Dual Effects of D-amphetamine on Dopamine Neurons Mediated by Dopamine and Nondopamine Receptors

By increasing dopamine (DA) release and activating feedback mechanisms, amphetamine and related psychostimulants are known to inhibit DA cell firing. Here, we report that D-amphetamine also has an excitatory effect on DA cells, which under control conditions, is masked by the inhibitory effect of D-amphetamine and is revealed when D2-like receptors are blocked. Thus, using in vivo single-unit recording in rats, we found that the selective D2 antagonist raclopride not only blocked the inhibition induced by D-amphetamine but also enabled D-amphetamine to excite DA cells. The excitation, expressed as an increase in both firing rate and bursting, persisted when both D1- and D2-like receptors were blocked by SCH23390 and eticlopride, suggesting that it is not mediated by DA receptors. The norepinephrine uptake blocker nisoxetine mimicked the effect of D-amphetamine, especially the increase in bursting, whereas the 5-HT uptake blocker fluoxetine produced no significant effect. Adrenergic alpha1 antagonists prazosin and WB4101 and the nonselective alpha antagonist phenoxybenzamine completely blocked increase in bursting induced by D-amphetamine and partially blocked the increase in firing rate. The alpha2 antagonist idazoxan and the beta antagonist propranolole, however, failed to prevent D-amphetamine from producing the excitation. Thus, revising the traditional concept, this study suggests that D-amphetamine has two effects on DA cells, a DA-mediated inhibition and a non-DA-mediated excitation. The latter is mediated in part through adrenergic alpha1 receptors.