Differential effect of dopamine catabolism and uptake inhibition on dopamine-induced calcium dysregulation and viability loss

The present study was aimed at evaluating of the effects of dopamine (DA) t oxicity on PC12 cells' calcium homeostasis, cellular viability, and free ra dical levels. Moreover, the effect of receptor inhibition, and DA metabolis m and reuptake antagonism on all parameters was also evaluated. Acute treat ment with DA impaired the ability of PC12 cells to buffer excess calcium af ter K+-depolarization, decreased cellular viability by approximately 35%, a nd increased free radical levels by about 10% in a dose dependent manner. P retreatment with both active and inactive pargyl monoamine oxidase inhibito rs (MAOi) protected PC12 cells from DA toxicity on cellular viability and f ree radical levels, regardless of the presence or absence of their target e nzymes in PC12 cells. These results suggest a lack of specific involvement of DA metabolism by MAO in dopamine's effects on cellular viability and pro duction of free radicals. However, DA-induced dysregulation of calcium home ostasis seems to be more specifically mediated by DA metabolism by MAO. Res ults indicate that, in order for toxicity to occur the DA must be taken up into the cells. DA receptors do not mediate dopamine cytoxicity, and the D- 2 receptor plays a modest role in DA-induced calcium dysregulation and gene ration of free radicals. Moreover, DA-induced cell viability loss is not me diated by calcium, nor by caspase-3 enzyme, but is prevented by inhibition of mitochondrial permeability transition pores. (C) 1999 Elsevier Science I nc.