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Enhancing AMPA to NMDA throughput as a convergent mechanism for antidepressant action.

ABSTRACT: In this article, we first review current knowledge of the AMPA and NMDA glutamate receptors, their physiological properties and functions and their regulation by signaling cascades. We then discuss our hypothesis that the therapeutic effects of monoaminergic antidepressants and ketamine, an NMDA receptor antagonist, may be mediated by increased AMPA to NMDA throughput in critical neuronal circuits. We hypothesize that ketamine mediates this throughput directly, thus resulting in rapid antidepressant effects whereas monoaminergic antidepressants work indirectly and gradually; this may explain, in part, the delayed onset of several weeks to months that is observed with traditional antidepressants.

SUBMITTER: Du J

PROVIDER: S-EPMC4234070 | biostudies-literature | 2006

REPOSITORIES: biostudies-literature

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Enhancing AMPA to NMDA throughput as a convergent mechanism for antidepressant action.

Du Jing J Machado-Vieira Rodrigo R Maeng Sungho S Martinowich Keri K Manji Husseini K HK Zarate Carlos A CA

Drug discovery today. Therapeutic strategies 20060101 4

In this article, we first review current knowledge of the AMPA and NMDA glutamate receptors, their physiological properties and functions and their regulation by signaling cascades. We then discuss our hypothesis that the therapeutic effects of monoaminergic antidepressants and ketamine, an NMDA receptor antagonist, may be mediated by increased AMPA to NMDA throughput in critical neuronal circuits. We hypothesize that ketamine mediates this throughput directly, thus resulting in rapid antidepres ...[more]

PMID: 25411578

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Project description:Traditional pharmacological treatments for depression have a delayed therapeutic onset, ranging from several weeks to months, and there is a high percentage of individuals who never respond to treatment. In contrast, ketamine produces rapid-onset antidepressant, anti-suicidal, and anti-anhedonic actions following a single administration to patients with depression. Proposed mechanisms of the antidepressant action of ketamine include N-methyl-D-aspartate receptor (NMDAR) modulation, gamma aminobutyric acid (GABA)-ergic interneuron disinhibition, and direct actions of its hydroxynorketamine (HNK) metabolites. Downstream actions include activation of the mechanistic target of rapamycin (mTOR), deactivation of glycogen synthase kinase-3 and eukaryotic elongation factor 2 (eEF2), enhanced brain-derived neurotrophic factor (BDNF) signaling, and activation of ?-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptors (AMPARs). These putative mechanisms of ketamine action are not mutually exclusive and may complement each other to induce potentiation of excitatory synapses in affective-regulating brain circuits, which results in amelioration of depression symptoms. We review these proposed mechanisms of ketamine action in the context of how such mechanisms are informing the development of novel putative rapid-acting antidepressant drugs. Such drugs that have undergone pre-clinical, and in some cases clinical, testing include the muscarinic acetylcholine receptor antagonist scopolamine, GluN2B-NMDAR antagonists (i.e., CP-101,606, MK-0657), (2R,6R)-HNK, NMDAR glycine site modulators (i.e., 4-chlorokynurenine, pro-drug of the glycineB NMDAR antagonist 7-chlorokynurenic acid), NMDAR agonists [i.e., GLYX-13 (rapastinel)], metabotropic glutamate receptor 2/3 (mGluR2/3) antagonists, GABAA receptor modulators, and drugs acting on various serotonin receptor subtypes. These ongoing studies suggest that the future acute treatment of depression will typically occur within hours, rather than months, of treatment initiation.

Dataset Information

Enhancing AMPA to NMDA throughput as a convergent mechanism for antidepressant action.

Publications

Enhancing AMPA to NMDA throughput as a convergent mechanism for antidepressant action.

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