Chronic, combinatorial targeting of NMDARs and 5-HT₄Rs exerts extended behavioral effects against stress-induced...

Serotonin (5-HT) receptors and N-methyl-D-aspartate receptors (NMDARs) have both been implicated in stress-induced psychiatric disorders. However, there is a paucity of studies evaluating the effectiveness of novel combinatorial pharmacological treatments to treat stress-related disorders. Here, we evaluated whether administration of combinatorial (R,S)-ketamine, an NMDAR antagonist and Food and Drug Administration (FDA)-approved anesthetic, and prucalopride, a 5-HT type IV receptor (5-HT₄R) agonist and FDA-approved drug for chronic idiopathic constipation (CIC), would have additional effects when administered after stress. 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 for 1x, 2x, or 7x per week for 2 weeks after either contextual fear conditioning (CFC), learned helplessness (LH), stress enhanced fear learning (SEFL), or chronic corticosterone (CORT) stress in both sexes. Drug efficacy was assayed using assays to measure fear, behavioral despair, perseverative, and/or hyponeophagia. Combinatorial drug administration was also tested using intranasal delivery. We found that combinatorial K + P exerted additional effects, compared to either drug alone, in reducing a variety of stress-induced behaviors in both sexes. Moreover, intranasal dosing was also effective. Our results indicate that chronic administration of K + P has extended benefits for combating stress-induced pathophysiology. Our findings provide strong evidence that future clinical studies using this chronic treatment strategy may prove advantageous in decreasing a broad range of stress-induced psychiatric disorders.