models have shown alteration in key modulators of brain function, such as neuroactive steroid molecules. Moreover, transcriptomic analyses indicated the nucleus accumbens (NAc) as a key region affected in PSSD-related neurobiological alterations in males; however, the underlying mechanisms remain largely unexplored. Objective Building upon previous findings in males, we sought to determine whether molecular alterations occur in the female brain, focusing on NAc. To this end, we examined the expression of genes encoding key steroidogenic enzymes to evaluate potential disturbances in neurosteroid synthesis that could contribute to long-term sexual and motivational dysfunction following SSRI withdrawal. Methods Adult female rats were chronically treated with paroxetine (10mg/kg/day), a commonly prescribed SSRI, for 14 days and analyzed at two time points: after the treatment (T0) and one month after drug suspension (T1). NAc was dissected for quantitative PCR (qPCR) analysis of genes involved in steroidogenesis, including steroidogenic acute regulatory protein (StAR), translocator protein (TSPO), 3β-hydroxysteroid dehydrogenase (3β-HSD), 5α-reductase type I (5αR I), 3α-hydroxysteroid oxidoreductase (3α-HSOR), and cytochrome P450 side-chain cleavage enzyme (P450scc, coded by CYP11A1 gene). Each experimental group consisted of eight animals. Gene expression data were normalized to a housekeeping gene and analyzed using appropriate statistical tests to determine significant differences relative to controls. Results The study revealed time-dependent alterations in the expression of genes involved in steroidogenesis within NAc. During SSRI treatment (T0), StAR expression was significantly increased, whereas TSPO and 3α-HSOR levels were reduced compared to controls. One month after treatment, during suspension (T1), StAR, TSPO, 3β-HSD, and 3α-HSOR expression was significantly lower than control levels. No significant changes were observed for 5αR I or CYP11A1 at either time point. Conclusions Chronic SSRI treatment induces both acute and persistent alterations in neurosteroidogenic gene expression in NAc of female subjects. These findings, together with our previous observations obtained in males, clearly indicate that SSRIs withdrawal may disrupt neurosteroidogenesis in the two sexes. In addition, the finding that in female animals, drug withdrawal affected neurosteroid production in a key brain region involved in motivation and sexual behavior, may suggest a potential link of these molecules in regulating these mechanisms. Disclosure No