Journal
NEUROPHARMACOLOGY
Volume 100, Issue -, Pages 17-26Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.neuropharm.2015.07.028
Keywords
Ketamine; Depression; NMDAR; GluN2B; AMPAR; Ambient glutamate; Cortex; Inhibition; Disinhibition; NMDA receptor; AMPA receptor; Homeostatic synaptic plasticity; Protein synthesis
Categories
Funding
- National Institutes of Mental Health [MH R01 MH099378-01]
- Brain and Behavior Research Foundation (YIA) [18996]
- NATIONAL INSTITUTE OF MENTAL HEALTH [R01MH099378] Funding Source: NIH RePORTER
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A single, low dose of ketamine evokes antidepressant actions in depressed patients and in patients with treatment-resistant depression (TRD). Unlike classic antidepressants, which regulate monoamine neurotransmitter systems, ketamine is an antagonist of the N-methyl-D-aspartate (NMDA) family of glutamate receptors. The effectiveness of NMDAR antagonists in TRD unveils a new set of targets for therapeutic intervention in major depressive disorder (MDD) and TRD. However, a better understanding of the cellular mechanisms underlying these effects is required for guiding future therapeutic strategies, in order to minimize side effects and prolong duration of efficacy. Here we review the evidence for and against two hypotheses that have been proposed to explain how NMDAR antagonism initiates protein synthesis and increases excitatory synaptic drive in corticolimbic brain regions, either through selective antagonism of inhibitory interneurons and cortical disinhibition, or by direct inhibition of cortical pyramidal neurons. This article is part of the Special Issue entitled 'Synaptopathy - from Biology to Therapy'. (C) 2015 Elsevier Ltd. All rights reserved.
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