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Methamphetamine causes differential regulation of pro-death and anti-death Bcl-2 genes in the mouse neocortex

Molecular Neuropsychiatry Section, NIDA-IRP, National Institutes of Health, Baltimore, Maryland 21224, USA

¹Correspondence: Molecular Neuropsychiatry Section, NIH/NIDA Intramural Research Program, 5500 Nathan Shock Dr., Baltimore, MD 21224, USA. E-mail: JCADET{at}intra.nida.nih.gov

Bcl-2, an inner mitochondrial membrane protein, inhibits apoptotic neuronal cell death. Expression of Bcl-2 inhibits cell death by decreasing the net cellular generation of reactive oxygen species. Studies by different investigators have provided unimpeachable evidence of a role for oxygen-based free radicals in methamphetamine (METH) -induced neurotoxicity. In addition, studies from our laboratory have shown that immortalized rat neuronal cells that overexpress Bcl-2 are protected against METH-induced apoptosis in vitro. Moreover, the amphetamines can cause differential changes in the expression of Bcl-X splice variants in primary cortical cell cultures. These observations suggested that METH might also cause perturbations of Bcl-2-related genes when administered to rodents. Thus, the present study was conducted to determine whether the use of METH might indeed be associated with transcriptional and translational changes in the expression of Bcl-2-related genes in the mouse brain. Here we report that a toxic regimen of METH did cause significant increases in the pro-death Bcl-2 family genes BAD, BAX, and BID. Concomitantly, there were significant decreases in the anti-death genes Bcl-2 and Bcl-X_L. These results thus support the notion that injections of toxic doses of METH trigger the activation of the programmed death pathway in the mammalian brain.—Jayanthi, S., Deng, X., Bordelon, M., McCoy, M. T., Cadet, J. L. Methamphetamine causes differential regulation of pro-death and anti-death Bcl-2 genes in the mouse neocortex.

Key Words: neurotoxicity • apoptosis • bcl-2 gene family • cDNA array

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