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Long-Term Fluoxetine Administration Causes Substantial Lipidome Alteration of the Juvenile Macaque Brain.

ABSTRACT: Fluoxetine is an antidepressant commonly prescribed not only to adults but also to children for the treatment of depression, obsessive-compulsive disorder, and neurodevelopmental disorders. The adverse effects of the long-term treatment reported in some patients, especially in younger individuals, call for a detailed investigation of molecular alterations induced by fluoxetine treatment. Two-year fluoxetine administration to juvenile macaques revealed effects on impulsivity, sleep, social interaction, and peripheral metabolites. Here, we built upon this work by assessing residual effects of fluoxetine administration on the expression of genes and abundance of lipids and polar metabolites in the prelimbic cortex of 10 treated and 11 control macaques representing two monoamine oxidase A (MAOA) genotypes. Analysis of 8871 mRNA transcripts, 3608 lipids, and 1829 polar metabolites revealed substantial alterations of the brain lipid content, including significant abundance changes of 106 lipid features, accompanied by subtle changes in gene expression. Lipid alterations in the drug-treated animals were most evident for polyunsaturated fatty acids (PUFAs). A decrease in PUFAs levels was observed in all quantified lipid classes excluding sphingolipids, which do not usually contain PUFAs, suggesting systemic changes in fatty acid metabolism. Furthermore, the residual effect of the drug on lipid abundances was more pronounced in macaques carrying the MAOA-L genotype, mirroring reported behavioral effects of the treatment. We speculate that a decrease in PUFAs may be associated with adverse effects in depressive patients and could potentially account for the variation in individual response to fluoxetine in young people.

SUBMITTER: Tkachev A

PROVIDER: S-EPMC8348031 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Fluoxetine (FLX) and other selective serotonin reuptake inhibitors are widely used to treat depressive disorders during pregnancy. Early-life exposure to FLX is known to disrupt the normal function of the stress axis in humans, rodents, and teleosts. We used a zebrafish line with a cortisol-inducible fluorescent transgene to study the effects of developmental daily exposure to FLX (54 µg/L) on the transcriptomic profile of brain tissues in exposed larvae and later as 6-month-old adults. High throughput RNA sequencing was conducted on brain tissues in unstressed and stressed conditions. Long-lasting effects of FLX were observed in telencephalon (Tel) and hypothalamus (Hyp) of adult zebrafish with 1927 and 5055 genes significantly (≥1.2 fold-change, false-discovery p-value < 0.05) dysregulated in unstressed condition, respectively. Similar findings were observed in Hyp with 1245 and 723 genes being significantly dysregulated in stressed adults, respectively. Differentially expressed genes converted to Homo sapiens orthologues were used for Ingenuity Pathway Analysis. The results showed alteration of pathways involved in neuroendocrine signaling, cholesterol metabolism and synaptogenesis. Enriched networks included lipid metabolism, molecular transport, and nervous system development. Analysis of putative upstream transcription regulators showed potential dysregulation of clocka and nr3c1 which control circadian rhythm, stress response, cholesterol metabolism and histone modifications. Several genes involved in epigenetic regulation were also affected by FLX, including dnmt3a, adarb1, adarb2, hdac4, hdac5, hdac8, and atf2. We report life-long disruptive effects of FLX on pathways associated with neuroendocrine signaling, stress response and the circadian rhythm, and all of which are implicated in the development of depressive disorders in humans. Our results raise concern for the persistent endocrine-disrupting potential of brief antidepressant exposure during embryonic development.

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Long-Term Fluoxetine Administration Causes Substantial Lipidome Alteration of the Juvenile Macaque Brain.

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