Paroxetine binding to the rat norepinephrine transporter in vivo

Michael J. Owens, David L. Knight, Charles Nemeroff

Research output: Contribution to journalArticle

57 Citations (Scopus)

Abstract

Background: The norepinephrine transporter (NET)/uptake site is an antidepressant-sensitive transporter located on plasma membranes of noradrenergic neurons and other specialized cells that remove norepinephrine (NE) from the synapse to terminate the actions of NE. The antidepressant paroxetine is believed to produce its therapeutic effects primarily by acting as a highly selective antagonist of the serotonin transporter (SERT). However, in vitro data indicates that paroxetine inhibits the NET. The present study was designed to determine whether paroxetine inhibits in NET in vivo. Methods: Rats were administered paroxetine (6.5, 10.0, or 15.0 mg/kg/day) via osmotic minipumps for 1 week. Following attainment of steady state serum concentrations, cortical NET function was assessed by both [3H]- nisoxetine binding and [3H]-norepinephrine uptake assays conducted ex vivo. Results: In unwashed brain homogenates, serum paroxetine concentrations greater than 100 ng/mL were positively correlated with the observed K(d) for [3H]-nisoxetine. At [3H]-nisoxetine concentrations associated with 50% transporter occupancy in vehicle treated rats, [3H]-nisoxetine binding was decreased 21% and 34% in rats exhibiting serum paroxetine concentrations > 100 ng/mL and > 500 ng/mL, respectively. Conclusions: Although paroxetine is a very potent inhibitor of the SERT, paroxetine also inhibits the NET at serum concentrations > 100 ng/mL. This novel finding may underlie the broad therapeutic utility of paroxetine in mood and anxiety disorders. (C) 2000 Society of Biological Psychiatry.

Original languageEnglish
Pages (from-to)842-845
Number of pages4
JournalBiological Psychiatry
Volume47
Issue number9
DOIs
StatePublished - May 1 2000
Externally publishedYes

Fingerprint

Norepinephrine Plasma Membrane Transport Proteins
Paroxetine
nisoxetine
Norepinephrine
Serotonin Plasma Membrane Transport Proteins
Serum
Antidepressive Agents
Adrenergic Neurons
Therapeutic Uses
Anxiety Disorders
Mood Disorders
Synapses
Cell Membrane

Keywords

  • [H]-nisoxetine binding
  • Drug concentrations
  • Norepinephrine transporter
  • Norepinephrine uptake
  • Paroxetine
  • Selectivity

ASJC Scopus subject areas

  • Biological Psychiatry

Cite this

Paroxetine binding to the rat norepinephrine transporter in vivo. / Owens, Michael J.; Knight, David L.; Nemeroff, Charles.

In: Biological Psychiatry, Vol. 47, No. 9, 01.05.2000, p. 842-845.

Research output: Contribution to journalArticle

Owens, Michael J. ; Knight, David L. ; Nemeroff, Charles. / Paroxetine binding to the rat norepinephrine transporter in vivo. In: Biological Psychiatry. 2000 ; Vol. 47, No. 9. pp. 842-845.
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