Hydroxynorketamine, but not ketamine, acts via α7 nicotinic acetylcholine receptor to control presynaptic function and gene expression

Major depressive disorder (MDD) is a disabling psychiatric disorder and a major cause of global health burden, affecting approximately 280 million people. Traditional antidepressants primarily target the monoaminergic system, have significant side effects and leave approximately 40% of patients unresponsive to treatment. Ketamine (KET) is a fast-acting antidepressant that transiently inhibits N-methyl-d-aspartate receptors (NMDARs) to produce its antidepressant effects. KET is rapidly metabolised to hydroxynorketamine (HNK), which reduces depressive behaviour in rodents. HNK has been shown to inhibit acetylcholine-evoked currents in α7 nicotinic acetylcholine receptors (α7nAChRs), but the role of α7nAChRs in mediating the cellular effects of HNK remains unknown. Overall, it is unclear how KETs and HNKs converge on similar systemic effects by acting on different membrane receptors.In this study, we first investigated the cellular effects induced by acute KET and HNK treatment by examining changes in neurotransmitter release and nuclear translocation of pCREB. We used live antibody labelling, immunocytochemistry and live imaging methods to show that KET and HNK have convergent effects on reducing glutamate release and synaptic vesicle release competence. The effects of KET are mimicked by Ro25-6981, a selective antagonist of GluN2B-containing NMDARs. Investigating the role of α7nAChRs in mediating KET and HNK effects, we show that genetic deletion and pharmacological blockade of Chrna7, the pore-forming subunit of α7nAChRs, abolishes presynaptic and nuclear regulation of HNK but leaves KET effects intact.We propose that cell type-specific and subsequent modulation of glutamatergic and cholinergic neurotransmission by KET and HNK, respectively, underlies the therapeutic effect of KET.