Comparative affinity of duloxetine and venlafaxine for serotonin and norepinephrine transporters in vitro and in vivo, human serotonin receptor subtypes, and other neuronal receptors

Neuropsychopharmacology. 2001 Dec;25(6):871-80. doi: 10.1016/S0893-133X(01)00298-6.

Abstract

The blockade of serotonin (5-HT) and norepinephrine (NE) transporters in vitro and in vivo by the dual 5-HT/NE reuptake inhibitors duloxetine and venlafaxine was compared. Duloxetine inhibited binding to the human NE and 5-HT transporters with K(i) values of 7.5 and 0.8 nM, respectively, and with a K(i) ratio of 9. Venlafaxine inhibited binding to the human NE and 5-HT transporters with K(i) values of 2480 and 82 nM, respectively, and with a K(i) ratio of 30. Duloxetine inhibited ex vivo binding to rat 5-HT transporters and NE transporters with ED(50) values of 0.03 and 0.7 mg/kg, respectively, whereas venlafaxine had ED(50) values of 2 and 54 mg/kg, respectively. The depletion of rat brain 5-HT by p-chloramphetamine and depletion of rat hypothalamic NE by 6-hydroxydopamine was blocked by duloxetine with ED(50) values of 2.3 and 12 mg/kg, respectively. Venlafaxine had ED(50) values of 5.9 and 94 mg/kg for blocking p-chloramphetamine- and 6-hydroxydopamine-induced monoamine depletion, respectively. Thus, duloxetine more potently blocks 5-HT and NE transporters in vitro and in vivo than venlafaxine.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Biogenic Monoamines / metabolism
  • Carrier Proteins / metabolism*
  • Cell Line
  • Cyclohexanols / pharmacology*
  • Dose-Response Relationship, Drug
  • Duloxetine Hydrochloride
  • Humans
  • Male
  • Membrane Glycoproteins / metabolism*
  • Membrane Transport Proteins*
  • Monoamine Oxidase / metabolism
  • Nerve Tissue Proteins*
  • Neurons / drug effects*
  • Norepinephrine Plasma Membrane Transport Proteins
  • Oxidopamine / pharmacology
  • Radioligand Assay
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Serotonin / drug effects*
  • Serotonin Agents / pharmacology
  • Serotonin Plasma Membrane Transport Proteins
  • Serotonin Uptake Inhibitors / pharmacology*
  • Sympatholytics / pharmacology
  • Symporters / metabolism*
  • Thiophenes / pharmacology*
  • Venlafaxine Hydrochloride
  • p-Chloroamphetamine / antagonists & inhibitors

Substances

  • Biogenic Monoamines
  • Carrier Proteins
  • Cyclohexanols
  • Membrane Glycoproteins
  • Membrane Transport Proteins
  • Nerve Tissue Proteins
  • Norepinephrine Plasma Membrane Transport Proteins
  • Receptors, Serotonin
  • SLC6A2 protein, human
  • SLC6A4 protein, human
  • Serotonin Agents
  • Serotonin Plasma Membrane Transport Proteins
  • Serotonin Uptake Inhibitors
  • Slc6a2 protein, rat
  • Slc6a4 protein, rat
  • Sympatholytics
  • Symporters
  • Thiophenes
  • p-Chloroamphetamine
  • Venlafaxine Hydrochloride
  • Oxidopamine
  • Duloxetine Hydrochloride
  • Monoamine Oxidase