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

• Published in: The Journal of neuroscience 2000-05, Vol.20 (9), p.3504-3511
• Main Authors: Shi, Wei-Xing, Pun, Chen-Lun, Zhang, Xue-Xiang, Jones, Michelle D, Bunney, Benjamin S
• Format: Article
• Language: English
• Subjects: Action Potentials - drug effects; Action Potentials - physiology; Adrenergic alpha-Antagonists - pharmacology; Animals; Dextroamphetamine - pharmacology; Dopamine Agents - pharmacology; Dopamine Antagonists - pharmacology; Male; Neurons - drug effects; Neurons - physiology; Raclopride - pharmacology; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic, alpha - drug effects; Receptors, Adrenergic, alpha - physiology; Receptors, Dopamine - drug effects; Receptors, Dopamine - physiology; Substantia Nigra - drug effects; Substantia Nigra - physiology; Ventral Tegmental Area - drug effects; Ventral Tegmental Area - physiology
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/jneurosci.20-09-03504.2000

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.