Effect of chronic administration of duloxetine on serotonin and norepinephrine transporter binding sites in rat brain.
BACKGROUND
Chronic treatment of rats with certain selective serotonin or norepinephrine reuptake inhibitors produces significant decreases, respectively, in serotonin and norepinephrine transporter binding sites in brain. Duloxetine may be a dual serotonin/norepinephrine reuptake inhibitor, as it is only a slightly more potent inhibitor of serotonin than norepinephrine uptake in vitro. Consequently, we hypothesized that chronic duloxetine treatment, at doses producing serum levels within its therapeutic range, would affect both monoamine transporters dose-dependently, with a higher dose causing greater reductions of binding sites for both transporters.


METHODS
Rats were treated with either 4 or 8 mg/kg/d of duloxetine, paroxetine, desipramine, or vehicle via subcutaneous osmotic minipumps for 21 days. Binding sites for serotonin and norepinephrine transporters were measured in amygdala and hippocampus using quantitative autoradiography.


RESULTS
Both doses of duloxetine and paroxetine produced equivalent and significant decreases in [3H] cyanoimipramine binding to serotonin transporters, but only desipramine treatment significantly reduced [3H] nisoxetine binding to norepinephrine transporters.


CONCLUSIONS
At doses producing rat serum concentrations in the range achieved in patients at recommended daily doses of the drug, duloxetine behaves in vivo more as a selective serotonin reuptake inhibitor than a dual reuptake inhibitor in its capacity to selectively reduce serotonin transporter density.
Gould
Georgianna G
GG
Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229-3900, USA. gouldg@uthscsa.edu
Javors
Martin A
MA
Frazer
Alan
A
D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology*; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001345:Autoradiography; D001921:Brain / Q000187:drug effects*; D002851:Chromatography, High Pressure Liquid; D003891:Desipramine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D000068736:Duloxetine Hydrochloride; D008297:Male; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000187:drug effects*; D017374:Paroxetine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018342:Receptors, Adrenergic, beta-1 / Q000187:drug effects; D050486:Serotonin Plasma Membrane Transport Proteins / Q000187:drug effects*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D013876:Thiophenes / Q000494:pharmacology*
D018759:Adrenergic Uptake Inhibitors; D000928:Antidepressive Agents; D003891:Desipramine; D000068736:Duloxetine Hydrochloride; D050484:Norepinephrine Plasma Membrane Transport Proteins; D017374:Paroxetine; D018342:Receptors, Adrenergic, beta-1; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; D013876:Thiophenes; C493226:Slc6a2 protein, rat