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

Guhathakurta D, Petrušková A, Akdas EY, Perelló Amorós B, Frischknecht R, Anni D, Weiss EM, Walter M, Fejtová A (2024)

Publication Language: English

Publication Type: Journal article

Publication year: 2024

Journal

Translational Psychiatry Springer Nature

Book Volume: 14

Article Number: 47

DOI: 10.1038/s41398-024-02744-y

Abstract

Ketamine is clinically used fast-acting antidepressant. Its metabolite hydroxynorketamine (HNK) shows a robust antidepressant effect in animal studies. It is unclear, how these chemically distinct compounds converge on similar neuronal effects. While KET acts mostly as N-methyl-d-aspartate receptor (NMDAR) antagonist, the molecular target of HNK remains enigmatic. Here, we show that KET and HNK converge on rapid inhibition of glutamate release by reducing the release competence of synaptic vesicles and induce nuclear translocation of pCREB that controls expression of neuroplasticity genes connected to KET- and HNK-mediated antidepressant action. Ro25-6981, a selective antagonist of GluN2B, mimics effect of KET indicating that GluN2B-containing NMDAR might mediate the presynaptic effect of KET. Selective antagonist of α7 nicotinic acetylcholine receptors (α7nAChRs) or genetic deletion of Chrna7, its pore-forming subunit, fully abolishes HNK-induced synaptic and nuclear regulations, but leaves KET-dependent cellular effects unaffected. Thus, KET or HNK-induced modulation of synaptic transmission and nuclear translocation of pCREB can be mediated by selective signaling via NMDAR or α7nAChRs, respectively. Due to the rapid metabolism of KET to HNK, it is conceivable that subsequent modulation of glutamatergic and cholinergic neurotransmission affects circuits in a cell-type-specific manner and contributes to the therapeutic potency of KET. This finding promotes further exploration of new combined medications for mood disorders.

Authors with CRIS profile

Debarpan Guhathakurta Department of Psychiatry and Psychotherapy Aneta Petrušková Professur für Molekulare Psychiatrie Enes Yagiz Akdas Department of Psychiatry and Psychotherapy Bartomeu Perelló Amorós Lehrstuhl für Tierphysiologie Renato Frischknecht Lehrstuhl für Tierphysiologie Daniela Anni Department of Psychiatry and Psychotherapy Eva-Maria Weiss Department of Psychiatry and Psychotherapy Anna Fejtová Professur für Molekulare Psychiatrie

Involved external institutions

Universitätsklinikum Jena DE Germany (DE)

How to cite

APA:

Guhathakurta, D., Petrušková, A., Akdas, E.Y., Perelló Amorós, B., Frischknecht, R., Anni, D.,... Fejtová, A. (2024). Hydroxynorketamine, but not ketamine, acts via α7 nicotinic acetylcholine receptor to control presynaptic function and gene expression. Translational Psychiatry, 14. https://doi.org/10.1038/s41398-024-02744-y

MLA:

Guhathakurta, Debarpan, et al. "Hydroxynorketamine, but not ketamine, acts via α7 nicotinic acetylcholine receptor to control presynaptic function and gene expression." Translational Psychiatry 14 (2024).

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