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Prophylactic efficacy of 5-HT₄R agonists against stress.

ABSTRACT: Enhancing stress resilience could protect against stress-induced psychiatric disorders in at-risk populations. We and others have previously reported that (R,S)-ketamine acts as a prophylactic against stress when administered 1 week before stress. While we have shown that the selective 5-hydroxytryptamine (5-HT) (serotonin) reuptake inhibitor (SSRI) fluoxetine (Flx) is ineffective as a prophylactic, we hypothesized that other serotonergic compounds such as serotonin 4 receptor (5-HT₄R) agonists could act as prophylactics. We tested if three 5-HT₄R agonists with varying affinity could protect against stress in two mouse strains by utilizing chronic corticosterone (CORT) administration or contextual fear conditioning (CFC). Mice were administered saline, (R,S)-ketamine, Flx, RS-67,333, prucalopride, or PF-04995274 at varying doses, and then 1 week later were subjected to chronic CORT or CFC. In C57BL/6N mice, chronic Flx administration attenuated CORT-induced weight changes and increased open-arm entries in the elevated plus maze (EPM). Chronic RS-67,333 administration attenuated CORT-mediated weight changes and protected against depressive- and anxiety-like behavior. In 129S6/SvEv mice, RS-67,333 attenuated learned fear in male, but not female mice. RS-67,333 was ineffective against stress-induced depressive-like behavior in the forced swim test (FST), but prevented anxiety-like behavior in both sexes. Prucalopride and PF-04995274 attenuated learned fear and decreased stress-induced depressive-like behavior. Electrophysiological recordings following (R,S)-ketamine or prucalopride administration revealed that both drugs alter AMPA receptor-mediated synaptic transmission in CA3. These data show that in addition to (R,S)-ketamine, 5-HT₄R agonists are also effective prophylactics against stress, suggesting that the 5-HT₄R may be a novel target for prophylactic drug development.

SUBMITTER: Chen BK

PROVIDER: S-EPMC6969048 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Prophylactic efficacy of 5-HT<sub>4</sub>R agonists against stress.

Chen Briana K BK Mendez-David Indira I Luna Victor M VM Faye Charlène C Gardier Alain M AM David Denis J DJ Denny Christine A CA

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20191010 3

Enhancing stress resilience could protect against stress-induced psychiatric disorders in at-risk populations. We and others have previously reported that (R,S)-ketamine acts as a prophylactic against stress when administered 1 week before stress. While we have shown that the selective 5-hydroxytryptamine (5-HT) (serotonin) reuptake inhibitor (SSRI) fluoxetine (Flx) is ineffective as a prophylactic, we hypothesized that other serotonergic compounds such as serotonin 4 receptor (5-HT<sub>4</sub>R ...[more]

PMID: 31600767

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Prophylactic efficacy of 5-HT₄R agonists against stress.

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Prophylactic efficacy of 5-HT<sub>4</sub>R agonists against stress.

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Prophylactic efficacy of 5-HT4R agonists against stress.

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Prophylactic efficacy of 5-HT<sub>4</sub>R agonists against stress.

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Prophylactic efficacy of 5-HT₄R agonists against stress.