Differential cytotoxic responses of PC12 cells chronically exposed to psychostimulants or to hydrogen peroxide

• Published in: Toxicology (Amsterdam) 2006-01, Vol.217 (1), p.54-62
• Main Authors: Cunha-Oliveira, Teresa, Rego, A. Cristina, Morgadinho, Maria Teresa, Macedo, Tice, Oliveira, Catarina Resende
• Format: Article
• Language: English
• Subjects: 3,4-Dihydroxyphenylacetic Acid - metabolism; Adenosine Triphosphate - metabolism; Amphetamine; Amphetamine - toxicity; Animals; Biological and medical sciences; Cell Survival - drug effects; Central Nervous System Stimulants - toxicity; Cocaine; Cocaine - toxicity; Cytosol - drug effects; Cytosol - metabolism; Dopamine - metabolism; Drug abuse; Drug addictions; Hydrogen Peroxide - toxicity; Medical sciences; Neurotoxicity; Oxidative stress; PC12 Cells; Rats; Time Factors; Toxicology
• ISSN: 0300-483X; 1879-3185
• DOI: 10.1016/j.tox.2005.08.022

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 (H 2O 2), 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 H 2O 2 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 H 2O 2 were totally resistant to acute H 2O 2, 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 H 2O 2 challenge, whilst a decrement in intracellular ATP was observed. This study shows that chronic treatment of PC12 cells with cocaine or H 2O 2 modifies the cytotoxic response to an acute exposure to these agents.