A tale of two receptors: simultaneous targeting of NMDARs and 5-HT4Rs exerts additional effects against stress.

Background: Serotonin (5-HT) receptors and N-methyl-D-aspartate receptors (NMDARs) have been implicated in the pathophysiology of depression and anxiety disorders. Here, we evaluated whether targeting both receptors through combined dosing of (R,S)-ketamine, an NMDAR antagonist, and prucalopride, a 5-HT type IV receptor (5-HT₄R) agonist, would have additional effects, resulting in reductions in stress-induced fear, behavioral despair, and hyponeophagia.

Methods: A single injection of saline (Sal), (R,S)-ketamine (K), prucalopride (P), or a combined dose of (R,S)-ketamine and prucalopride (K+P) was administered before or after contextual fear conditioning (CFC) stress in both sexes. Drug efficacy was assayed using the forced swim test (FST), elevated plus maze (EPM), open field (OF), marble burying (MB), and novelty-suppressed feeding (NSF). Patch clamp electrophysiology was used to measure the effects of combined drug on neural activity in hippocampal CA3. c-fos and parvalbumin (PV) expression in the hippocampus (HPC) and medial prefrontal cortex (mPFC) was examined using immunohistochemistry and network analysis.

Results: A combination of K+P, given before or after stress, exerted additional effects, compared to either drug alone, in reducing a variety of stress-induced behaviors in both sexes. Combined K+P administration significantly altered c-fos and PV expression and network activity in the HPC and mPFC.

Conclusions: Our results indicate that K+P has extended benefits, in comparison to K or P alone, for combating stress-induced pathophysiology at the behavioral and neural level. Our findings provide preliminary evidence that future studies using this combined treatment strategy may prove advantageous in protecting against a broader range of stress-induced psychiatric disorders.