Synaptic vesicle glycoprotein 2C (SV2C) and psychostimulant actions

Project Summary/Abstract New approaches to treat methamphetamine addiction are desperately needed. Enhanced synaptic transmission of dopamine is a key feature of methamphetamine action. We have identified a novel mediator of dopamine release that we propose will reduce the reinforcing properties of methamphetamine. An isoform (A, B, or C) of the synaptic vesicle glycoprotein 2 (SV2) is found on every synaptic vesicle in the nervous system, suggesting an important yet unknown role for SV2 in neurotransmission. While SV2A and B are ubiquitously distributed throughout the brain, SV2C expression is highly restricted to dopaminergic regions such as the basal ganglia. Of particular note, SV2C expression is highest in the ventral pallidum, a region of emerging importance in addiction research that is thought to mediate the translation of limbic motivation into motor output. Data generated in our laboratory show that genetic deletion of SV2C results in a 50% decrease in stimulated dopamine release, a 20% decrease in vesicular dopamine storage capacity, and enhance leakage of dopamine from the vesicle. Furthermore, mice lacking SV2C show a loss of METH conditioned place preference compared to wild- type animals. Given the observed effect of SV2C loss on dopamine transmission and its restricted expression pattern we hypothesize that SV2C, through its ability to retain dopamine within synaptic vesicles, regulates the psychostimulant effects of methamphetamine, and therefore is a druggable target for psychostimulant substance use disorder. The experiments proposed here will establish a novel in vitro assay to measure SV2C activity (Aim 1) and identify compounds that regulate SV2C activity (Aim 2). Our technical resources and expertise in measuring numerous aspects of dopamine neurotransmission uniquely position our lab to accomplish this timely project.