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Antidepressants targetting the serotonin transporter (SERT) act via a competitive mechanism (2008)

Antidepressants targetting the serotonin transporter (SERT) act via a competitive mechanism (2008)

  1. Jatelka
    Journal of Pharmacology and Experimental Therapeutics 2008 Sep 18. [Epub ahead of print]

    Apparsundaram S (http://www.ncbi.nlm.nih.gov/sites/e...l.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Stockdale DJ (http://www.ncbi.nlm.nih.gov/sites/e...l.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Henningsen RA (http://www.ncbi.nlm.nih.gov/sites/e...l.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Milla ME (http://www.ncbi.nlm.nih.gov/sites/e...l.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Martin RS (http://www.ncbi.nlm.nih.gov/sites/e...l.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus).

    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 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, employing Cheng-Prusoff analysis (Cheng & Prusoff, 1973). Two different SERT-selective radioligands, [(3)H]DASB (N,N-dimethyl-2-(2-amino-4-cyanophenyl thio)-benzylamine) and [(3)H]S-citalopram were used to probe competitive binding to recombinantly expressed human SERT (hSERT), or native SERT in rat cortical membranes. All the SERT inhibitors that we tested were able to inhibit [(3)H]DASB and [(3)H]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-beta-carboxy-3-beta-(4-iodophenyl)tropane (beta-CIT). The equilibrium dissociation constant of 5-HT and SERT inhibitors were also derived using Scatchard analysis of the dataset, and were found to be comparable to 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.