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Br J Pharmacol. 2017 Aug;174(15):2471-2483. doi: 10.1111/bph.13857. Epub 2017 Jul 5.

Response of Htr3a knockout mice to antidepressant treatment and chronic stress.

Author information

1
Inserm UMR S894, Centre de Psychiatrie et Neuroscience, Université Paris Descartes, Paris, France.
2
Inserm UMR S1158, Neurophysiologie Respiratoire Expérimentale et Clinique, Université Pierre et Marie Curie, Paris, France.
3
Inserm UMR S1130, Neurosciences Paris Seine, Université Pierre et Marie Curie, Paris, France.
4
EA 4475, Pharmacologie de la circulation cérébrale, Université Paris Descartes, Paris, France.

Abstract

BACKGROUND AND PURPOSE:

It has recently been suggested that 5-HT3 receptor blockade enhances the efficacy of selective 5-HT (serotonin) reuptake inhibitor (SSRI) antidepressants and may reverse stress-induced deficits in rodents.

EXPERIMENTAL APPROACH:

To further explore this hypothesis, we used mice lacking the 5-HT3 receptor (Htr3a KO) and their wild-type (WT) controls to assess their response in behavioural paradigms relevant to anxiety and depression. Mice were studied under basal, antidepressant treatments and chronic social defeat stress (CSDS) conditions.

KEY RESULTS:

In basal conditions, Htr3a KO mice displayed anxiolytic- and antidepressant-like behaviours in the elevated plus maze, the social interaction and the forced swim tests (FST), but behaved as WT mice in response to acute citalopram in the FST. However, the effects of fluoxetine were blunted in Htr3a KO mice in these same tests. In an in vitro electrophysiological paradigm, a low-dose citalopram treatment triggered 5-HT1A receptor desensitization only in the dorsal raphe nucleus of Htr3a KO, although a high dose desensitized 5-HT1A autoreceptor function equally in Htr3a KO and WT mice, suggesting that citalopram may become effective at lower doses when 5-HT3 receptors are inactivated. In addition, Htr3a deletion blocked CSDS-induced modification in the cortical expression of two genes involved in oxidative stress, CaMKIIa and SOD1.

CONCLUSIONS AND IMPLICATIONS:

Taken together, these data show that Htr3a deletion promotes SSRI efficacy and prevents the occurrence of stress-induced deleterious effects, suggesting that the 5-HT3 receptor may represent an interesting target for the treatment of stress-related disorders.

PMID:
28493335
PMCID:
PMC5513867
DOI:
10.1111/bph.13857
[Indexed for MEDLINE]
Free PMC Article

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