(2R,6R)-Hydroxynorketamine elicits rapid antidepressant effects by promoting astrocytic μ-δ opioid receptor heterodimerization
Liang, Y.; Wang, L.; Li, Y.; Li, X.; Sun, Y.; Yang, M.; Guo, X.; Mu, J.; Xu, C.; Thapa, R.; Cheng, Y.; Zhang, H.; He, Z.; Yan, S.; Yang, S.; Fong, T. H.; Bai, H.; Xu, J.; Zhang, Q.; Lui, L.; Li, M.; Xu, D.; Geng, W.; Su, J.; Tang, A.; Wang, C.; Zhou, Q.; Cai, X.
Show abstract
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 stress-induced behavioural deficits through opioid receptor signaling. Pharmacological and genetic analyses reveal a requirement for both {micro}- and {delta}-opioid receptors in astrocytes. Chronic stress reduces {micro}-{delta} receptor heterodimers in the hippocampus, and a single dose of HNK restores their abundance. PAINT-MINFLUX nanoscopy quantifies increased {micro}-{delta} heterodimerization, and molecular dynamics simulations indicate selective binding of HNK to the {micro}-receptor protomer via Asp147 and Tyr148. Mutating these residues abolishes HNK-driven heterodimer formation, downstream signaling and rapid antidepressant-like effects in vivo. Astrocytic {micro}-{delta} opioid receptor heterodimers thus represent a targetable mechanism for next-generation rapid-acting antidepressants.
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