Fluoxetine, but not other selective serotonin uptake inhibitors, increases norepinephrine and dopamine extracellular levels in prefrontal cortex.
BACKGROUND
The selective serotonin uptake inhibitor (SSRI) fluoxetine has been shown to not only increase the extracellular concentrations of serotonin, but also dopamine and norepinephrine extracellular concentrations in rat prefrontal cortex. The effect of other SSRIs on monoamine concentrations in prefrontal cortex has not been thoroughly studied.


OBJECTIVE
The aim of this study was to compare the ability of five systemically administered selective serotonin uptake inhibitors to increase acutely the extracellular concentrations of serotonin, norepinephrine and dopamine in rat prefrontal cortex.


METHODS
The extracellular concentrations of monoamines were determined in the prefrontal cortex of conscious rats using the microdialysis technique.


RESULTS
Fluoxetine, citalopram, fluvoxamine, paroxetine and sertraline similarly increased the extracellular concentrations of serotonin from 2- to 4-fold above baseline. However, only fluoxetine produced robust and sustained increases in extracellular concentrations of norepinephrine and dopamine after acute systemic administration. Fluoxetine at the same dose blocked ex vivo binding to the serotonin transporter, but not the norepinephrine transporter, suggesting that the increase of catecholamines was not due to non-selective blockade of norepinephrine uptake. Prefrontal cortex extracellular concentrations of fluoxetine at the dose that increased extracellular monoamines were 242 nM, a concentration sufficient to block 5-HT(2C) receptors which is a potential mechanism for the fluoxetine-induced increase in catecholamines.


CONCLUSIONS
Amongst the SSRIs examined, only fluoxetine acutely increases extracellular concentrations of norepinephrine and dopamine as well as serotonin in prefrontal cortex, suggesting that fluoxetine is an atypical SSRI.
Bymaster
Frank P
FP
Neuroscience Research Division, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285-0510, USA. F.Bymaster@Lilly.com
Zhang
Wei
W
Carter
Petra A
PA
Shaw
Janice
J
Chernet
Eyassu
E
Phebus
Lee
L
Wong
David T
DT
Perry
Kenneth W
KW
D000818:Animals; D004298:Dopamine / Q000096:biosynthesis / Q000378:metabolism*; D005110:Extracellular Space / Q000187:drug effects* / Q000378:metabolism; D005473:Fluoxetine / Q000494:pharmacology*; D008297:Male; D017551:Microdialysis; D009638:Norepinephrine / Q000096:biosynthesis / Q000378:metabolism*; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017367:Selective Serotonin Reuptake Inhibitors / Q000097:blood / Q000378:metabolism / Q000494:pharmacology*
D004298:Dopamine; D005473:Fluoxetine; D009638:Norepinephrine; D017367:Selective Serotonin Reuptake Inhibitors