Dopamine neurotransmission has been implicated in the modulation of many cognitive processes. Both rapid (phasic) and slower (tonic) changes in its extracellular concentration contribute to its complex actions. Fast in vivo electrochemical techniques can measure extracellular dopamine on a rapid time scale but without the selectivity afforded with slower techniques that use chemical separations. Cyclic voltammetry improves chemical resolution over other electrochemical methods, and it can resolve dopamine changes in the brains of behaving rodents over short epochs (<10 s). With this method, however, selective detection of slower dopamine changes is still elusive. Here we demonstrate that principal component regression of cyclic voltammetry data enables quantification of changes in dopamine and extracellular pH. Using this method, we show that cocaine modifies dopamine release in two ways: dopamine concentration transients increase in frequency and magnitude, whereas a gradual increase in steady-state dopamine concentration occurs over 90 s.cyclic voltammetry ͉ nucleus accumbens ͉ principal component regression F ast changes in the extracellular concentration of neurotransmitter can arise from phasic neuronal firing, whereas longlasting changes are associated with tonic firing (1). Dopaminergic neurons exhibit both of these firing patterns. Phasic activity accompanies salient stimuli, whereas tonic firing regulates the steady-state extracellular concentration (2). For this reason, chemical sensors for dopamine should be able to operate on a wide range of time scales in behaving animals. Microdialysis, a commonly used in vivo chemical sampling technique, is well suited to measure the minute-to-minute changes (tonic) that occur after uptake inhibition by agents such as cocaine (3,4). In vivo voltammetry, another approach for dopamine sampling, can measure much faster events, enabling phasic dopamine changes to be measured (5).A limitation of all voltammetric techniques has been their chemical selectivity. Fast-scan cyclic voltammetry at carbonfiber microelectrodes (6) provides rapid measurements and yields a chemical signature, the cyclic voltammogram, that allows distinction among electroactive molecules that are present in the brain. The electrode is highly sensitive to dopamine relative to dihydroxyphenylacetic acid and ascorbate, two major interferants, and the voltammogram of dopamine is distinct from those for a variety of neurochemical substances, although it is the same as that for norepinephrine (7). However, measurements in behaving rats have revealed that rapid dopamine changes are usually accompanied by other rapid changes in the electrochemical signal (5,8,9). Measurements with ion-selective electrodes demonstrated that these signals arise from a change in the pH of the brain extracellular fluid (10). Therefore, an objective method is needed to resolve the detected chemical events, assign them to specific compounds, and evaluate their temporal characteristics.Voltammetric electrodes are similar to othe...