Dual Effects of d-Amphetamine on Dopamine Neurons Mediated by Dopamine and Nondopamine Receptors

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Abstract
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 ofd-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 ofd-amphetamine, especially the increase in bursting, whereas the 5-HT uptake blocker fluoxetine produced no significant effect. Adrenergic α1 antagonists prazosin and WB4101 and the nonselective α antagonist phenoxybenzamine completely blocked increase in bursting induced by d-amphetamine and partially blocked the increase in firing rate. The α2 antagonist idazoxan and the β 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 α1 receptors.

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