Brain concentrations and the neurochemical effects of passively administered fluoxetine in Flinders sensitive line rat offspring
| dc.contributor.author | Steyn, Stephanus Frederik | |
| dc.date.accessioned | 2024-12-09T08:16:29Z | |
| dc.date.available | 2024-12-09T08:16:29Z | |
| dc.date.issued | 2023 | |
| dc.description | A research report submitted in partial fulfillment of the requirements for the degree Master of Science in Medicine in Clinical Pharmacy in the Faculty of Science, University of the Witwatersrand, Johannesburg 2023 | |
| dc.description.abstract | Background: Globally, 36 % of women who have recently given birth, experience symptoms of depression and anxiety. Effective antidepressant treatments are limited, with fluoxetine being a popular treatment option. Fluoxetine is expressed in the breast milk, yet it is unclear to what extent fluoxetine, or its active metabolite, norfluoxetine, reaches the brain of the developing child and what the effects of such exposure on the related neurobiological processes would be. Due to ethical considerations and practical restrictions, clinical investigations into the neurodevelopmental effects of passively administered antidepressants (via the breast milk) are problematic. Therefore, pre-clinical investigations into this topic are not only important but clinically relevant. Aims & objectives: We aimed to quantify the concentration of passively administered, i.e., via the breast milk during nursing, fluoxetine, and its active metabolite, norfluoxetine in the whole brains of exposed Flinders sensitive line (FSL) rats (an established rodent model of depression). We further aimed to establish if said exposure would associate with changes in whole-brain serotonergic function and redox status. Methods: Adult FSL dams received fluoxetine (10 mg/kg/day), or placebo for fourteen days, beginning on postpartum day 04. Offspring (n = 16 per exposure group; 1:1 male: female) were passively exposed to fluoxetine until postnatal day 18 and euthanized on postnatal day 22. Whole brain fluoxetine, norfluoxetine, serotonin, 5-hydroxyindoleacetic acid (5-HIAA), and reduced and oxidized glutathione (GSH and GSSG) concentrations were measured via liquid chromatography/mass spectrometry (LC-MS). Results: Fluoxetine, was undetectable in the brain of FSL offspring, while norfluoxetine concentrations, averaged 41.28 ± 6.47 ng/g. Neither serotonin, nor its metabolite (5-HIAA), was affected by passively administered fluoxetine in the juvenile brain. In terms of redox status, pups exposed to fluoxetine presented with a compromised antioxidant defence, as evinced by a lower GSH/GSSG ratio. Discussion and conclusion: Although fluoxetine and norfluoxetine concentrations have been measured in breast milk and infant plasma, to the best of our knowledge, it has not been quantified in the juvenile brain until now. Our results are in line with clinical findings, suggesting the infant norfluoxetine/fluoxetine ratio to be elevated, probably because of the prolonged half-life of norfluoxetine. Although only norfluoxetine was detected, this did not influence the central serotonin concentrations of offspring. However, it associated with increased oxidative stress, of which the pathophysiological significance remains to be established. Taken together, our findings confirm that passively administered fluoxetine does reach the infant brain in the form of norfluoxetine and may manipulate processes of oxidative stress regulation. Further studies into the long-term bio-behavioural effects are however needed to effectively inform breast feeding mothers on the safety of antidepressant-use during the postpartum period | |
| dc.description.submitter | MM2024 | |
| dc.faculty | Faculty of Health Sciences | |
| dc.identifier | https://orcid.org/ 0000-0002-0023-9711 | |
| dc.identifier.citation | Steyn, Stephanus Frederik. (2023). Brain concentrations and the neurochemical effects of passively administered fluoxetine in Flinders sensitive line rat offspring [Master’s dissertation PhD thesis, University of the Witwatersrand, Johannesburg].https://hdl.handle.net/10539/43193 | |
| dc.identifier.uri | https://hdl.handle.net/10539/43193 | |
| dc.language.iso | en | |
| dc.publisher | University of the Witwatersrand, Johannesburg | |
| dc.rights | 2023 University of the Witwatersrand, Johannesburg. All rights reserved. The copyright in this work vests in the University of the Witwatersrand, Johannesburg. No part of this work may be reproduced or transmitted in any form or by any means, without the prior written permission of University of the Witwatersrand, Johannesburg. | |
| dc.rights.holder | University of the Witwatersrand, Johannesburg | |
| dc.school | School of Therapeutic Sciences | |
| dc.subject | Breast milk | |
| dc.subject | Flinders resistant line (FRL) | |
| dc.subject | Flinders sensitive line (FSL) | |
| dc.subject | Norfluoxetine Oxidative stress | |
| dc.subject | UCTD | |
| dc.subject.other | SDG-3: Good health and well-being | |
| dc.title | Brain concentrations and the neurochemical effects of passively administered fluoxetine in Flinders sensitive line rat offspring | |
| dc.type | Dissertation |