Abstract

Glutamate-induced excitotoxicity is a major mechanism of neuronal damage in various neurodegenerative diseases, including Parkinson's disease, where dopamine deficiency is a key feature. This study investigated the hypothesis that dopamine, beyond its role as a neurotransmitter, possesses a protective function against glutamate-mediated toxicity, and that its deficiency exacerbates excitotoxic vulnerability. Using a rat hippocampal primary culture model and fluorescence microscopy, we examined the effect of dopamine on neuronal calcium signaling and survival following exposure to toxic levels of glutamate. Our findings demonstrate that dopamine significantly reduces the amplitude of the calcium response evoked by N-methyl-D-aspartate (NMDA) receptor activation, a primary mediator of excitotoxicity, but does not affect responses mediated by AMPA or kainate receptors. This protective effect was shown to be dependent on both NMDA receptors and D2-type dopamine receptors, suggesting a complex modulatory interaction. Furthermore, dopamine was found to mitigate glutamate-induced mitochondrial depolarization, a critical step in the cell death cascade, and substantially improve overall neuronal survival. These results suggest a novel, non-classical neuroprotective role for dopamine, highlighting a potential therapeutic strategy for mitigating excitotoxic damage in neurodegenerative conditions.