Short- and medium-term exposures of diazepam induce metabolomic alterations associated with the serotonergic, dopaminergic, adrenergic and aspartic acid neurotransmitter systems in zebrafish (Danio rerio) embryos/larvae

Pavel A. Markin, Alex Brito, Natalia E. Moskaleva, Franco Tagliaro, Vadim V. Tarasov, Michael R. La Frano, Mark V. Savitskii, Svetlana A. Appolonova

Research output: Contribution to journalArticlepeer-review

Abstract

Introduction: Diazepam is a well-known psychoactive drug widely used worldwide for the treatment of anxiety, seizures, alcohol withdrawal syndrome, muscle spasms, sleeplessness, agitation, and pre/post-operative sedation. It is part of the benzodiazepine family, substances known to primarily act by binding and enhancing gamma-aminobutyric acid (GABAA) receptors. The objective of the present work was to investigate the influence of short and medium-term diazepam exposures on neurotransmitters measured through targeted metabolomics using a zebrafish embryo model. Methods: Short-term (2.5 h) and medium-term (96 h) exposures to diazepam were performed at drug concentrations of 0.8, 1.6, 16, and 160 μg/L. Intervention groups were compared with a vehicle control group. Each group consisted of 20 zebrafish eggs/larvae. Metabolites related with neurotransmission were determined by ultra-high-performance liquid chromatography coupled with tandem mass spectrometry (UPLC-MS/MS). Results: Thirty-six compounds were quantified. Significantly increased tryptophan and serotonin concentrations were found in the intervention groups receiving higher doses of diazepam in 2.5 h exposure (p < 0.05 control versus intervention groups). Tyrosine concentrations were higher (p < 0.05) at higher concentrations in 2.5 h exposure, but lower (p < 0.05) at higher concentrations in 96 h exposure. Both phenylalanine and aspartic acid concentrations were higher (p < 0.05) at higher doses in 2.5 h and 96 h exposure. Conclusions: Short- and medium-term exposures to diazepam induce dose- and time-dependent metabolomic alterations associated with the serotonergic, dopaminergic/adrenergic, and aspartic acid neurotransmitter systems in zebrafish.

Original languageEnglish (US)
Article number100816
JournalComparative Biochemistry and Physiology - Part D: Genomics and Proteomics
Volume38
DOIs
StatePublished - Jun 2021
Externally publishedYes

Keywords

  • Benzodiazepines
  • Metabolites
  • Metabolomics
  • Neurotransmission
  • Omics
  • Zebrafish

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Aquatic Science
  • Animal Science and Zoology
  • Molecular Biology
  • Genetics

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