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Research ArticleNEUROPHARMACOLOGY

Antidepressants Targeting the Serotonin Reuptake Transporter Act via a Competitive Mechanism

Subbu Apparsundaram, Daniel J. Stockdale, Robert A. Henningsen, Marcos E. Milla and Renee S. Martin
Journal of Pharmacology and Experimental Therapeutics December 2008, 327 (3) 982-990; DOI: https://doi.org/10.1124/jpet.108.142315
Subbu Apparsundaram
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Daniel J. Stockdale
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Robert A. Henningsen
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Marcos E. Milla
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Renee S. Martin
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Abstract

Although several antidepressants (including fluoxetine, imipramine, citalopram, venlafaxine, and duloxetine) are known to inhibit the serotonin transporter (SERT), whether or not these molecules compete with 5-hydroxytryptamine (serotonin) (5-HT) for binding to SERT has remained controversial. We have performed radioligand competition binding experiments and found that all data can be fitted via a simple competitive interaction model, using Cheng-Prusoff analysis (Biochem Pharmacol 22:3099–3108, 1973). Two different SERT-selective radioligands, [3H]N,N-dimethyl-2-(2-amino-4-cyanophenyl thio)-benzylamine (DASB) and [3H]S-citalopram, were used to probe competitive binding to recombinantly expressed human SERT or native SERT in rat cortical membranes. All the SERT inhibitors that we tested were able to inhibit [3H]DASB and [3H]S-citalopram binding in a concentration-dependent manner, with unity Hill coefficient. In accordance with the Cheng-Prusoff relationship for a competitive interaction, we observed that test compound concentrations associated with 50% maximal inhibition of radiotracer binding (IC50) increased linearly with increasing radioligand concentration for all ligands: 5-HT, S-citalopram, R-citalopram, paroxetine, clomipramine, fluvoxamine, imipramine venlafaxine, duloxetine, indatraline, cocaine, and 2-β-carboxy-3-β-(4-iodophenyl)tropane. The equilibrium dissociation constant of 5-HT and SERT inhibitors were also derived using Scatchard analysis of the data set, and they were found to be comparable with the data obtained using the Cheng-Prusoff relationship. Our studies establish a reference framework that will contribute to ongoing efforts to understand ligand binding modes at SERT by demonstrating that 5-HT and the SERT inhibitors tested bind to the serotonin transporter in a competitive manner.

Footnotes

  • This study was wholly funded by Roche Pharmaceuticals (Palo Alto, CA).

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

  • doi:10.1124/jpet.108.142315.

  • ABBREVIATIONS: 5-HT, 5-hydroxytryptamine (serotonin); NET, norepinephrine transporter; TM, transmembrane; LeuT, leucine transporter; DASB, N,N-dimethyl-2-(2-amino-4-cyanophenyl thio)-benzylamine; h, human; β-CIT, 2-β-carboxy-3-β-(4-iodophenyl)tropane; SERT, serotonin transporter.

    • Received June 13, 2008.
    • Accepted September 4, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 381 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 381, Issue 3
1 Jun 2022
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Research ArticleNEUROPHARMACOLOGY

Antidepressants Targeting the Serotonin Reuptake Transporter Act via a Competitive Mechanism

Subbu Apparsundaram, Daniel J. Stockdale, Robert A. Henningsen, Marcos E. Milla and Renee S. Martin
Journal of Pharmacology and Experimental Therapeutics December 1, 2008, 327 (3) 982-990; DOI: https://doi.org/10.1124/jpet.108.142315

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Research ArticleNEUROPHARMACOLOGY

Antidepressants Targeting the Serotonin Reuptake Transporter Act via a Competitive Mechanism

Subbu Apparsundaram, Daniel J. Stockdale, Robert A. Henningsen, Marcos E. Milla and Renee S. Martin
Journal of Pharmacology and Experimental Therapeutics December 1, 2008, 327 (3) 982-990; DOI: https://doi.org/10.1124/jpet.108.142315
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