Abstract A deeper understanding of the targets and mechanisms of fast-acting antidepressants, exemplified by ketamine, remains indispensable for better therapeutic strategies and understanding depression. Beyond the canonical neuron-centric NMDAR inhibition hypothesis, brain opioid system and glia-mediated processes are increasingly implicated in ketamine’s antidepressant efficacy, yet their...
Ketamine produces rapid antidepressant effects but is constrained by psychotomimetic properties and abuse potential. The ketamine metabolite (2R,6R)-hydroxynorketamine (HNK) shows antidepressant-like efficacy without N-methyl-D-aspartate receptor (NMDAR) blockade, yet its upstream targets remain unclear. Here we show that HNK potentiates hippocampal excitatory transmission and reverses...