Inhibition of dopamine uptake by D2 antagonists: an in vivo study

J. Neurochem. (2011) 116, 449–458. D2‐like antagonists potentiate dopamine release. They also inhibit dopamine uptake by a mechanism yet to be clarified. Here, we monitored dopamine uptake in the striatum of anesthetized mice. The dopamine overflow was evoked by brief electrical stimulation of the medial forebrain bundle (four pulses at 100 Hz) and was monitored with carbon fiber electrodes combined with continuous amperometry. The decay phase of evoked overflows reflects dopamine half‐life, which entirely depends on uptake. The D2‐like antagonists haloperidol and eticlopride enhanced the half‐life by 45% and 48%, respectively, a moderate effect as compared to the uptake blocker nomifensine (528%). Both D2‐like antagonists did not affect dopamine uptake in mice lacking D2 receptors. Inhibition of tonic dopamine release by gamma‐butyrolactone did not mimic the enhancing effect of D2 antagonists on dopamine half‐life. However, prolonged stimulation boosted dopamine uptake and this effect was not observed after haloperidol treatment or in mice lacking D2 receptors. Therefore, dopamine uptake is accelerated in conditions of excessive D2 stimulation but not finely tuned in resting conditions. Inhibition of dopamine uptake by D2 antagonists synergizes with the potentiation of dopamine release to strongly alter the phasic dopamine signaling.