¿NOVEL INSIGHTS INTO THE EXPERIMENTAL MODEL OF POST-FINASTERIDE SYNDROME: BEHAVIORAL ALTERATIONS AND THEIR MOLECULAR BASIS'

Finasteride, a 5α-reductase inhibitor widely prescribed for benign prostatic hyperplasia and androgenetic alopecia, has been associated with a spectrum of adverse effects in a subset of users. In some cases, these side effects persist even after drug discontinuation, resulting in a condition known as post-finasteride syndrome (PFS). PFS is characterized by sexual dysfunction, mood disturbances, cognitive impairment, and persistent alterations in neuroactive steroid levels. Despite increasing clinical reports, the pathophysiology of PFS remains poorly understood, and no effective treatments are currently available. To address this gap, a comprehensive characterization of the experimental PFS model was performed to explore the molecular mechanisms underlying PFS and identify potential therapeutic approaches. The animal model, consisting of 20 days of finasteride administration (T0) followed by one month of drug suspension (T1) in adult male rats, was evaluated at the behavioral level. In parallel, transcriptomic profiling was conducted in two brain regions (i.e., hippocampus and hypothalamus) considered potentially relevant to PFS-related symptoms in order to identify dysregulated molecular pathways. Behavioral evaluations included locomotor activity, anxiety-like behavior, and exploratory drive using the open field test (OF), elevated plus maze (EPM), and novelty-seeking test (NST). Results highlighted a clear distinction between the immediate and delayed effects of finasteride. While subchronic treatment (T0) induced only modest behavioral changes, more pronounced alterations manifested subsequent to drug withdrawal (T1). Specifically, marked locomotor activity, diminished exploration of the central zone in the open field test, and pronounced avoidance of novel stimuli were observed, collectively indicative of hyperactivity and an anxiety-like phenotype. These findings, reflecting increased behavioral vulnerability, are consistent with clinical manifestations reported in post-finasteride syndrome and support the translational relevance of the model. Based on the behavioral phenotype, the effects of finasteride withdrawal were investigated in the striatum and nucleus accumbens, as brain regions critically involved in locomotion and motivational drive. Dopaminergic alterations were observed in the striatum at T1, particularly in dopamine metabolism, while the nucleus accumbens appeared unaffected, suggesting a selective vulnerability of striatal circuits to finasteride's action. In parallel, transcriptomic analysis (RNA sequencing, differential expression analysis, and gene set enrichment analysis) revealed that the hypothalamus was primarily affected at the transcriptional level during treatment, whereas the hippocampus exhibited persistent dysregulation of specific pathways at both time points. Notably, pathways associated with mitochondrial dysfunction, synaptogenesis, and synaptic plasticity emerged as particularly relevant in hippocampus and were selected for further molecular validation. Preliminary data suggested that finasteride treatment may impair mitochondrial function, as highlighted by alterations in mitochondrial dynamics, oxidative stress response, and energy production processes at both time points. However, further investigations are necessary to validate these results and clarify their relevance to the pathophysiology of PFS. Regarding synaptic remodelling, initial protein expression analyses indicated an upregulation observed primarily during the finasteride suspension. However, a deeper investigation of excitatory and inhibitory synapses by immunofluorescence analysis revealed dysregulations both after treatment and following withdrawal. Specifically, an increase in inhibitory synapses was detected at T0 and persisted during the withdrawal, while excitatory synapses were downregulated immediately after treatment and subsequently upregulated at T1. Overall, these findings provide new insights into the neurobiological effects associated with finasteride treatment and its discontinuation. The experimental model employed showed strong translational relevance, as it reproduces several behavioral and molecular features reported in post-finasteride syndrome. Notably, the localized alterations in striatal dopaminergic metabolism highlighted the specificity of finasteride effects on striatal circuits, which may contribute to the dysregulation of motor and motivational functions observed. In parallel, transcriptomic analyses revealed a region-specific impact of finasteride, with the hypothalamus predominantly affected by treatment and the hippocampus showing persistent pathway alterations across both time points. Among these, mitochondrial dysfunction and synaptic impairment emerged as key dysregulated processes, further confirmed by molecular and immunofluorescence analyses. These findings not only enhance the understanding of neural circuits and molecular cascades potentially involved in PFS but also identify possible targets for future therapeutic strategies.