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

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 invest igators have provided unimpeachable evidence of a role for oxygen-based fre e radicals in methamphetamine (METH)-induced neurotoxicity. In addition, st udies from our laboratory have shown that immortalized rat neuronal cells t hat overexpress Bcl-2 are protected against METH-induced apoptosis in vitro . Moreover, the amphetamines can cause differential changes in the expressi on of Bcl-X splice variants in primary cortical cell cultures. These observ ations suggested that METH might also cause perturbations of Bcl-2-related genes when administered to rodents. Thus, the present study was conducted t o determine whether the use of METH might indeed be associated with transcr iptional 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 B cl-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.