Dopamine D2 agonists, bromocriptine and quinpirole, increase MPP+-induced toxicity in PC12 cells

Dopaminergic cell loss in the mesencephalic substantia nigra is the hallmark of Parkinson's disease and may be associated with abnormal oxidative metabolic activity. However, the delicate balance underlying dopamine decline and oxidative stress is still a matter of debate. The aim of this study was to analyze the possible modulation of dopamine D-2 agonists and antagonists on MPP+ (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridinium ion)-induced cellular death in differentiated and undifferentiated PC12 cells. Using colorimetric assays, western blots and reverse transcriptase-PCR, we demonstrated that two D-2 agonists, bromocriptine and quinpirole, consistently increased MPP+-induced cytotoxicity in both differentiated and undifferentiated PC12 cells, whereas D-2 antagonists did not modulate cell death. However, this increase in cellular death was reversed when bromocriptine or quinpirole were used in the presence of D-2 antagonists. On the other hand, 1-{2-[bis-(4-fluorophenyl)methoxy]ethyl}-4(3-phenylpropyl)piperazine (GBR 12909) a potent inhibitor of the dopamine transporter, partially reversed MPP+-induced cellular death and completely abolished the increase of cellular death induced by bromocriptine. Dopamine agonists and antagonists also modulate the expression of the dopamine transporter in PC12 cells; in particular, bromocriptine may alter MPP+ uptake by increasing DAT expression. We also show that, in our cellular paradigm, D-2 receptor mRNA levels are more abundant that D-3 mRNA levels and MPP+ and/or bromocriptine could not modulate D2 gene expression while D3 gene expression clearly decreased after MPP+ and/or bromocriptine treatment.