[Ketamine: a neuropsychotropic drug with an innovative mechanism of action].
Jean-Philippe Guilloux, Thi Mai Loan Nguyen, Alain M Gardier
Biologie aujourd'hui 2023 DOI: 10.1051/jbio/2023026 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Intervention | Ketamine |
| Topics | Ketamine Serotonin Esketamine |
| Keywords | Antidepressant Antidépresseur Cortex préfrontal médian Excitation/glutamate Inhibition/gaba Kétamine Medial prefrontal cortex Sérotonine |
| Key findings | The authors propose that ketamine's rapid and sustained antidepressant effects in treatment-resistant depression depend on blockade of the NMDA glutamate receptor, activation of AMPA receptors, and downstream mTOR- and BDNF-dependent synaptic plasticity in medial prefrontal cortex pyramidal cells. They note that debates persist about structural remodeling of frontocortical and hippocampal neurons and the contribution of excitatory versus inhibitory neurotransmitters. |
Abstract
Ketamine, a non-competitive antagonist of the N-methyl-D-aspartate-glutamate receptor (R-NMDA), has a rapid (from 24 h post-dose) and prolonged (up to one week) antidepressant effect in treatment resistant depression and in rodent models of anxiety/depression. Arguments regarding its cellular and molecular mechanisms underlying its antidepressant activity mainly come from animal studies. However, debates still persist on the structural remodeling of frontocortical/hippocampal neurons and the role of excitatory/inhibitory neurotransmitters involved in its behavioral effect. Neurochemical and behavioral changes are maintained 24 h after administration of ketamine, well beyond its plasma elimination half-life. The glutamatergic pyramidal cells of the medial prefrontal cortex are primarily implicated in the therapeutic effects of ketamine. Advances in knowledge of the consequences of R-NMDA blockade allowed to specify the underlying mechanisms involving the activation of AMPA glutamate receptors, which triggers a cascade of intracellular events dependent on the mechanistic target of rapamycin, brain-derived neurotrophic factor, and synaptic protein synthesis facilitating synaptic plasticity (number of dendritic spines, synaptogenesis). This review focuses on abnormalities of neurotransmitter systems involved in major depressive disorders, their potential impact on neural circuitry and beneficial effects of ketamine. Recent preclinical data pave the way for future studies to better clarify the mechanism of action of fast-acting antidepressant drugs for the development of novel, more effective therapies.