Glutamate NMDA receptor antagonists rapidly reverse behavioral and synaptic deficits caused by chronic stress exposure

By Nanxin Li, Rong‐jian Liu, J. Dwyer, M. Banasr, Boyoung Lee, H. Son, Xiao-Yuan Li, G. Aghajanian, R. Duman. Biological Psychiatry, 2011

1,040 citations recorded by the source corpus.

Background Despite widely reported clinical and preclinical studies of rapid antidepressant actions of glutamate N-methyl-D-aspartic acid (NMDA) receptor antagonists, there has been very little work examining the effects of these drugs in stress models of depression that require chronic administration of antidepressants, or the molecular mechanisms that could account for the rapid responses. Methods We used a rat 21-day chronic unpredictable stress (CUS) model to test the rapid actions of NMDA receptor antagonists on depressant-like behavior, neurochemistry, and spine density and synaptic function of prefrontal cortex (PFC) neurons. Results The results demonstrate that acute treatment with the non-competitive NMDA channel blocker ketamine or the selective NR2B antagonist Ro 25-6981 rapidly ameliorates CUS-induced anhedonia and anxiogenic behaviors. We also find that CUS exposure decreases the expression levels of synaptic proteins and spine number and the frequency/amplitude of synaptic currents (EPSCs) in layer V pyramidal neurons in the PFC, and that these deficits are rapidly reversed by ketamine. Blockade of the mammalian target of rapamycin (mTOR) protein synthesis cascade abolishes both the behavioral and biochemical effects of ketamine. Conclusions The results indicate that the structural and functional deficits resulting from long-term stress exposure, which could contribute to the pathophysiology of depression, are rapidly reversed by NMDA receptor antagonists in an mTOR-dependent manner.

Subfields: Cellular and Molecular Neuroscience, Pharmacology

View Paper: https://www.semanticscholar.org/paper/bb6390f0185ebb25e6f075af0f0a52cd24d748f4

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cellular and Molecular Neuroscience

1. Bruce S. McEwen
2. R. Duman
3. G. Sanacora
4. P. Willner
5. John H. Krystal
6. P. Belujon
7. M. Popoli
8. G. Treccani

In Pharmacology

1. P. Belujon
2. Anthony A. Grace
3. G. Sanacora
4. R. Duman
5. P. Willner
6. Bruce S. McEwen
7. K. Al-Harbi

Citations in the corpus

• Altered connectivity in depression: GABA and glutamate neurotransmitter deficits and reversal by novel treatments (2019, background): “The increase in synapse number and function is accompanied by increased levels of synaptic proteins, including GluA1 in the PFC (Li et al., 2010; Li et al., 2011; Maeng et al., 2008).”
• The Link between Depression and Chronic Pain: Neural Mechanisms in the Brain (2017, background): “Furthermore, by antagonizing the glutamatergic NMDA receptor, ketamine was found to accelerate the release of presynaptic glutamate, thereby enhancing the regional activity of the excitatory network, and eventually leading to a significant change in synaptic plasticity and connectivity [108, 109].”
• Towards a glutamate hypothesis of depression (2011, background): “…sustained effects in rodent models similar to those seen in depressed patients (Autry et al., 2011; Du et al., 2006; Koike et al., 2011; Li et al., 2010, 2011; Maeng et al., 2008; Yilmaz et al., 2002), others have failed to demonstrate the enduring effects of an acute ketamine dosing…”
• The chronic mild stress (CMS) model of depression: History, evaluation and usage (2016, background): “Within 24 h, a single ketamine injection also reversed the loss of synaptic proteins and atrophy of dendritic spines in the PFC and the associated electrophysiological deficits (Li et al., 2010, 2011b; Duman et al., 2012; Tang et al., 2015a).”
• Major depressive disorder: hypothesis, mechanism, prevention and treatment (2024, background): “378,379 Keta-mine may induce the activation of mTOR by the upstream kinase Akt, regulate the phosphorylation of GSK-3 β , and exert anti-depressant effects.”
• The stressed synapse: the impact of stress and glucocorticoids on glutamate transmission (2011, result): “Further support for this line of reasoning is given by a recent study showing that acute treatment with NMDA channel blockers rapidly ameliorates chronic unpredictable stress-induced decreases in the expression levels of synaptic proteins and in spine number and the frequency and amplitude of synapt”
• Dopamine System Dysregulation in Major Depressive Disorders (2017, background): “, 2000) and cortical (Liu and Aghajanian, 2008; Li et al., 2011) pyramidal neurons, and increase in the length of dendrites and density of dendritic spines in amygdala neurons (Sharma and Thakur, 2015).”
• A standardized protocol for repeated social defeat stress in mice (2011, neutral): “There has been growing interest in identifying compounds that produce a more rapid antidepressant effect than classic selective serotonin reuptake inhibitor (SSRI) treatment”