Differential cytotoxic responses of PC12 cells chronically exposed to psychostimulants or to hydrogen peroxide.
Repeated abuse of stimulant drugs, cocaine and amphetamine, is associated with extraneuronal dopamine accumulation in specific brain areas. Dopamine may be cytotoxic through the generation of reactive oxygen species, namely hydrogen peroxide (H2O2), resulting from dopamine oxidative metabolism. In this work, we studied the cytotoxicity in PC12 cells (a dopaminergic neuronal model) chronically and/or acutely exposed to cocaine or amphetamine, as compared to H2O2 exposure. Chronic cocaine treatment induced sensitization to acute cocaine insult and increased cocaine-evoked accumulation of extracellular dopamine, although no changes in dihydroxyphenylacetic acid (DOPAC) levels were observed. Moreover, dopamine was depleted in cells chronically exposed to amphetamine and acute amphetamine toxicity persisted in these cells, indicating that dopamine was not involved in amphetamine cytotoxicity. PC12 cells chronically treated with H2O2 were totally resistant to acute H2O2, but not to acute cocaine or amphetamine exposure, suggesting that the toxicity induced by these stimulant drugs is unrelated to adaptation to oxidative stress. Interestingly, chronic cocaine treatment largely, but not completely, protected the cells against a H2O2 challenge, whilst a decrement in intracellular ATP was observed. This study shows that chronic treatment of PC12 cells with cocaine or H2O2 modifies the cytotoxic response to an acute exposure to these agents.
Cunha-Oliveira
Teresa
T
Center for Neuroscience and Cell Biology and Institute of Biochemistry, Faculty of Medicine, University of Coimbra, 3004-504 Coimbra, Portugal.
Rego
A Cristina
AC
Morgadinho
Maria Teresa
MT
Macedo
Tice
T
Oliveira
Catarina Resende
CR
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000661:Amphetamine / Q000633:toxicity*; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D000697:Central Nervous System Stimulants / Q000633:toxicity; D003042:Cocaine / Q000633:toxicity*; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000633:toxicity*; D016716:PC12 Cells; D051381:Rats; D013997:Time Factors
D000697:Central Nervous System Stimulants; D015102:3,4-Dihydroxyphenylacetic Acid; D000255:Adenosine Triphosphate; D006861:Hydrogen Peroxide; D000661:Amphetamine; D003042:Cocaine; D004298:Dopamine