(2R,6R)-Hydroxynorketamine promotes dendrite outgrowth in human inducible pluripotent stem cell-derived neurons through AMPA receptor with timing and exposure compatible with ketamine infusion pharmacokinetics in humans.

The mechanisms underlying the prolonged antidepressant effects after a single infusion of ketamine are only partially understood. Ketamine's half-life of ∼2 h cannot explain antidepressant effects that last for 1 week, suggesting the triggering of long-lasting neuroplasticity. Recent human pharmacokinetics (PK) data indicate that a ketamine metabolite, (2R,6R)-hydroxynorketamine (HNK), persists in the high submicromolar range for additional 6-12 h. As in rodents HNK can induce dendrite outgrowth through AMPA receptor-mediated mechanisms, in this work, we aimed to show that HNK produces similar effects in human neurons at concentrations and exposure time compatible with human PK after ketamine infusion. Human dopaminergic neurons were differentiated in-vitro from inducible pluripotent stem cells obtained from healthy donors. Exposure to submicromolar HNK for 6 h produced dendrite outgrowth when measured 3 days after exposure. This neuroplasticity was similar to that obtained with exposure to low micromolar concentrations of ketamine for 1 or 6 h. HNK and ketamine effects were blocked by pretreatment with the AMPA receptor antagonists NBQX and GYKI 52466, and by the mammalian target of rapamycin pathway blocker rapamycin. It is reasonable to conclude that the mechanistic similarity between ketamine and HNK and their diachronic brain exposure owing to the different plasma PK observed after single therapeutic ketamine infusion should contribute to the final sustained antidepressant action.