Differential time-course profiles of dopamine release and uptake changes induced by three dopamine uptake inhibitors

Using real-time voltammetry, we compared the effects of cocaine (1.0, 3.0, or 10 microM), WIN 35428 (0.1, 0.5, or 2.0 microM), and nomifensine (0.2, 1.0, or 5.0 microM) on electrically evoked dopamine release and uptake in the rat accumbens slice. The time course for onset and offset of the drug effects were determined by perfusing single drug concentration for 30 min, followed by a 60-min washout. Cocaine elicited a rapid, concentration-independent increase in dopamine release and a more gradual, concentration-dependent inhibition of uptake. During washout, uptake inhibition rapidly abated to near baseline values. During the same period, the potentiation of dopamine release exhibited a slower offset for all concentrations and, for 10 microM cocaine, was even greater than that observed during drug perfusion ("rebound" increase). The release rebound was not observed during continuous 90-min perfusion, verifying that cocaine washout per se was a sufficient condition. Selective D1 or D2 antagonists (0.5 microM SCH 39166 or 2 microM sulpiride, respectively) were without effect on cocaine-induced release alterations. WIN 35428 and nomifensine induced similar changes in dopamine kinetics during perfusion. However, in contrast to cocaine, no consistent release rebound was observed during their washout. For 2 microM WIN 38425, washout and continuous perfusion groups exhibited similar changes in dopamine release and uptake. The time-course mismatch between uptake inhibition and DA release potentiation as well as release rebound during washout suggests that altered dopamine release might play a role in behavioral effects of cocaine.