Cortical spreading depression dynamics are altered by topical D2 receptor ligands

Cortical spreading depression (CSD) is a transient wave of neuronal and glial depolarization that propagates slowly through the cerebral cortex and is implicated in neurological events such as migraine aura. While glutamate, GABA, and serotonin have established roles in CSD modulation, the contribution of dopaminergic signaling, particularly via D2 receptors (D2Rs), remains unclear. In this study, we examined whether topical cortical application of D2R-targeting agents alters CSD propagation and neuronal activation in vivo. Using a KCl-induced CSD model in anesthetized male Wistar rats, we applied metoclopramide (MCP), raclopride (RCP), and quinpirole (QNP) directly onto the cortex. MCP completely blocked CSD propagation at all time points. RCP and QNP produced opposing, time-dependent effects: RCP initially reduced CSD speed, followed by an increase after prolonged exposure, whereas QNP transiently accelerated propagation at 5 min but suppressed it with longer exposure. These changes were accompanied by alterations in waveform morphology, particularly in the secondary negative deflection. c-Fos immunoreactivity revealed reduced neuronal activation in MCP- and QNP-treated animals, mainly in superficial cortical layers, while RCP showed no significant effect. To support these findings, a reaction-diffusion computational model incorporating drug diffusion, receptor binding kinetics, and excitability parameters successfully reproduced the experimental CSD propagation profiles. Together, these results demonstrate that cortical D2R ligands modulate CSD dynamics and neuronal activation in a ligand-specific and time-dependent manner. This study provides mechanistic insight into how dopaminergic signaling influences cortical excitability and CSD propagation, advancing our understanding of dopamine's role in fundamental neurophysiological processes.