Biological Psychiatry
January 1, 2018
Chun Yang, Q. Ren, Y. Qu et al.
249 citations
The antidepressant effects of the two enantiomers of ketamine rely on different signaling pathways in mice. (S)-ketamine requires mTOR signaling, as blocking mTOR with rapamycin or AZD8055 eliminated its effects, while (R)-ketamine does not. Instead, (R)-ketamine requires ERK signaling; blocking ERK with SL327 eliminated its effects. (S)-ketamine restored reduced mTOR phosphorylation in the prefrontal cortex of stressed mice, whereas (R)-ketamine restored reduced ERK phosphorylation in the prefrontal cortex and hippocampal dentate gyrus. These findings indicate that mTOR activation is not necessary for (R)-ketamine's antidepressant actions.
Pharmacology, Biochemistry and Behavior
June 1, 2019
Lijia Chang, Kai Zhang, Yaoyu Pu et al.
174 citations
In a mouse model of chronic social defeat stress, a single intranasal dose of (R)-ketamine produced stronger antidepressant effects than (R,S)-ketamine or (S)-ketamine. Conversely, (S)-ketamine caused the greatest increase in locomotor activity and deficits in prepulse inhibition, followed by (R,S)-ketamine, while (R)-ketamine showed the least. In conditioned place preference tests, repeated intranasal (S)-ketamine and (R,S)-ketamine increased preference scores dose-dependently, indicating abuse liability, whereas (R)-ketamine did not. These findings suggest intranasal (R)-ketamine may be a safer antidepressant option.
Translational Psychiatry
January 27, 2020
Kai Zhang, Chun Yang, Lijia Chang et al.
120 citations
In mice with depression-like symptoms from chronic social defeat stress, (R)-ketamine produced more potent and longer-lasting antidepressant effects than (S)-ketamine. RNA sequencing of the prefrontal cortex showed that transforming growth factor (TGF)-β signaling may explain these differences. (R)-ketamine, but not (S)-ketamine, reversed reduced expression of Tgfb1 and its receptors in the prefrontal cortex and hippocampus. Blocking TGF-β1 with inhibitors or a neutralizing antibody prevented (R)-ketamine's antidepressant effects. Depleting microglia also blocked these effects. Recombinant TGF-β1 itself produced rapid and lasting antidepressant effects in mice, suggesting a microglial TGF-β1-dependent mechanism and potential for new human antidepressants.
Neuropsychopharmacology
February 1, 2003
Y. Qu, Lisa Chang, J. Klaff et al.
In unanesthetized adult rats, an injection of the 5-HT2A/2C receptor agonist DOI (2.5 mg/kg intraperitoneally) caused widespread increases of about 60% in the incorporation coefficient of arachidonic acid from blood into brain, particularly in neocortical regions with high densities of 5-HT2A receptors. These increases were entirely blocked by chronic pretreatment with the 5-HT2 receptor antagonist mianserin. The findings suggest that the 5-HT2 syndrome involves widespread activation of phospholipase A2 via 5-HT2A receptors, leading to release of the second messenger arachidonic acid, and that chronic mianserin prevents this activation.