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- Title
Esmethadone (REL-1017) and Other Uncompetitive NMDAR Channel Blockers May Improve Mood Disorders via Modulation of Synaptic Kinase-Mediated Signaling.
- Authors
Stahl, Stephen M.; De Martin, Sara; Mattarei, Andrea; Bettini, Ezio; Pani, Luca; Guidetti, Clotilde; Folli, Franco; de Somer, Marc; Traversa, Sergio; Inturrisi, Charles E.; Pappagallo, Marco; Gentilucci, Marco; Alimonti, Andrea; Fava, Maurizio; Manfredi, Paolo L.
- Abstract
This article presents a mechanism of action hypothesis to explain the rapid antidepressant effects of esmethadone (REL-1017) and other uncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonists and presents a corresponding mechanism of disease hypothesis for major depressive disorder (MDD). Esmethadone and other uncompetitive NMDAR antagonists may restore physiological neural plasticity in animal models of depressive-like behavior and in patients with MDD via preferential tonic block of pathologically hyperactive GluN2D subtypes. Tonic Ca2+ currents via GluN2D subtypes regulate the homeostatic availability of synaptic proteins. MDD and depressive behaviors may be determined by reduced homeostatic availability of synaptic proteins, due to upregulated tonic Ca2+ currents through GluN2D subtypes. The preferential activity of low-potency NMDAR antagonists for GluN2D subtypes may explain their rapid antidepressant effects in the absence of dissociative side effects.
- Subjects
AFFECTIVE disorders; MENTAL depression; NEUROPLASTICITY; ANTIDEPRESSANTS; METHYL aspartate receptors
- Publication
International Journal of Molecular Sciences, 2022, Vol 23, Issue 20, p12196
- ISSN
1661-6596
- Publication type
Article
- DOI
10.3390/ijms232012196