PERSISTENT SEXUAL DYSFUNCTION AND NEUROTRANSMITTER DYSREGULATION FOLLOWING PAROXETINE TREATMENT AND SUSPENSION: DATA FROM TRANSCRIPTOMIC ANALYSIS

To investigate the potential mechanisms behind sexual dysfunction induced by paroxetine, a selective serotonin reuptake inhibitor (SSRI), during treatment and after discontinuation. This study focuses on identifying transcriptomic changes in the hypothalamus and nucleus accumbens (NAc), two brain regions involved in sexual behavior, to provide insights into post-SSRI sexual dysfunction (PSSD).

Male rats were treated daily with paroxetine for 2 weeks, and RNA-sequencing was used to analyze the whole transcriptomic profile in the hypothalamus and NAc at the end of treatment (T0) and 1 month after withdrawal (T1). Differentially expressed genes (DEGs) were identified at both time points. Gene-Set Enrichment, Gene Ontology, and Reactome analyses were conducted to explore biological pathways affected by the treatment.

In the hypothalamus, 7 DEGs were found at T0 and 1 at T1, while in the NAc, 245 DEGs were identified at T0 and 6 at T1. Inflammatory signatures and immune system activation were present at T0 in both brain regions, suggesting a potential link between SSRI treatment and inflammation. Dysregulation of genes related to neurotransmitters involved in sexual behavior and the reward system—such as dopamine (ST8SIA3), glutamate (GRID2), and GABA (GAD2)—as well as pathways involving neurexin, neuroligin, and BDNF signaling were observed, particularly in the NAc. Persistent alterations in the NAc at T1 suggest lasting effects on sexual function even after discontinuation of paroxetine.

Paroxetine treatment induces significant transcriptomic changes in brain regions associated with sexual behavior, leading to neurotransmitter dysregulation and persistent sexual dysfunction. The inflammatory response observed may contribute to the pro-depressive effects of SSRIs, particularly in non-depressed individuals. These findings provide valuable insight into the mechanisms underlying PSSD and suggest that sexual dysfunction may persist even after discontinuation of SSRIs.

Authors declare no conflict of interest.