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.
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.
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.
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.