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 burst firing in already firing neurons is not. We concur that some DA escapes the synapse during both burst and irregular firing modes, but this unknown concentration of 'perisynaptic' DA does not contribute substantially to the slower-changing DA levels encompassing large striatal regions (i.e., the classical definition of 'tonic DA'1.

We carefully state that during bursting, reuptake “limits the amount of DA that escapes synaptic cleft, thereby occluding detection of a ... measurable increase in extracellular dopamine.” We show that sustained burst firing does not impact our DA measures, implying that bursting does not play a unique role in tonic DA transmission. We conservatively state that extracellular DA measured by traditional in vivo neurochemistry is not altered dramatically by increases in bursting that occur without increased population activity. The distribution of reuptake sites is also unclear, given the uncertainty in labeling DA transporter intrasynaptically using pre-embedding techniques. Indeed, a primary role of intrasynaptic uptake on inactivation of DA transmission is predicted given the potent effects of psychostimulants on behavior2 and displacement by synaptic DA release in functional imaging studies3.

The behaving animal studies cited by the Phillips-Wightman letter4 describe correlations between behavioral salience and “highly synchronous” bursting. However one cannot extrapolate from single-neuron recordings whether: 1) the entire population of neurons is firing spikes synchronously, or 2) the number of spontaneously firing neurons is altered. A burst recorded from one neuron at a set latency after a behaviorally relevant stimulus is not comparable to simultaneous electrical activation of the entire bundle of DA axons.

Our study shows that the DA system is compartmentalized, consisting of a synaptic (and potentially perisynaptic) compartment and a tonically maintained, extrasynaptic compartment, each of which is differentially affected by uptake processes.