Effect of Cocaine on Mitochondrial Electron Transport Chain Evaluated in Primary Cultures of Neonatal Rat Myocardial Cells and in Isolated Mitochondrial Preparations

Abstract

Cardiotoxicity is commonly associated with cocaine abuse. Previous studies have indicated that cocaine alters myocardial mitochondrial function. This study was undertaken to investigate the effect of cocaine on activity of the mitochondrial electron transport chain in cultures of neonatal rat cardiomyocytes and in isolated myocardial mitochondria. Cocaine concentrations (10(-5) to 10(-3) M) were used, and these concentrations have been reported in human cocaine users and are within a similar range of cocaine concentrations used in studies in vivo. After 24 hr treatment of cocaine, there was a slight increase in lactate dehydrogenase leakage in the cells treated with cocaine (10(-3) M). Reduction of tetrazolium compounds, neotetrazolium chloride (NTC) and triphenyltetrazolium chloride (TTC) was analyzed in intact cells to assess activity of the mitochondrial electron transport chain. Cocaine (10(-3) M) did not significantly change TTC and NTC reduction. In isolated mitochondria, cocaine (10(-3) M) significantly inhibited glutamate/malate-mediated respiration. These data suggest that cocaine at high concentrations may inhibit complex I of the mitochondrial electron transport chain of myocardial cells.

Mitochondrial complex I dysfunction induced by cocaine and cocaine plus morphine in brain and liver mitochondria

“…Cocaine plasma concentrations in human cocaine abusers have been found in the range between 0.3 M and 1 mM (Heard et al, 2008;Yuan and Acosta, 2000). The concentration used in the present study (1 mM) or higher concentrations (up to 7 mM) have been previously used in in vitro studies by other investigators (Badisa et al, 2010;Garcia et al, 2012;Yuan and Acosta, 2000) (e.g.…”

“…The involvement of complex I in cocaine's toxicity was suggested by the decrease in its activity and subunit expression observed after exposure to cocaine (Devi and Chan, 1997;Dietrich et al, 2004;Yuan and Acosta, 2000).…”

“…Cocaine abuse has been associated with mitochondrial dysfunction and impairment of energy metabolism in brain (Lehrmann et al, 2003), liver (Devi and Chan, 1997) and heart (Yuan and Acosta Jr., 2000) cells. The mitochondrial respiratory chain seems to mediate acute cocaine toxicity, as suggested by the partial resistance to cocaine toxicity in cells lacking functional mitochondria (rho-zero), when compared with rho-plus cells (Cunha-Oliveira et al, 2006).…”

Role of Mitochondria on the Neurological Effects of Cocaine

“…Complex I seems to be a direct target of cocaine in rat brain mitochondria (Cunha-Oliveira et al, 2013d;Dietrich et al, 2004), and also in heart (Vergeade et al, 2010;Yuan & Acosta, 1996, 2000 and liver mitochondria (Cunha-Oliveira et al, 2013c;Devi & Chan, 1997). In vitro exposure to cocaine was shown to affect the respiratory chain in different manners in liver and brain FIGURE 21.2 Interactions of cocaine with mitochondrial functions.…”

Oxidative Stress and Drugs of Abuse: An Update

“…Cocaine exposure in rat cortical neurons was shown to induce mitochondrial dysfunction, including loss of mitochondrial potential and decrease in ATP levels, and activa-tion of the mitochondrial apoptotic pathway [119,128]. In addition, exposure to cocaine leads to the downregulation of mitochondrial gene expression [129], resulting in reduced activity and protein levels of mitochondrial complex I [63,129,130]. Cocaine may interact directly with mitochondria and other intracellular targets [131], because it is able to enter into the cell due to its positive charge at physiological pH.…”