Original Article

Neuropsychopharmacology (2001) 25, 871–880. doi:10.1016/S0893-133X(01)00298-6

Comparative Affinity of Duloxetine and Venlafaxine for Serotonin and Norepinephrine Transporters in vitro and in vivo, Human Serotonin Receptor Subtypes, and Other Neuronal Receptors

Frank P Bymaster1, Laura J Dreshfield-Ahmad MS1, Penny G Threlkeld MS1, Janice L Shaw MS1, Linda Thompson BS1, David L Nelson Ph.D1, Susan K Hemrick-Luecke MS1 and David T Wong Ph.D1

1Neuroscience Research Division, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285-0510

Correspondence: Dr Frank P Bymaster, Neuroscience Research Division, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285-0510, Tel.: 317-276-9444, Fax: 317-276-5546, E-mail: f.bymaster@lilly.com

Received 27 November 2000; Revised 19 April 2001; Accepted 1 May 2001

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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 Ki values of 7.5 and 0.8 nM, respectively, and with a Ki ratio of 9. Venlafaxine inhibited binding to the human NE and 5-HT transporters with Ki values of 2480 and 82 nM, respectively, and with a Ki ratio of 30. Duloxetine inhibited ex vivo binding to rat 5-HT transporters and NE transporters with ED50 values of 0.03 and 0.7 mg/kg, respectively, whereas venlafaxine had ED50 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 ED50 values of 2.3 and 12 mg/kg, respectively. Venlafaxine had ED50 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.

Keywords:

Duloxetine; Venlafaxine; Depression; Norepinephrine uptake; Serotonin uptake; 5-HT receptors

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