Comparison of the effects of atypical antipsychotics on decreased libido in zebrafish and their mechanisms.

Antipsychotic-induced decreased libido is a common clinical concern, yet drug-specific differences and their underlying neurobiological mechanisms remain poorly understood. We chronically exposed adult male zebrafish to risperidone (RIS), olanzapine (OLZ), quetiapine (QTP), or aripiprazole (ARP) to evaluate their effects on courtship behavior. Brain and testicular transcripts related to the hypothalamic-pituitary-gonadal (HPG) axis, kisspeptin, and monoamine receptors, along with systemic 11-ketotestosterone (11-KT) concentrations, were subsequently analyzed. RIS significantly decreased courtship duration, followed by a downward trend in the OLZ group, whereas QTP and ARP showed no detrimental effects. At the molecular level, RIS significantly reduced brain kiss2 and upregulated prl1 transcript levels. Conversely, the ARP group demonstrated a local transcriptional upregulation of neurosteroidogenic enzymes (cyp11c1 and hsd11b2) and downregulation of the inhibitory gnihr1 pathway in the brain, which may help preserve reproductive drive. Furthermore, RIS and OLZ groups showed significant transcriptional upregulation of central dopamine and serotonin receptors, reflecting marked monoaminergic alterations. These findings suggest that QTP and ARP have minimal impacts on libido, while RIS and OLZ carry a higher risk. This differential susceptibility is likely mediated by a complex interplay of kiss2 downregulation, prolactin elevation, altered local neurosteroidogenesis, and monoamine receptor transcript adjustments, rather than a uniform suppression of the peripheral HPG axis.