Effects of sustained serotonin reuptake inhibition on the firing of dopamine neurons in the rat ventral tegmental area.
BACKGROUND
Selective serotonin (5-HT) reuptake inhibitors (SSRIs) are efficacious in depression because of their ability to increase 5-HT neurotransmission. However, owing to a purported inhibitory effect of 5-HT on dopamine (DA) neuronal activity in the ventral tegmental area (VTA), this increase in 5-HT transmission might result in a suppression of the firing activity of DA neurons. Since the mesolimbic DA system plays an important role in motivation and reward, a potential decrease in the firing of DA neurons may lead, in some patients, to a lack of adequate response to SSRIs.


METHODS
We administered the SSRIs citalopram or escitalopram in rats. We determined DA neuronal activity using in-vivo electrophysiology.


RESULTS
Sustained administration of escitalopram robustly decreased the firing rate and burst activity of DA neurons. There was no difference in the mean number of spontaneously active DA neurons per tract among the 3 groups (citalopram, escitalopram, control). This inhibition was reversed by the selective 5-HT(2C) receptor antagonist SB 242084. Citalopram, however, did not alter the overall firing rate but inhibited the burst activity of DA neurons.


CONCLUSIONS
Our experiments were carried out with the rats under general anesthesia. Therefore, under such conditions the absolute changes produced by SSRIs may heve been different from those occurring in freely moving rats. The exact location of the 5-HT(2C) receptors mediating the inhibitory effects of the SSRIs could not be determined in these studies.


CONCLUSIONS
The difference between escitalopram and citalopram in their effect on DA neuronal activity may be explained by the higher efficacy of escitalopram as a 5-HT reuptake inhibitor. Since the inhibitory effect of escitalopram on DA neuronal activity is mediated via 5-HT(2C) receptors, antagonists of these receptors might be effective adjuncts in SSRI-resistant depression.
Dremencov
Eliyahu
E
University of Ottawa Institute of Mental Health Research, Ottawa, ON, Canada.
El Mansari
Mostafa
M
Blier
Pierre
P
D000200:Action Potentials / Q000187:drug effects; D000631:Aminopyridines / Q000008:administration & dosage; D000704:Analysis of Variance; D000818:Animals; D002404:Catheterization; D015283:Citalopram / Q000008:administration & dosage*; D004298:Dopamine / Q000378:metabolism*; D007211:Indoles / Q000008:administration & dosage; D008297:Male; D008839:Microelectrodes; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists / Q000008:administration & dosage; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage*; D017557:Ventral Tegmental Area / Q000187:drug effects* / Q000502:physiology
D000631:Aminopyridines; D015283:Citalopram; D004298:Dopamine; D007211:Indoles; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists; D017367:Selective Serotonin Reuptake Inhibitors; C107820:6-chloro-5-methyl-1-((2-(2-methylpyrid-3-yloxy)pyrid-5-yl)carbamoyl)indoline