Biological psychiatry
July 7, 2025
Cory B Langreck, Briana Chen, Victor M Luna et al.
9 citations
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.
Biological psychiatry
May 1, 2025
Alessia Mastrodonato, Michelle Jin, Noelle Kee et al.
5 citations
A single injection of (R,S)-ketamine or its metabolite (2S,6S)-hydroxynorketamine (HNK) given one week before stress attenuated learned fear in male mice. The drugs altered neural activity in distinct and overlapping brain regions: (2S,6S)-HNK affected dorsal CA3, while both drugs changed activity in ventral CA3, CA1, infralimbic and prelimbic cortex, insular cortex, retrosplenial cortex, piriform cortex, nucleus reuniens, and periaqueductal gray. (R,S)-ketamine uniquely affected the paraventricular nucleus of the thalamus. (R,S)-ketamine increased connectivity between cortical and subcortical regions, whereas (2S,6S)-HNK increased connectivity within those regions. The findings identify novel fear network nodes that could be targeted to treat fear-induced disorders.
Neuropharmacology
November 1, 2024
Thi Mai Loan Nguyen, Jean-Philippe Guilloux, Céline Defaix et al.
3 citations
Ketamine produces rapid and lasting antidepressant effects in depressed patients. A metabolite called (2R,6R)-hydroxynorketamine (HNK) may contribute to these effects. In anxious male mice, blocking the liver enzyme cytochrome P450 with fluconazole before ketamine or HNK altered drug metabolism: it raised ketamine and norketamine levels in blood and brain but sharply reduced HNK levels. Fluconazole also prevented ketamine's sustained antidepressant-like actions in behavioral tests and its enhancement of cortical GABA levels 24 hours after injection. Giving (2R,6R)-HNK alone reversed fluconazole's blockade of ketamine's antidepressant-like activity. The findings suggest that HNK is essential for ketamine's sustained antidepressant effects and that drug interactions with cytochrome P450 inhibitors may affect ketamine treatment in patients.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
April 22, 2025
Briana K Chen, Alicia Whye, Louise C Matthews et al.
2 citations
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.
The international journal of neuropsychopharmacology
October 1, 2024
Nicholas E Bulthuis, Josephine C McGowan, Liliana R Ladner et al.
2 citations
Ketamine, a rapid-acting antidepressant, requires a specific NMDA receptor subunit (GluN2B) on adult-born neurons in the hippocampus to produce its effects, but this requirement differs between sexes. In male mice, GluN2B on 6-week-old adult-born neurons is necessary for ketamine to reduce behavioral despair, suppress feeding anxiety, and alter fear behavior. In female mice, GluN2B on these neurons is needed only for reducing feeding anxiety. Removing GluN2B from younger 2-week-old neurons did not replicate these effects. Eliminating adult neurogenesis increased fear expression, which ketamine administration counteracted. These findings indicate that 6-week-old adult-born hippocampal neurons partially mediate ketamine's rapid antidepressant actions, suggesting a target for improving treatment efficacy.
Alzheimer's research & therapy
July 15, 2025
Briana K Chen, Holly C Hunsberger, Alicia Whye et al.
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.