Zinc-Dependent Modulation of Dopamine Release and Uptake Is Altered in Parkinson’s Disease Model Zebrafish

Parkinson's disease (PD) is a neurodegenerative movement disorder in which dopaminergic neurons progressively degenerate, resulting in impaired dopamine system function. The release and uptake of dopamine (DA) are modulated, in part, by free, ionic zinc (Zn²⁺), an essential signaling metal. Although alterations in Zn²⁺ homeostasis are implicated in PD, the influence of Zn²⁺ on DA release and uptake that occurs within the subsecond time frame has not been studied in PD, or other disorders. In this study, we combined caged-compound photolysis with fast-scan cyclic voltammetry (FSCV) at carbon-fiber microelectrodes to investigate the impact of Zn²⁺ photorelease on DA release and reuptake in PD-model zebrafish, generated by chronic treatment with rotenone, and vehicle-treated control fish. Our findings reveal that Zn²⁺ photorelease inhibited peak DA overflow by about 20% in brains from PD model fish but not in those from vehicle-treated fish. Further analysis of the stimulated release plots showed a significant decrease in the first order rate constant of uptake (<i>k</i>) and an increase in the half-life (<i>t</i>_1/2) in brains from vehicle-treated fish but not in those from PD model fish. These differences were not apparent when waiting more than 200 ms to electrically stimulate the brain after the end of light application. Treatment with the free-radical scavenger TEMPOL reversed the effect of Zn²⁺ photorelease on DA release but not on DA uptake. Thus, oxidative stress likely plays a key role, acting reversibly on DA release and irreversibly on DA uptake. In summary, our study demonstrates the feasibility of our approach in elucidating the mechanisms underlying the effects of metal ions on Parkinson's disease.