Paroxetine binding to the rat norepinephrine transporter in vivo.
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 Kd 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.
Owens
M J
MJ
Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Knight
D L
DL
Nemeroff
C B
CB
D000818:Animals; D001693:Biological Transport, Active; D002138:Calibration; D002352:Carrier Proteins / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D005473:Fluoxetine / Q000031:analogs & derivatives / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D009638:Norepinephrine / Q000037:antagonists & inhibitors; D050484:Norepinephrine Plasma Membrane Transport Proteins; D017374:Paroxetine / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017367:Selective Serotonin Reuptake Inhibitors / Q000378:metabolism*; D013056:Spectrophotometry, Ultraviolet; D027981:Symporters
D002352:Carrier Proteins; D005473:Fluoxetine; D009638:Norepinephrine; D050484:Norepinephrine Plasma Membrane Transport Proteins; D017374:Paroxetine; D017367:Selective Serotonin Reuptake Inhibitors; D027981:Symporters; C493226:Slc6a2 protein, rat; C011386:nisoxetine