Abstract Background In preclinical studies, an increase in α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) to N-methyl-D-aspartate receptor (NMDA) throughput is the predominant hypothesis posited to explain the rapid antidepressant effect of ketamine and S-ketamine. Several lines of evidence show that this AMPA increase takes place in the medial prefrontal cortex (mPFC), which activation has been shown to induce antidepressant-like effects. The present electrophysiological study was aimed at investigating whether a single dose of drugs with antidepressant-like effects that act on glutamate receptors as a primary target induce an increase of evoked AMPA-induced response of pyramidal neurons in the mPFC. Methods Microiontophoretic applications of AMPA and NMDA were carried out in male anesthetized rats, following acute administration racemic ketamine, S-ketamine, R-ketamine and ifenprodil to first assess their effects on their evoked response of mPFC pyramidal neurons. In a second series of experiments, the effects of these drugs were also assessed on the spontaneous firing activity of these neurons. Results An increase in the AMPA-, but not NMDA-evoked response was observed following a single acute injection of ketamine and S-ketamine, when compared to saline treated rats. However, R-ketamine and the NMDA receptor GluN2B subunit antagonist ifenprodil had no effect on AMPA- and NMDA-induced responses of mPFC pyramidal neurons. The spontaneous firing activity of pyramidal neurons was enhanced by S-ketamine and ifenprodil. Conclusion An increase in the AMPA-induced response appears to constitute a common factor underlying the antidepressant-like effects of ketamine and S-ketamine. This increase did not correlate with change in mPFC pyramidal neurons firing activity.
Mansari et al. (2026) studied this question.