Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
May 1, 2025
Kyle A Brown, Musa I Ajibola, Todd D Gould
13 citations
A metabolite of ketamine, (2R,6R)-hydroxynorketamine (HNK), maintains antidepressant-like effects in mice without adverse effects. Using brain slices from mice, researchers developed a model to study how HNK produces rapid versus sustained synaptic changes. HNK rapidly strengthened connections between neurons in the hippocampus, an effect that did not require NMDA receptor activity. However, maintaining a primed state that enhanced later long-term potentiation (a form of synaptic plasticity) did require NMDA receptors. HNK's rapid effects depended on adenylyl cyclase 1 and protein kinase A activity. The findings suggest that targeting such priming mechanisms could be a strategy for developing antidepressants.
Neuron
November 19, 2025
Kyle A Brown, Musa I Ajibola, Gustavo C Medeiros et al.
6 citations
Ketamine, a rapid-acting antidepressant, relieves depression symptoms for days after the drug leaves the body, and repeated doses produce longer-lasting effects. This review proposes that ketamine and similar drugs act as synaptic primers, making synapses more responsive to subsequent doses, a process derived from metaplasticity. The indirect relationship between ketamine's pharmacokinetics and sustained pharmacodynamics defines a dosing model called primer pharmacology, which can optimize therapeutic outcomes. The plasticity mechanisms engaged by antidepressants overlap with those triggered by stress and psychotherapy, suggesting combined treatment strategies. Emerging primers like psilocybin also fit this framework, offering a model to guide clinical and translational psychiatry.
The Journal of neuroscience : the official journal of the Society for Neuroscience
February 3, 2026
Kyle A Brown, Patrick J Morris, Craig J Thomas et al.
The antidepressant effects of ketamine arise from its metabolite (2R,6R)-hydroxynorketamine (2R6R), not from ketamine itself. In mouse hippocampal slices, 2R6R rapidly strengthens synapses and induces long-lasting metaplasticity—a form of plasticity that primes synapses for future change—whereas ketamine alone does not. This rapid and sustained plasticity requires mTOR signaling and can be mimicked by activating mTOR. The sustained phase also depends on IP3 receptors, L-type calcium channels, and delayed BDNF/TrkB signaling, but not on new protein synthesis. The findings outline a sequence of molecular events underlying 2R6R's synaptic actions, with implications for developing rapid-acting antidepressants and understanding activity-dependent plasticity.
bioRxiv : the preprint server for biology
October 22, 2024
Kyle A Brown, Musa I Ajibola, Todd D Gould
preprint
A metabolite of ketamine, (2R,6R)-hydroxynorketamine (HNK), rapidly potentiates synaptic transmission at the Schaffer collateral-CA1 synapse in mouse hippocampal slices, an effect that does not require N-methyl-D-aspartate receptor (NMDAR) activity. However, NMDAR activity is necessary to sustain a metaplastic state that lowers the threshold for long-term potentiation (LTP) hours after HNK exposure. The rapid potentiation depends on protein kinase A (PKA) and adenylyl cyclase 1 (AC1), but not AC5. These findings suggest that HNK's rapid synaptic actions initiate sustained priming mechanisms that favor antidepressant-relevant plasticity, offering a target for novel antidepressant strategies.