Computational analysis of stimulated dopaminergic synapses suggests release largely occurs from a single pool of...

Results from several experiments monitoring extracellular dopamine (DA) after stimulating axons at high frequencies have been interpreted as evidence for release from two populations of vesicles in dopaminergic varicosities. In addition, these experiments have suggested that cocaine and other dopamine transporter (DAT) inhibitors promote transfer of vesicles or dopamine itself from a reserve pool to a readily available pool. We developed a computer model simulation of these experiments with the goal of determining a set of mathematical formulas that describe dopamine movement between multiple storage compartments. However, the simulations show that data can be accurately simulated with release largely from a homogeneous population of vesicles, and that effects of dopamine transporter inhibitors can be explained without requiring that these drugs promote movement of dopamine from a reserve to an available pool. The data also suggest that dopamine recycling is highly efficient, even under high-frequency signaling conditions, and that the "kiss and run" mechanism of dopamine release probably predominates under conditions of very rapid neuron firing.