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


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.

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Serotonin 2A receptor


Atypical antipsychotic


Dorsal raphe


Forced swimming test


Locus coeruleus


Major depressive disorder




Norepinephrine transporter


Serotonin transporter


Selective serotonin reuptake inhibitor


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This work has been supported by the technical assistance of the Animal Care Facility of the Institut Fédératif de Recherche IFR141 of the University of Paris Sud 11. We particularly thank Dr Isabelle Seif and Pauline Robert for their active role in the breeding of 5-HT2AR/5-HT2CR wild-type and knock-out mice. The authors also thank Dr M. El Mansari for helpful discussions and critical reading of the manuscript.

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Correspondence to B. P. Guiard.

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G. Quesseveur and C. Repérant contributed equally to this study.

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Quesseveur, G., Repérant, C., David, D.J. et al. 5-HT2A receptor inactivation potentiates the acute antidepressant-like activity of escitalopram: involvement of the noradrenergic system. Exp Brain Res 226, 285–295 (2013). https://doi.org/10.1007/s00221-013-3434-3

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  • 5-HT
  • 5-HT2A receptor
  • Antidepressants
  • Antipsychotics
  • Norepinephrine
  • SSRIs