Investigating the Role of Glyoxalase 1 as a Therapeutic Target for Cocaine and Oxycodone Use Disorder

Methylglyoxal (MG) is an endogenously produced non-enzymatic side product of glycolysis that acts as a partial agonist at GABA_A receptors. MG that is metabolized by the enzyme glyoxalase-1 (GLO1). Inhibition of GLO1 increases methylglyoxal levels, and has been shown to modulate various behaviors, including decreasing seeking of cocaine-paired cues and ethanol consumption. The goal of these studies was to determine if GLO1 inhibition could alter cocaine- or oxycodone-induced locomotor activation and/or conditioned place preference (CPP) to cocaine or oxycodone. We used both pharmacological and genetic manipulations of GLO1 to address this question. Administration of the GLO1 inhibitor s-bromobenzylglutathione cyclopentyl diester (pBBG) did not alter the locomotor response to cocaine or oxycodone. Additionally, pBBG had no significant effect on place preference for cocaine or oxycodone. Genetic knockdown of Glo1, which is conceptually similar to pharmacological inhibition, did not have any significant effects on cocaine place preference, nor did Glo1 overexpression affect locomotor response to cocaine. In summary, our results show that neither pharmacological nor genetic manipulations of GLO1 influence locomotor response or CPP to cocaine or oxycodone.