Intranasal delivery of paroxetine: A preclinical study on pharmacokinetics, depressive-like behaviour, and neurochemical sex differences.

Treatment of major depressive disorder remains a major unmet clinical need. Given the advantages of intranasal administration for targeted brain delivery, the present study aimed at investigating the pharmacokinetics of paroxetine, after its intranasal instillation and assessing its potential therapeutic effect on female and male mice subjected to unpredictable chronic mild stress (UCMS) protocol. IN administration revealed direct nose to-brain paroxetine delivery but dose- and sex-dependent differences. Pharmacokinetics was nonlinear and paroxetine concentrations were consistently higher in plasma and brain of male mice. Additionally, UCMS decreased animal preference for sucrose in both male and female mice following acute (p < 0.01) and chronic stress (p < 0.05), suggesting anhedonia. Both male and female mice exhibited depressive-like behavior in the forced swimming test. UCMS females displayed a significantly longer immobility time and shorter climbing time than the control group (p < 0.05), while no differences were found between male mice. Two weeks of paroxetine intranasal administration reduced immobility time and lengthened climbing and swimming time, approaching values similar to those observed in the healthy control group. The therapeutic effect was stronger on female mice. Importantly, melatonin plasma levels were significantly decreased in female mice following UCMS (p < 0.05), while males exhibited heightened corticosterone levels. On the other hand, treatment with IN paroxetine significantly increased corticosterone and melatonin levels in both sexes compared to healthy mice (p < 0.05). Intranasal paroxetine delivery undoubtedly ameliorated the behavioral despair, characteristic of depressive-like animals. Despite its efficiency in male and female mice subjected to UCMS, females were more prone to this novel therapeutic strategy.