Increase of the AMPA-evoked response of pyramidal neurons in the rat medial prefrontal cortex following acute administration of ketamine and S-ketamine, but not R-ketamine

Abstract Background In preclinical studies, an increase in α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) to N-methyl-D-aspartate (NMDA) receptor 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. Significance statement An increase in AMPA receptors throughput has emerged as common effect in response to drugs aiming at glutamate receptors as a primary target. This study investigated the effects of 4 such drugs on AMPA- and NMDA-evoked responses and the spontaneous firing activity of pyramidal neurons in medial prefrontal cortex. While racemic ketamine and its enantiomer S-ketamine augmented the AMPA-evoked responses, R-ketamine and ifenprodil did not. Evoked NMDA responses were not altered by these drugs. Only S-ketamine and ifenprodil increased the spontaneous firing activity of pyramidal neurons. Thus, only S-ketamine administration resulted in a simultaneous increase in AMPA response and pyramidal neurons firing activity. An increase in AMPA responsiveness in the rat mPFC correlates with the clinical antidepressant effect of racemic ketamine and S-ketamine.