PhD Scientific Days 2025

Poster Session II. - G: Pharmaceutical Sciences and Health Technologies

The Effect of NMDA Receptor Blockers on Presynaptic Transmission

Name of the presenter

Lincmajer Zoltan

Institute/workplace of the presenter

Department of Pharmacodynamics

Authors

Zoltan Lincmajer¹, Dora Loska¹, Eva Szoko¹, Tamas Tabi¹

1: Department of Pharmacodynamics

Text of the abstract

Introduction

N-methyl-D-aspartate receptors (NMDA-R) are key elements of glutamatergic neurotransmission and synaptic plasticity. NMDA-R antagonists, e.g. ketamine have traditionally been used for anesthesia. More recently, its antidepressant property has come into focus. Recently another NMDA antagonist, dextromethorphan (DM) also gained significant interest, as it can also exert sustained antidepressant effects. Selective inhibition of distinct NMDA-R subtypes may considerably influence both therapeutic outcomes and adverse effect profiles. Therefore, detailed investigation of the dose-dependent pharmacodynamic properties of DM is of high relevance.

Aims

Our aim was to investigate the effects of NMDA-R antagonists on presynaptic glutamate neurotransmission using a synaptosomal model. Additionally, we aimed to explore the dose-dependent effects of DM and its potential molecular mechanisms of action relevant to psychopharmacology.

Methods

Using a previously optimized synaptosomal model, we quantified glutamate release via an enzyme-coupled fluorescence assay. To assess monoamine transport, we used ASP⁺, a fluorescent substrate selective for monoamine transporters, and monitored its intracellular accumulation by fluorescence detection.
Results
At low DM concentrations (1 nM-10 µM), a significant increase in glutamate release was observed, indicative of enhanced synaptic activity, presumably due to inhibition of GluN2A-containing NMDA-R. At higher concentrations (100 µM), glutamate release was normalized, likely due to concomitant GluN2B receptor blockade or non-NMDA mechanisms.
In monoamine transport assays, DM at 400 and 800 µM significantly decreased ASP⁺ uptake, whereas lower concentrations had no significant effect.

Conclusion

Our findings support that DM modulates presynaptic glutamatergic neurotransmission in a dose-dependent manner, which may be attributed to selective inhibition of NMDA-R subtypes. The observed decrease in monoamine uptake at higher concentrations suggests that DM affects multiple neurotransmitter systems in a concentration-dependent fashion. These results contribute to a better understanding of DM’s pharmacological profile and highlight the importance of distinguishing between synaptic and extrasynaptic NMDA-R mechanisms.

Funding

Semmelweis 250+ and Gedeon Richter Talentum Excellence PhD Scholarships are appreciated.