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Peripheral fibroblast metabolic pathway alterations in juvenile rhesus monkeys undergoing long-term fluoxetine
Shu-Yi Su1, Casey E Hogrefe-Phi2, John M Asara3
1Max Planck Institute of Psychiatry, Department of Translational Research in Psychiatry, Kraepelinstrasse 2-10, 80804 Munich, Germany.
Abstract:
We report on biochemical pathways perturbed upon chronic fluoxetine administration to juvenile macaques using global metabolomics analyses of fibroblasts derived from skin biopsies. After exposure to tissue culture conditions confounding environmental factors are eliminated and identification of metabolites whose levels are affected by the drug become apparent with a better signal-to-noise ratio compared to data obtained from plasma and cerebrospinal fluid (CSF). Levels of more than 200 metabolites were analyzed to interrogate affected molecular pathways and identify biomarkers of drug response. In addition, we have correlated the metabolomics results with monoamine oxidase (MAOA) genotype and impulsivity behavioral data. Affected pathways include Purine and Pyrimidine metabolisms that have been previously implicated to contribute to neuropsychiatric disorders.
Insights
Chronic fluoxetine treatment alters biochemical pathways in juvenile macaques. Metabolomics of fibroblasts revealed changes in purine and pyrimidine metabolism, potentially linked to neuropsychiatric disorders.
Area of Science:
- Biochemistry
- Neuroscience
- Pharmacology
Background:
- Selective serotonin reuptake inhibitors (SSRIs) like fluoxetine are widely used for neuropsychiatric disorders.
- Understanding drug effects at a molecular level is crucial for personalized medicine.
- Juvenile animal models offer insights into developmental effects of medications.
Purpose of the Study:
- To investigate biochemical pathway alterations induced by chronic fluoxetine administration in juvenile macaques.
- To identify potential biomarkers for fluoxetine response using metabolomics.
- To correlate metabolic changes with monoamine oxidase A (MAOA) genotype and impulsivity.
Main Methods:
- Global metabolomics analysis of fibroblasts derived from macaque skin biopsies.
- Quantification of over 200 metabolites to identify drug-affected pathways.
- Correlation of metabolomic data with MAOA genotype and behavioral impulsivity data.
Main Results:
- Chronic fluoxetine exposure perturbed specific biochemical pathways.
- Purine and pyrimidine metabolism were significantly affected.
- Metabolomic profiles showed potential for identifying drug response biomarkers.
Conclusions:
- Fibroblast metabolomics provides a robust method for studying drug effects, minimizing confounding factors.
- Fluoxetine impacts purine and pyrimidine metabolism, pathways relevant to neuropsychiatric conditions.
- Metabolic profiling may aid in predicting treatment outcomes and understanding individual drug responses.
