High-speed chronoamperometry was used to determine the moment-to-moment and day-to-day changes in dopamine-related electrochemical signals in the nucleus accumbens of rats allowed to self-administer cocaine (0.8 mg/kg/injection) intravenously. The first, unexpected, cocaine injection caused an abrupt and long-lasting decrease in electrochemical signal. The second and subsequent injections caused shorter decreases in signal that were followed, beginning 2–3 min after injection, with a return of signal toward the preinjection baseline. Thus, the signal increased just prior to each lever press, peaked at the moment of lever pressing, and decreased for some minutes after each response. Over the first testing session, the phasic fluctuations kept the signal somewhat below the preinjection baseline. On the second and subsequent days, there were large increases in signal following presentation of the light stimulus that marked the onset of drug availability and that was paired with each cocaine injection; this light stimulus had no effect on the first day, prior to drug-light pairings. The first injection of the second and subsequent days caused an additional increase in signal; the magnitude of the increase was comparable to that caused by the initial stimulus, and the two increases summated to elevate voltammetric signals well above the normal baseline. Subsequent injections caused immediate but short-lived decreases in signal, as were seen on the first day; again, the signal returned to or rose slightly above the preinjection level by the time of the next lever press and injection. No decrease was seen after lever presses when earned injections were occasionally withheld; rather, the signal continued to increase slowly until another lever press was made and a subsequent injection was received. When access to the lever was blocked and the infusion pump was inactivated at the end of self-administration sessions, the animals became agitated and the electrochemical signal increased and remained elevated for 20–40 min before gradually declining toward the original baseline. Thus, the effects of cocaine on DA-associated signals in nucleus accumbens (1) changed dramatically during the development of the self-administration habit and (2) depended on environmental and behavioral as well as pharmacological factors. In trained animals, cocaine self-administration was accompanied by a tonic elevation of DA-associated signals and by phasic fluctuations time-locked to each cocaine injection.