Effects of sustained serotonin reuptake inhibition on the firing of dopamine neurons in the rat ventral tegmental area

Effects of sustained serotonin reuptake inhibition on the firing of dopamine neurons in the rat ventral tegmental area

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J Psychiatry Neurosci 2010; 34(3): 223-229

Eliyahu Dremencov, PhD; Mostafa El Mansari, PhD; Pierre Blier, MD, PhD

Dremencov, El Mansari, Blier— University of Ottawa Institute of Mental Health Research; Dremencov — Brains Online BV and University Center for Pharmacy, University of Groningen, the Netherlands; Blier — Departments of Psychiatry and Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ont.

Abstract

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-HT2C receptor antagonist SB 242084. Citalopram, however, did not alter the overall firing rate but inhibited the burst activity of DA neurons.

Limitations: 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-HT2C 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-HT2C receptors, antagonists of these receptors might be effective adjuncts in SSRI-resistant depression.


Submitted Jan. 9, 2008; Revised Aug. 20, Oct. 28, 2008; Accepted Oct. 28, 2008

Acknowledgements: We thank Dr. Owen Kelly for his help with statistical analysis and Lundbeck A/S for financially supporting this project. Dr. Blier received a Canada Research Chair in Psychopharmacology and an Endowed Chair from the University of Ottawa Institute of Mental Health Research. Dr. Dremencov received a postdoctoral fellowship from Bar-Ilan University (Israel).

Competing interests: None declared for Drs. Dremencov and El Mansari. Dr. Blier has been a consultant for and received speaker fees from Lundbeck, Wyeth, Janssen and Eli Lilly, has produced educational media and has received research grants from all 4 companies.

Contributors: All authors contributed to study design and data analysis and approved publication of the article. Dr. Dremencov acquired the data and wrote the article. Drs. El Mansari and Blier reviewed the article.

Correspondence to: Dr. P. Blier, Institute of Mental Health Research, 1145 Carling Ave., Ottawa ON K1Z 7K4; fax 613 761-3610; pierre.blier@rohcg.on.ca