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(2S,6S)- and (2R,6R)-hydroxynorketamine inhibit the induction of NMDA receptor-dependent LTP at hippocampal CA1 synapses in mice

The ketamine metabolite (2R,6R)-hydroxynorketamine has been proposed to have rapid and persistent antidepressant actions in rodents, but its mechanism of action is controversial. We have compared the ability of (R,S)-ketamine with the (2S,6S)- and (2R,6R)-isomers of hydroxynorketamine to affect the...

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Detalles Bibliográficos
Autores principales: Kang, Heather, Park, Pojeong, Han, Muchun, Tidball, Patrick, Georgiou, John, Bortolotto, Zuner A., Lodge, David, Kaang, Bong-Kiun, Collingridge, Graham L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: SAGE Publications 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7545754/
https://www.ncbi.nlm.nih.gov/pubmed/33088919
http://dx.doi.org/10.1177/2398212820957847
Descripción
Sumario:The ketamine metabolite (2R,6R)-hydroxynorketamine has been proposed to have rapid and persistent antidepressant actions in rodents, but its mechanism of action is controversial. We have compared the ability of (R,S)-ketamine with the (2S,6S)- and (2R,6R)-isomers of hydroxynorketamine to affect the induction of N-methyl-d-aspartate receptor–dependent long-term potentiation in the mouse hippocampus. Following pre-incubation of these compounds, we observed a concentration-dependent (1–10 μM) inhibition of long-term potentiation by ketamine and a similar effect of (2S,6S)-hydroxynorketamine. At a concentration of 10 μM, (2R,6R)-hydroxynorketamine also inhibited the induction of long-term potentiation. These findings raise the possibility that inhibition of N-methyl-d-aspartate receptor–mediated synaptic plasticity is a site of action of the hydroxynorketamine metabolites with respect to their rapid and long-lasting antidepressant-like effects.