Fast-acting antidepressant activity of ketamine: highlights on brain serotonin, glutamate, and GABA neurotransmission in preclinical studies

Publication date: Available online 7 March 2019Source: Pharmacology & TherapeuticsAuthor(s): Thu Ha PHAM, Alain M. GARDIERAbstract:Ketamine, a non-competitive antagonist of N-methyl-D-aspartate (NMDA) receptor, displays a fast antidepressant activity in treatment-resistant depression and in rodent models of anxiety/depression. A large body of evidence concerning the cellular and molecular mechanisms underlying its fast antidepressant-like activity comes from animal studies. Although structural remodeling of frontocortical/hippocampal neurons has been proposed as critical, the role of excitatory/inhibitory neurotransmitters in this behavioral effect is unclear. Neurochemical and behavioral changes are maintained 24h after ketamine administration, well beyond its plasma elimination half-life. Thus, ketamine is believed to initiate a cascade of cellular mechanisms supporting its fast antidepressant-like activity. To date, the underlying mechanism involves glutamate release, then downstream activation of AMPA receptors, which trigger mammalian target of rapamycin (mTOR)-dependent structural plasticity via brain-derived neurotrophic factor (BDNF) and protein neo-synthesis in the medial prefrontal cortex (mPFC), a brain region strongly involved in ketamine therapeutic effects. However, these mPFC effects are not restricted to glutamatergic pyramidal cells, but extend to other neurotransmitters (GABA, serotonin), glial cells, and brain circuits (mPFC/dorsal raphe nucleus-DRN). It co...
Source: Pharmacology and Therapeutics - Category: Drugs & Pharmacology Source Type: research