Hydroxynorketamine, but not ketamine, acts via α7 nicotinic acetylcholine receptor to control presynaptic function and gene expression
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00023752%3A_____%2F24%3A43921326" target="_blank" >RIV/00023752:_____/24:43921326 - isvavai.cz</a>
Alternative codes found
RIV/00216208:11120/24:43926565
Result on the web
<a href="https://www.nature.com/articles/s41398-024-02744-y" target="_blank" >https://www.nature.com/articles/s41398-024-02744-y</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1038/s41398-024-02744-y" target="_blank" >10.1038/s41398-024-02744-y</a>
Alternative languages
Result language
angličtina
Original language name
Hydroxynorketamine, but not ketamine, acts via α7 nicotinic acetylcholine receptor to control presynaptic function and gene expression
Original language description
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.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
30215 - Psychiatry
Result continuities
Project
<a href="/en/project/GA20-25349S" target="_blank" >GA20-25349S: Psychoplastogenicity of psilocybin – the interplay of serotonergic mechanisms, sleep–wake cycle and neuroplasticity on memory consolidation</a><br>
Continuities
P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)
Others
Publication year
2024
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
Translational Psychiatry
ISSN
2158-3188
e-ISSN
2158-3188
Volume of the periodical
14
Issue of the periodical within the volume
"Article number: 47"
Country of publishing house
GB - UNITED KINGDOM
Number of pages
14
Pages from-to
1-14
UT code for WoS article
001155057800005
EID of the result in the Scopus database
2-s2.0-85182710431