Glutamate N-methyl-D-aspartate Receptor Antagonists Rapidly Reverse Behavioral and Synaptic Deficits Caused by Chronic Stress Exposure

Abstract

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.

Neurocognitive Effects of Ketamine and Association with Antidepressant Response in Individuals with Treatment-Resistant Depression: A Randomized Controlled Trial

“…Both processing speed and attention have been linked to dopamine functioning within prefrontal-subcortical circuits (Cropley et al, 2006), and ketamine is known to modulate dopamine signaling within the striatum and prefrontal cortex in animals (Moghaddam et al, 1997) and humans (Kegeles et al, 2000;Rabiner, 2007;Smith et al, 1998). Mechanistic studies in animals show that ketamine rapidly enhances synaptic plasticity at the level of prefrontal cortical neurons (Li et al, 2010(Li et al, , 2011, and is able to rapidly reverse stress-induced dendritic atrophy and behavioral depression in a brain-derived neurotrophic factor (BDNF)-dependent manner (Li et al, 2011;Liu et al, 2012). A recent study found that ketamine reversed deficit dopamine signaling in a learned helplessness model of depression and normalized synaptic plasticity within the nucleus accumbens (indexed by long-term potentiation) via activation of dopamine D1 receptors (Belujon and Grace, 2014).…”

Negative Allosteric Modulators Selective for The NR2B Subtype of The NMDA Receptor Impair Cognition in Multiple Domains

“…Furthermore, although deficient synaptic plasticity (LTP) is thought to underlie cognitive impairment, the delayed antidepressant effect is thought to be driven by enhanced synaptic plasticity in key brain regions implicated in MDD (Duman et al, 2012). In particular, in rodent models of chronic stress, ketamine and NR2B NAMs have been shown to activate the BDNFmTOR signaling pathways, leading to increased translation of synaptic proteins, enhanced synaptogenesis, and alleviation of depression-related behaviors (Duman et al, 2012;Li et al, 2010Li et al, , 2011. Indeed, using hippocampal LTP as a measure of plasticity it was recently reported that LTP is robustly enhanced in slice preparations taken from animals dosed 24 h previously with i.v.…”

Rapid-onset antidepressant efficacy of glutamatergic system modulators: The neural plasticity hypothesis of depression

“…In addition to the monoamine-based antidepressants, NMDAR antagonists rapidly reverse the low levels of synaptic proteins and spine loss in the medial PFC [50] . [51,52] .…”

“…A few days (~5 days) of fluoxetine administration increases synaptic density in the hippocampal CA1 pyramidal cell layer, and 14 days of treatment has similar effects in the CA3 pyramidal cell layer [48] . In the olfactory bulbectomy model of depression, chronic treatment with the tricyclic antidepressant amitriptyline blocks the stress-induced decrease in spine density in hippocampal DG, CA1, and CA3 neurons [49] .In addition to the monoamine-based antidepressants, NMDAR antagonists rapidly reverse the low levels of synaptic proteins and spine loss in the medial PFC [50] . [51,52] .…”

“…In contrast to most approved antidepressants which target the monoaminergic system, ketamine has a direct and rapid effect on the glutamatergic system and synaptic plasticity [47] . Ketamine rapidly increases the expression of synaptic proteins and the number of excitatory spine synapses in the PFC [50,114,115] . In the FST, ketamine reduces immobility (a behavioral endophenotype reversible by antidepressants) concomitant with a rapid increase in glutamate release, activation of AMPARs, and increased hippocampal BDNF concentration [116,117] .…”