Investigating the Effect of Oxaliplatin on Vesicular Dopamine Cargo and Release Dynamics in Brain with Single-Vesicle...

Long-term use of platinum-based chemotherapeutic agents is linked to central nervous system (CNS) toxicity, presenting as memory impairment, motor dysfunction, and difficulties with multitasking. While oxaliplatin-induced peripheral neurotoxicity is well studied, its impact on CNS signaling remains poorly understood. Here, we applied single-vesicle electrochemical methods, including intracellular vesicle impact electrochemical cytometry (IVIEC) and single-cell amperometry (SCA) in fresh mouse brain slices to assess oxaliplatin's impact on substantia nigra pars compacta neurons. Our results show that oxaliplatin treatment significantly increases vesicular dopamine storage, elevates the frequency of stimulus-evoked exocytotic events, and prolongs fusion-pore opening, leading to greater overall dopamine release per neuron. This hyperactive dopaminergic state, observed alongside neuronal loss, points to a compensatory presynaptic overdrive that may ultimately contribute to excitotoxic damage. Our study provides novel insights into the central neurotoxicity of oxaliplatin and highlights potential strategies for preserving nigrostriatal dopaminergic function during platinum-based chemotherapy.