The investigations were aimed to study the possible association of dopamine DA-D(2) receptor in rotenone-induced cytotoxicity in PC12 cells, one among the most studied cell line in neurotoxicity studies. PC12 cells were subjected to receive an exposure of rotenone (10(-6) to 10(-4) M) for 24 and 48 hours. Cytotoxicity studies were carried out using standard end points including, (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) (MTT), lactate dehydrogenase (LDH) release and neutral red uptake (NRU). Cells were found to be vulnerable to rotenone in dose-dependent manner. In general, 10(-4) and 10(-5) M concentrations were found to be cytotoxic, whereas 10(-6) M and lower concentrations used have shown nonsignificant effect on cell viability. Further, studies were extended to study the rotenone-induced alterations in cellular glutathione (GSH) level and dopamine DA-D(2) receptor expression. Significant (p < 0.001) chronological depletion in GSH levels were recorded following rotenone exposure. Expression of dopamine DA-D(2) receptor was also found to be effected significantly (p < 0.001) at 24 hours of rotenone exposure (10(-4) and 10(-5)). However, no further depletion in the expression of dopamine DA-D(2) receptor could be recorded with extended exposure period, that is, 48 hours. Rotenone at 10(-6) M and lower concentrations was found to be ineffective in PC12 cells. Data suggest the vulnerability of PC12 cells against experimental exposure of rotenone, which possibly routed through dopamine DA-D(2) receptor and oxidative stress machinery.