SC COBRE in Oxidants, Redox Balance and Stress Signaling

Joachim Uys, Ph.D.

Joachim Uys, Ph.D.
Research Instructor
Cell and Molecular Pharmacology and Experimental Therapeutics

Ph.D. University of Stellenbosch, South Africa, 2002


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.