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Role of the AMPA receptor in antidepressant effects of ketamine and potential of AMPA receptor potentiators as a novel antidepressant.
- Source :
-
Neuropharmacology . Jan2023, Vol. 222, pN.PAG-N.PAG. 1p. - Publication Year :
- 2023
-
Abstract
- Ketamine exerts rapid and long-lasting antidepressant effects in patients with treatment-resistant depression. However, its clinical use is limited by its undesirable psychotomimetic side effects. Accumulating evidence from preclinical studies has shown that the antidepressant effects of ketamine are dependent on α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA-R) activation, which triggers activation of the mechanistic target of rapamycin pathway and brain-derived neurotrophic factor release. Thus, AMPA-R has emerged as a promising new target for novel antidepressants with a rapid onset of action. However, almost all known AMPA-R potentiators carry the risk of a narrow bell-shaped dose-response curve and a poor safety margin against seizures. Our data suggest that agonistic activity is not only related to the risks of bell-shaped dose-response curves and seizures but also to the reduced synaptic transmission and procognitive effects of AMPA-R potentiators. In this review, we describe our original screening approach that led to the discovery of an investigational AMPA-R potentiator with low agonistic activity, TAK-653. We further review the in vitro and in vivo profiles of TAK-653, including its procognitive and antidepressant-like effects, as well as its safety profile, in comparison with known AMPA-R potentiators with agonistic activity and AMPA, an AMPA-R agonist. The low agnostic activity of TAK-653 may overcome limitations of known AMPA-R potentiators. This article is part of the Special Issue on 'Ketamine and its Metabolites'. • AMPA-R activation is involved in the antidepressant activity of ketamine. • Minimal agonism is key to enhancing synaptic transmission and procognitive effects. • TAK-653 with low agonistic effects was discovered by an original screening approach. • TAK-653 has a wide safety window with procognitive effect at broad range of dosages. • TAK-653 stimulated BDNF-mTOR signaling and showed antidepressant-like effects. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 00283908
- Volume :
- 222
- Database :
- Academic Search Index
- Journal :
- Neuropharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 160250417
- Full Text :
- https://doi.org/10.1016/j.neuropharm.2022.109308