Mu opioid receptor (MOR) activation is required for the antidepressant-like effects of both (R,S)-ketamine and the selective NMDAR antagonist fluoroethylnormemantine (FENM) against stress-induced maladaptive behaviors. (R,S)-ketamine and its enantiomers showed weak partial agonism of MOR, while FENM had negligible direct MOR activity. Despite these differences, the long-acting MOR antagonist methocinnamox (MCAM) blocked the behavioral effects of both compounds when given before or after stress. The antinociceptive effect of (R,S)-ketamine was more potent and more sensitive to MCAM blockade than that of FENM. These findings suggest that NMDAR antagonists function indirectly through endogenous opioid signaling to produce their effects.
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.
Combining the drugs (R,S)-ketamine and prucalopride improved memory retrieval in a mouse model of Alzheimer's disease, suggesting a new multimodal strategy for treating cognitive decline. The treatment was less effective in females than in males and its effects depended on the age of the mice. Chronic treatment also reduced a marker of neuroinflammation (GFAP) in the hippocampus of female mice.