Cortical spreading depression dynamics are altered by topical D2 receptor ligands

Area of Science:

• Neuroscience
• Neuropharmacology
• Computational Neuroscience

Background:

• Cortical spreading depression (CSD) is a key neurophysiological event linked to migraine aura.
• The role of dopaminergic signaling, specifically D2 receptors (D2Rs), in CSD modulation is not well understood.
• Established roles of glutamate, GABA, and serotonin in CSD contrast with the unclear contribution of dopamine.

Purpose of the Study:

• To investigate the impact of D2R-targeting agents on CSD propagation and neuronal activation in vivo.
• To elucidate the specific effects of D2R ligands on cortical excitability and CSD dynamics.
• To explore the mechanistic link between dopaminergic signaling and CSD.

Main Methods:

• Utilized a KCl-induced CSD model in anesthetized male Wistar rats.
• Topical cortical application of metoclopramide (MCP), raclopride (RCP), and quinpirole (QNP).
• Monitored CSD propagation, waveform morphology, and neuronal activation via c-Fos immunoreactivity.
• Employed a reaction-diffusion computational model to simulate drug effects and CSD dynamics.

Main Results:

• Metoclopramide (MCP) completely blocked CSD propagation.
• Raclopride (RCP) and quinpirole (QNP) exhibited time-dependent and opposing effects on CSD speed and propagation.
• Reduced neuronal activation was observed with MCP and QNP, particularly in superficial cortical layers.
• Computational modeling successfully replicated experimental findings, validating the observed D2R ligand effects.

Conclusions:

• Cortical D2R ligands modulate CSD dynamics and neuronal activation in a ligand- and time-dependent manner.
• Dopaminergic signaling significantly influences cortical excitability and CSD propagation.
• Findings provide mechanistic insights into dopamine's role in fundamental neurophysiological processes.