Mitochondrial dysfunction and caspase activation in rat cortical neurons treated with cocaine or amphetamine.
Drug abuse is associated with brain dysfunction and neurodegeneration, and various recreational drugs induce apoptotic cell death. This study examined the role of the mitochondrial apoptotic pathway in psychostimulant-induced neuronal dysfunction. Using primary neuronal cultures, we observed that amphetamine (IC50=1.40 mM) was more potent than cocaine (IC50=4.30 mM) in inducing cell toxicity. Apoptotic cell death was further evaluated using cocaine and amphetamine concentrations that moderately decreased cell reduction capacity but did not affect plasma membrane integrity. Compared to cocaine, amphetamine highly decreased the mitochondrial membrane potential, as determined using the fluorescent probe rhodamine-123, whereas both drugs decreased mitochondrial cytochrome c. In contrast to amphetamine, cocaine cytotoxicity was partly mediated through effects on the electron transport chain, since cocaine toxicity was ameliorated in mitochondrial DNA-depleted cells lacking mitochondrially encoded electron transport chain subunits. Cocaine and amphetamine induced activation of caspases-2, -3 and -9 but did not affect activity of caspases-6 or -8. In addition, amphetamine, but not cocaine, was associated with the appearance of evident nuclear apoptotic morphology. These events were not accompanied by differences in the release of the apoptosis-inducing factor (AIF) from mitochondria. Our results demonstrate that although both amphetamine and cocaine activate the mitochondrial apoptotic pathway in cortical neurons, amphetamine is more likely to promote apoptosis.
Cunha-Oliveira
Teresa
T
Institute of Biochemistry, Faculty of Medicine, University of Coimbra, 3004-504 Coimbra, Portugal.
Rego
A Cristina
AC
Cardoso
Sandra M
SM
Borges
Fernanda
F
Swerdlow
Russell H
RH
Macedo
Tice
T
de Oliveira
Catarina R
CR
D000661:Amphetamine / Q000633:toxicity; D019969:Amphetamine-Related Disorders / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D020169:Caspases / Q000187:drug effects* / Q000378:metabolism; D045744:Cell Line, Tumor; D000697:Central Nervous System Stimulants / Q000633:toxicity*; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D003042:Cocaine / Q000633:toxicity; D019970:Cocaine-Related Disorders / Q000378:metabolism / Q000503:physiopathology; D045304:Cytochromes c / Q000378:metabolism; D004195:Disease Models, Animal; D045222:Electron Transport Chain Complex Proteins / Q000187:drug effects / Q000378:metabolism; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051336:Mitochondrial Membranes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009410:Nerve Degeneration / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051381:Rats
D000697:Central Nervous System Stimulants; D045222:Electron Transport Chain Complex Proteins; D045304:Cytochromes c; D000661:Amphetamine; D020169:Caspases; D003042:Cocaine