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Research ArticleCARDIOVASCULAR

Amphetamine Analogs Increase Plasma Serotonin: Implications for Cardiac and Pulmonary Disease

Dorota Zolkowska, Richard B. Rothman and Michael H. Baumann
Journal of Pharmacology and Experimental Therapeutics August 2006, 318 (2) 604-610; DOI: https://doi.org/10.1124/jpet.106.101618
Dorota Zolkowska
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Richard B. Rothman
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Michael H. Baumann
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Abstract

Elevations in plasma serotonin (5-HT) have been implicated in the pathogenesis of cardiac and pulmonary disease. Normally, plasma 5-HT concentrations are kept low by transporter-mediated uptake of 5-HT into platelets and by metabolism to 5-hydroxyindoleacetic acid (5-HIAA). Many abused drugs (e.g., substituted amphetamines) and prescribed medications (e.g., fluoxetine) target 5-HT transporters and could thereby influence circulating 5-HT. We evaluated the effects of amphetamines analogs [(±)-fenfluramine, (±)-3,4-methylenedioxymethamphetamine, (+)-methamphetamine, (+)-amphetamine, phentermine] on extracellular levels (i.e., plasma levels) of 5-HT and 5-HIAA in blood from catheterized rats. Effects of the 5-HT uptake blocker fluoxetine were examined for comparison. Drugs were tested in vivo and in vitro; plasma indoles were measured using a novel microdialysis method in whole blood. We found that baseline dialysate levels of 5-HT are ∼0.22 nM, and amphetamine analogs evoke large dose-dependent increases in plasma 5-HT ranging from 4 to 20 nM. The ability of drugs to elevate plasma 5-HT is positively correlated with their potency as 5-HT transporter substrates. Fluoxetine produced small, but significant, increases in plasma 5-HT. Although the drug-evoked 5-HT concentrations are below the micromolar levels required for contraction of pulmonary arteries, they approach concentrations reported to stimulate mitogenesis in pulmonary artery smooth muscle cells. Additional studies are needed to determine the effects of chronic administration of amphetamines on circulating 5-HT.

Footnotes

  • This work was supported by the National Institute on Drug Abuse IRP.

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

  • doi:10.1124/jpet.106.101618.

  • ABBREVIATIONS: 5-HT, 5-hydroxytryptamine or serotonin; 5-HIAA, 5-hydroxyindoleacetic acid; MAO, monoamine oxidase; VHD, valvular heart disease; PPH, primary pulmonary hypertension; SERT, serotonin transporter; IRP, Intramural Research Program; MDMA, (±)-3,4-methylenedioxymethamphetamine; HPLC, high-performance liquid chromatography; ECD, electrochemical detection; ANOVA, analysis of variance; SSRI, serotonin-selective reuptake inhibitor.

    • Received January 18, 2006.
    • Accepted April 25, 2006.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 385 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 385, Issue 1
1 Apr 2023
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Research ArticleCARDIOVASCULAR

Amphetamine Analogs Increase Plasma Serotonin: Implications for Cardiac and Pulmonary Disease

Dorota Zolkowska, Richard B. Rothman and Michael H. Baumann
Journal of Pharmacology and Experimental Therapeutics August 1, 2006, 318 (2) 604-610; DOI: https://doi.org/10.1124/jpet.106.101618

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Research ArticleCARDIOVASCULAR

Amphetamine Analogs Increase Plasma Serotonin: Implications for Cardiac and Pulmonary Disease

Dorota Zolkowska, Richard B. Rothman and Michael H. Baumann
Journal of Pharmacology and Experimental Therapeutics August 1, 2006, 318 (2) 604-610; DOI: https://doi.org/10.1124/jpet.106.101618
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