Grant: Project Grant

Psychiatric disorders are common, yet patient outcomes remain not ideal. Therefore, it is imperative to better understand the etiology associated with these disorders and to find novel treatment approaches for these disorders. Dopamine controls cognitive, emotional and reward mediated behaviours, to name a few. It has been shown that dysfunctions of the dopamine system underlie diverse psychiatric disorders, such as schizophrenia, psychosis and mania in bipolar disorder. Therefore, with the endocannabinoid system (ECS) helping shape how information is transmitted to dopamine neurons, it is important to understand its role in psychiatric disorders. Along with dopamine, there is evidence that changes in the endocannabinoid may be involved in psychiatric disorders. Here we will focus on one of the endogenous ligands of the ECBS, 2-arachidonoylglycerol (2-AG), which is synthesized by diacylglycerol lipase (DAGL) and metabolized by monoacylglycerol lipase (MAGL). There is significant interest in making drugs that target the ECS. Pharmaceutical companies have started clinical trials in various indications for MAGL and DAGL inhibitors to increase and decrease endocannabinoid levels respectively. Here we will set out to characterize the effects of 2-AG modulation in hyperDA states and assess the implications for people with vulnerability to high dopamine pathologies who may be prescribed these small molecules for other conditions. Using mouse and human models of dysregulated dopamine signaling, we will characterize the effect of 2-AG modulation in these disease states.