Differential Effects of Antidepressants on Hypothalamic Serotonin Levels in Rats: An In Vivo Microdialysis Study

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Abstract
Purpose: Antidepressants can induce urinary retention, difficulty in voiding, and delayed micturition, effects thought to result from detrusor relaxation and increased urethral sphincter tone mediated by enhanced central serotonergic activity. However, direct measurements of brain serotonin following antidepressant treatment remain limited. The relative risk of voiding difficulty across different antidepressant classes may help guide individualized antidepressant selection. This study aimed to assess changes in hypothalamic serotonin levels after administration of various antidepressants using an animal microdialysis model.Methods: Male Sprague-Dawley rats (280–330 g) were randomly assigned to 5 groups (n=8 per group) and received intraperitoneal injections of saline, clomipramine, fluoxetine, sertraline, or paroxetine (10 mg/kg). A microdialysis probe was stereotaxically implanted in the hypothalamus and perfused with artificial cerebrospinal fluid. Dialysate samples were collected every 20 minutes in freely moving animals and analyzed for serotonin levels via high-performance liquid chromatography with electrochemical detection.Results: All tested antidepressants significantly elevated extracellular serotonin in the hypothalamus compared to baseline. The magnitude of increase was greatest with clomipramine, followed by sertraline, paroxetine, and fluoxetine. Peak serotonin levels were observed at 120 minutes post-administration for clomipramine and sertraline, whereas paroxetine and fluoxetine peaked at 240 minutes.Conclusions: Antidepressant treatment increases hypothalamic serotonin, with clomipramine and sertraline producing the most pronounced effects. Considering that clomipramine and paroxetine combine high serotonergic elevation with notable anticholinergic activity, these drugs may pose a higher risk of voiding difficulties than fluoxetine or sertraline. This study focused on characterizing central serotonergic responses to antidepressant administration as a neurochemical endpoint. The relative risk of voiding difficulty across different antidepressant classes may help guide individualized antidepressant selection. Clinicians should exercise caution when prescribing these agents to elderly patients, individuals with benign prostatic hyperplasia, or those receiving concurrent anticholinergic medications.
Funding Information
  • Soonchunhyang University
  • National Research Foundation of Korea
  • Ministry of Education, Science and Technology (RS-2024-00333544)

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