Dual effects of D-amphetamine on dopamine neurons mediated by dopamine and nondopamine receptors.

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.

Endogenous DA-mediated feedback inhibition of DA neurons: involvement of both D(1)- and D(2)-like receptors.

To investigate the role of D(1)-like receptors in endogenous dopamine (DA)-mediated feedback control of DA neurons in vivo, single unit recordings were made from rat nigral DA cells using low cerveau isolé preparations. The D(2) antagonist raclopride, but not the D(1) antagonist SCH23390, increased baseline activity of DA neurons, suggesting that spontaneously released DA acts primarily through D(2)-like receptors to inhibit DA cells. However, feedback inhibition induced by an increased DA release by D-amphetamine (1 mg/kg, i.v.) was partially reversed by SCH23390. The same inhibition, on the other hand, was always completely reversed by raclopride, suggesting that the D(1)-mediated portion of the inhibition depends upon co-activation of D(2)-like receptors. In rats with forebrain hemitransections, D-amphetamine-induced inhibition was markedly decreased and the remaining inhibition was not blocked by SCH23390, supporting the suggestion that D(1)-D(2) co-activation-induced inhibition is mediated through long feedback pathways. In chloral hydrate-anesthetized rats, D-amphetamine-induced inhibition was also insensitive to SCH23390; however, the degree of the inhibition was not reduced. Combined with previous studies, these data suggest that chloral hydrate not only inactivates the D(1) feedback pathway but also enables the D(2) feedback pathway to operate independently of D(1)-like receptors. Conversely, in parkinsonian animals D(1) receptor activation alone has been reported to inhibit DA cells. Taken together, these results suggest that a major portion of endogenous DA-mediated feedback inhibition is due to concurrent activation of D(1)- and D(2)-like receptors. However, this D(1)-D(2) interdependence may alter under certain conditions and may play a role in the pathophysiology of Parkinson's disease.

D1-D2 interaction in feedback control of midbrain dopamine neurons.

Dopamine (DA) D1-like receptors are present in pathways implicated in feedback control of midbrain DA neurons. However, stimulation of these receptors either produces no effect on DA cells, or the effect is inconsistent. It is possible that the expression of a D1 feedback effect requires co-activation of D2-like receptors. To test this hypothesis, we recorded extracellularly the spontaneous activity of nigral DA cells in a low cerveau isolé rat preparation. SKF38393 and dyhydrexidine, two D1 agonists, were administered systemically to animals pretreated with different doses of the D2 agonist quinpirole. Supporting the hypothesis, the two D1 agonists consistently inhibited DA cells in animals given high doses of quinpirole (>/=40 microg/kg, i.v.). However, no significant D1 effect was observed in animals pretreated with only low doses (