A Tale of Two Receptors: Simultaneous Targeting of NMDA Receptors and 5-HT4 Receptors Exerts Additional Effects Against Stress

Background Serotonin (5-HT) receptors and NMDA 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 (K), an NMDAR antagonist, and prucalopride (P), a 5-HT 4 receptor agonist, would have additional effects, resulting in reductions in stress-induced fear, behavioral despair, and hyponeophagia. Methods A single injection of saline, K, P, or a combined dose of K+P was administered before or after contextual fear conditioning stress in both sexes. Drug efficacy was assayed using the forced swim test, elevated plus maze, open field, marble burying, and novelty-suppressed feeding. 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) were examined using immunohistochemistry and network analysis. Results A combination of K+P, given before or after stress, exerted additional effects, compared with 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, compared with 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.