Experimental Brain Research

, Volume 226, Issue 2, pp 285–295

5-HT2A receptor inactivation potentiates the acute antidepressant-like activity of escitalopram: involvement of the noradrenergic system

  • G. Quesseveur
  • C. Repérant
  • D. J. David
  • A. M. Gardier
  • C. Sanchez
  • B. P. Guiard
Research Article

DOI: 10.1007/s00221-013-3434-3

Cite this article as:
Quesseveur, G., Repérant, C., David, D.J. et al. Exp Brain Res (2013) 226: 285. doi:10.1007/s00221-013-3434-3

Abstract

Evidence suggests that the serotonin 2A receptor (5-HT2AR) modulates the therapeutic activity of selective serotonin reuptake inhibitors (SSRIs). Indeed, among the genetic factors known to influence the individual response to antidepressants, the HTR2A gene has been associated with SSRIs response in depressed patients. However, in these pharmacogenetic studies, the consequences of HTR2A gene polymorphisms on 5-HT2AR expression or function are lacking and the precise role of this receptor is still matter of debate. This study examined the effect of 5-HT2AR agonism or antagonism with DOI and MDL100907, respectively, on the serotonergic system and the antidepressant-like activity of the SSRI escitalopram in mouse. The 5-HT2AR agonist DOI decreased the firing rate of 5-HT neurons in the dorsal raphe (DR) nucleus of 5-HT2AR+/+ anesthetized mice. This inhibitory response persisted in 5-HT2CR−/− but was completely blunted in 5-HT2AR−/− mutants. Moreover, the suppressant effect of DOI on DR 5-HT neuronal activity in 5-HT2AR+/+ mice was attenuated by the loss of noradrenergic neurons induced by the neurotoxin DSP4. Conversely, in 5-HT2AR+/+ mice, the pharmacological inactivation of the 5-HT2AR by the selective antagonist MDL100907 reversed escitalopram-induced decrease in DR 5-HT neuronal activity. Remarkably, in microdialysis experiments, a single injection of escitalopram increased cortical extracellular 5-HT, but not NE, levels in awake 5-HT2AR+/+ mice. Although the addition of MDL100907 did not potentiate 5-HT neurotransmission, it allowed escitalopram to increase cortical NE outflow and consequently to elicit an antidepressant-like effect in the forced swimming test. These results suggest that the blockade of the 5-HT2AR may strengthen the antidepressant-like effect of escitalopram by facilitating the enhancement of the brain NE transmission. They provide support for the use of atypical antipsychotics with SSRIs as a relevant antidepressant augmentation strategy.

Keywords

5-HT 5-HT2A receptor Antidepressants Antipsychotics Norepinephrine SSRIs 

Abbreviations

5-HT

Serotonin

5-HT2AR

Serotonin 2A receptor

AAP

Atypical antipsychotic

DR

Dorsal raphe

FST

Forced swimming test

LC

Locus coeruleus

MDD

Major depressive disorder

NE

Norepinephrine

NET

Norepinephrine transporter

SERT

Serotonin transporter

SSRI

Selective serotonin reuptake inhibitor

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • G. Quesseveur
    • 1
  • C. Repérant
    • 1
  • D. J. David
    • 1
  • A. M. Gardier
    • 1
  • C. Sanchez
    • 2
  • B. P. Guiard
    • 1
  1. 1.Laboratoire de Neuropharmacologie EA3544, Faculté de PharmacieUniversité Paris-Sud XIChâtenay-Malabry CedexFrance
  2. 2.Department of NeuropharmacologyLundbeck Research USAParamusUSA

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