Extracellular dopamine (DA) levels are tightly constrained by presynaptic reuptake mediated by the DA transporter (DAT). Despite its necessity for DA neurotransmission, DAT regulation in situ is poorly understood, and it is unknown whether DAT regulation impacts dopaminergic signaling and/or behaviors. Here, we leveraged chemogenetics and conditional gene silencing and found that presynaptic Gq-coupled receptor activation, induced by either hM3Dq or mGluR5 activation, drives biphasic DAT trafficking in striatum. Two PD risk alleles, Vps35 and Rit2, were required for mGluR5-stimulated DAT insertion and retrieval, respectively. Conditional dopaminergic mGluR5 silencing abolished DAT trafficking and resulted in motor dysfunction. Moreover, ex vivo voltammetric studies demonstrate that DAT trafficking significantly impacts DA clearance. These studies reveal that presynaptic DAT trafficking is complex, multimodal, and region-specific, and identify cell autonomous mechanisms required for DAT trafficking. Importantly, the findings suggest that regulated DAT trafficking likely impacts both DA clearance and motor function.
Low or High Cocaine Responding Rats Differ in Striatal Extracellular Dopamine Levels and Dopamine Transporter Number