Extrasynaptic dopamine and phasic neuronal activity

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 neurons 1. 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 transporters 3. 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 extracellu-lar space with a half-life of 75 ms, and even slower for stimuli that mimic endogenous bursts 5. This allows extrasynaptic diffusion for 5–10 µm before it is removed by uptake 6. 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 firing 7 and phasic extrasynaptic dopamine 8 , 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. Floresco, West and Grace reply: Several errors are apparent in the issues raised by Drs. Phillips and Wightman. Obviously, neither a 240 µm dialysis probe nor a 10 µm voltammetric probe can measure intrasynaptic dopamine (DA) levels. We do not claim that " dopamine concentrations measured during bursting are similar to tonic firing unless dopamine uptake is blocked " ; we report that increased tonic firing is associated with increased DA levels, whereas increased …