Glutamate NMDA receptor antagonists rapidly reverse behavioral and synaptic deficits caused by chronic stress exposure
Nanxin Li, Rong-Jian Liu, J. Dwyer, Mounira Banasr, Boyoung Lee, H. Son, Xiao-Yuan Li, George K. Aghajanian, Ronald S. Duman
Biological Psychiatry February 3, 2011 DOI: 10.1016/j.biopsych.2010.12.015 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical experimental study Peer reviewed |
|---|---|
| Population | Rats subjected to chronic unpredictable stress |
| Interventions | Ketamine Ro 25-6981 |
| Duration | 21-day chronic unpredictable stress model; acute treatment |
| Key findings | Acute ketamine or Ro 25-6981 rapidly reversed chronic unpredictable stress-induced anhedonia and anxiety-like behaviors in rats, and ketamine restored stress-induced reductions in synaptic proteins, spine number, and synaptic currents in prefrontal cortex neurons. These effects depended on mTOR signaling, as mTOR blockade abolished them. |
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.