To the editor:

In a recent issue of Nature Neuroscience, Floresco et al. elegantly demonstrate that afferents to the ventral tegmental area can differentially modify the firing patterns of dopamine neurons1. They also report that the concentration of dopamine sampled by microdialysis during endogenous burst firing is similar to tonic firing unless dopamine uptake is blocked. From this, they deduced that dopamine does not escape the synapse during phasic firing, a conclusion we believe is flawed. To directly establish synaptic restriction would require submicron spatial resolution, which is unattainable with a 240-μm microdialysis probe. Indeed, previous work showed that phasically evoked striatal dopamine cannot diffuse all the way across dialyzed tissue to a microdialysis probe while uptake is active, even though dopamine escapes the synapse (detected with a voltammetric microsensor)2.

Floresco et al. argue that dopamine is contained within the synapse due to rapid removal as it encounters perisynaptic transporters. However, striatal terminals are optimized for paracrine transmission with uniformly distributed, extrasynaptic transporters3. Dopamine synapses are ∼200 nm in radius, so outward diffusion of released dopamine takes only ∼0.05 ms (ref. 4). However, dopamine released by a single impulse decays from the extracellular space with a half-life of 75 ms, and even slower for stimuli that mimic endogenous bursts5. This allows extrasynaptic diffusion for 5–10 μm before it is removed by uptake6. Although this distance may not be sufficient for dopamine to reach a microdialysis probe, it permits communication with a population of receptors outside the synapse. Floresco et al. contend that this extrasynaptic diffusion is an artifact of highly correlated firing with electrical stimulation. However, behavioral salience endogenously elicits both highly synchronous burst firing7 and phasic extrasynaptic dopamine8, similar to that seen with electrical stimulation. Spatial communication is fundamental to dopamine neurotransmission, and so clarification of this controversy will permit a better understanding of the transfer of information by dopamine and the computations it encodes.