Dual effects of D-amphetamine on dopamine neurons mediated by dopamine andnondopamine receptors

By increasing dopamine (DA) release and activating feedback mechanisms, amp hetamine and related psychostimulants are known to inhibit DA cell firing. Here, we report that D-amphetamine also has an excitatory effect on DA cell s, 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 anta gonist raclopride not only blocked the inhibition induced by D-amphetamine but also enabled D-amphetamine to excite DA cells. The excitation, expresse d 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 significa nt effect. Adrenergic alpha 1 antagonists prazosin and WB4101 and the nonse lective alpha antagonist phenoxybenzamine completely blocked increase in bu rsting induced by D-amphetamine and partially blocked the increase in firin g rate. The alpha 2 antagonist idazoxan and the beta antagonist propranolol e, however, failed to prevent D-amphetamine from producing the excitation. Thus, revising the traditional concept, this study suggests that D-amphetam ine has two effects on DA cells, a DA-mediated inhibition and a non-DA-medi ated excitation. The latter is mediated in part through adrenergic alpha 1 receptors.