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 resilience enhancing drug (e.g., 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, it remains to be determined if other serotonergic drugs could be effective prophylactics. Here, we hypothesized that serotonin 4 receptor (5-HT4R) agonists could be prophylactic against fear, depressive-like, and/or anxiety-like behavior. We tested if three 5-HT4R agonists with varying affinity (e.g., partial or selective agonists) could protect against stress in two mouse strains by utilizing a chronic corticosterone (CORT) administration or a contextual fear conditioning (CFC) paradigm. Mice were administered RS-67,333, prucalopride, or PF-04995274 at varying doses and then 1 week later were subjected to chronic CORT or CFC. Chronic administration of RS-67,333, but not Flx was efficacious as a prophylactic against CORT in C57BL/6NTac mice. A single injection of RS-67,333 attenuated learned fear in male, but not female 129S6/SvEv mice. RS-67,333 was ineffective against stress-induced depressive-like behavior in the forced swim test (FST). A single injection of either prucalopride or PF-04995274 attenuated learned fear and decreased stress-induced depressive-like behavior. 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.