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The Journal of Neuroscience, May 1, 2000, 20(9):3504-3511
Dual Effects of D-Amphetamine on Dopamine Neurons
Mediated by Dopamine and Nondopamine Receptors
Wei-Xing
Shi,
Chen-Lun
Pun,
Xue-Xiang
Zhang,
Michelle D.
Jones, and
Benjamin S.
Bunney
Department of Psychiatry, Yale University School of Medicine, New
Haven, Connecticut 06510
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  1 antagonists prazosin and WB4101 and the nonselective
antagonist phenoxybenzamine completely blocked increase in bursting
induced by D-amphetamine and partially blocked the increase
in firing rate. The 2 antagonist idazoxan and the  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 1 receptors.
Key words:
amphetamine; drug abuse; addiction; psychostimulant; dopamine; norepinephrine; prazosin; adrenergic; 1; substantia
nigra; ventral tegmental area; burst; single-unit recording
Copyright © 2000 Society for Neuroscience 0270-6474/00/2093504-08$05.00/0
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