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- Title
5-HT receptor inactivation potentiates the acute antidepressant-like activity of escitalopram: involvement of the noradrenergic system.
- Authors
Quesseveur, G.; Repérant, C.; David, D.; Gardier, A.; Sanchez, C.; Guiard, B.
- Abstract
Evidence suggests that the serotonin 2A receptor (5-HTR) 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-HTR expression or function are lacking and the precise role of this receptor is still matter of debate. This study examined the effect of 5-HTR 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-HTR agonist DOI decreased the firing rate of 5-HT neurons in the dorsal raphe (DR) nucleus of 5-HTR anesthetized mice. This inhibitory response persisted in 5-HTR but was completely blunted in 5-HTR mutants. Moreover, the suppressant effect of DOI on DR 5-HT neuronal activity in 5-HTR mice was attenuated by the loss of noradrenergic neurons induced by the neurotoxin DSP4. Conversely, in 5-HTR mice, the pharmacological inactivation of the 5-HTR 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-HTR 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-HTR 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.
- Subjects
SEROTONIN; GENETIC polymorphisms; ANTIDEPRESSANTS; NEUTRAL trade with belligerents; ANTIPSYCHOTIC agents
- Publication
Experimental Brain Research, 2013, Vol 226, Issue 2, p285
- ISSN
0014-4819
- Publication type
Article
- DOI
10.1007/s00221-013-3434-3