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.