Project Summary Psychostimulant drugs of abuse induce persistent functional changes in the neural reward circuitry that underlie the development of addiction. These regions include the nucleus accumbens (NAc), a key area for drug reward. Growing evidence suggests that altered interneuron function in NAc makes key contributions to the drug-induced circuit adaptations leading to addiction behaviors. We have shown that NAc parvalbumin- expressing (PV+) inhibitory interneurons are required for multiple addiction-related behaviors in mice, including amphetamine (AMPH)-induced locomotor sensitization and conditioned place preference (CPP). Others have shown that cocaine self-administration strengthens excitatory inputs from basolateral amygdala onto NAc PV+ interneurons, and artificially potentiating these synapses accelerates acquisition of cocaine self-administration in naïve mice, suggesting that synaptic plasticity in NAc PV+ interneurons is behaviorally relevant for the development of addiction-like behaviors. However, little is known about the molecular mechanisms by which psychostimulants alter PV+ inhibitory interneuron function, and how this contributes to addictive behaviors. A promising mechanistic target is the perineuronal net protein Brevican (Bcan), which plays a cell-autonomous role in stabilizing excitatory inputs onto PV+ interneurons. The overarching goal of this proposal is to test the hypothesis that repeated psychostimulant exposure modulates PV+ interneuron activity through regulation of Bcan expression. In Aim 1 I will characterize the regulation of Bcan expression in NAc PV+ interneurons over the development of AMPH CPP. In Aim 2 I will test how manipulating Bcan expression affects the synaptic inputs to these neurons. In Aim 3 I will test the effect of manipulating Bcan in NAc PV+ cells on the threshold to develop CPP. These studies will investigate cellular transcriptional and synaptic plasticity mechanisms within PV+ interneurons, and how they affect the expression of addiction-related behaviors.