New insights into axonal regulators of dopamine transmission in health and disease.

Dopamine release in the striatum is credited with being critical to the selection and learning of motivated actions and outcomes. Dysregulation of striatal dopamine release underlies multiple disorders of action selection and reward-processing, such as Parkinson's disease, schizophrenia and addiction disorders, and is a major target for therapeutic interventions. The axonal molecular and circuit mechanisms governing dopamine exocytosis are incompletely resolved, but accumulating evidence suggests some key points of divergence from canonical neurotransmitter synapses. In this review, we bring together recent insights into mechanisms shaping dopamine transmission in the striatum, spanning the molecular machinery regulating exocytosis, striatal modulators locally governing release probability, and the mechanisms regulating dopamine vesicle endocytosis. Together, these findings continue to support points of divergence from canonical presynaptic mechanisms, they inform principles of axonal neuromodulation, and point to potential contributions to the susceptibility to neurodegeneration in Parkinson's disease.