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

A combination of two FDA-approved drugs—(R,S)-ketamine, an anesthetic and NMDAR antagonist, and prucalopride, a 5-HT4 receptor agonist used for constipation—reduced stress-induced behavioral changes in male and female rodents after various stressors (fear conditioning, learned helplessness, stress-enhanced fear learning, and chronic corticosterone exposure). The combined treatment was more effective than either drug alone, and intranasal delivery also worked. Chronic administration of the combination broadly alleviated stress-related behaviors, suggesting potential for treating stress-induced psychiatric disorders in humans.

Study at a glance

Abstract

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.