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.
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.
bioRxiv Preprint Server
April 3, 2024
Thi Mai Loan Nguyen, Jean-Philippe Guilloux, Céline Defaix et al.
preprint
Ketamine's rapid antidepressant effects in depressed patients may depend on a specific metabolite, (2R,6R)-hydroxynorketamine ((6)-HNK). In male BALB/cJ mice with high anxiety, blocking liver enzymes that break down ketamine (using fluconazole) raised ketamine and norketamine levels in blood and brain but sharply reduced (6)-HNK levels. This blockade prevented ketamine's sustained antidepressant-like effects 24 hours later in behavioral tests and stopped the increase in cortical GABA levels. Giving a single dose of (2R,6R)-HNK alone restored the antidepressant-like activity. The findings indicate that (6)-HNK is essential for ketamine's lasting antidepressant effects and suggest that drug interactions affecting ketamine metabolism could matter in patients.