title: Dual effects of D-amphetamine on dopamine neurons mediated by dopamine and nondopamine receptors.
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 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.
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut 06510, USA. wei-xing.shi@yale.edu
authors.forename: W X
authors.initials: WX
authors.lastname: Shi
authors.forename: C L
authors.initials: CL
authors.lastname: Pun
authors.forename: X X
authors.initials: XX
authors.lastname: Zhang
authors.forename: M D
authors.initials: MD
authors.lastname: Jones
authors.forename: B S
authors.initials: BS
authors.lastname: Bunney
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D003913:Dextroamphetamine / Q000494:pharmacology*; D015259:Dopamine Agents / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000494:pharmacology; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D020891:Raclopride / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects* / Q000502:physiology; D011954:Receptors, Dopamine / Q000187:drug effects* / Q000502:physiology; D013378:Substantia Nigra / Q000187:drug effects / Q000502:physiology; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000502:physiology
chemical_list: D000317:Adrenergic alpha-Antagonists; D015259:Dopamine Agents; D018492:Dopamine Antagonists; D011942:Receptors, Adrenergic, alpha; D011954:Receptors, Dopamine; D020891:Raclopride; D003913:Dextroamphetamine