SC COBRE in Oxidants, Redox Balance and Stress Signaling
Joachim Uys, Ph.D.
Joachim Uys, Ph.D.
Glutathione S-transferase pi mediated redox regulation modulates cocaine sensitivity
Cocaine administration induces oxidative stress, thereby altering redox homeostasis. Preliminary studies show that chronic cocaine-induced changes in redox homeostasis included upregulation of Glutathione-S-Transferase pi (GSTpi) and altered redox potential. GSTpi plays a key role in oxidative and nitrosative stress response by catalyzing S-glutathionylation, a post-translational modification on cysteine residues with structural and functional consequences. In our model, upregulation of GSTpi was concurrent with increased S-glutathionylated proteins in the nucleus accumbens of cocaine-sensitized rats. Furthermore, using a genetic mouse model of GSTpi deletion and pharmacological inhibition we have shown an enhancement of cocaine-induced conditioned place preference and behavioral sensitization, which indicates that the reduction in GSTpi may promote the actions of cocaine to induce neuroplasticity. There are 4 polymorphisms within GSTpi (*A-D) that have functional consequences on the catalytic activity. We hypothesize that GSTpi contributes to cocaine-induced behavioral neuroplasticity through P-SSG of protective targets and polymorphisms may impact sensitization. A two pronged approached will support our hypothesis and provide a platform for future investigation. First, we will evaluate redox homeostasis and identify cocaine-induced S-glutathionylated proteins in rats trained to self-administer cocaine and in GSTpi knockout mice. Second, polymorphic frequencies of cocaine-addicted patients will be compared to the normal population. Preliminary data suggest that individuals carrying the low functioning alleles (GSTP*B and *C) are more sensitive to the effects of cocaine. Utilizing the self-administration model to characterize the role of GSTpi and potential direct targets (P-SSG) will be important to understanding the pathway and functional changes that overlap between animal models and human studies. There is a growing database of gene expression profiles in this system, however little information is known about redox-mediated post-translational events that may be “high-yield” targets for potential pharmacological intervention.