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.

The reinforcing properties of psychostimulants depend critically on their effects on dopamine (DA) neurons in the ventral tegmental area (VTA). Using in vivo single unit recording in rats and spectral analysis, this study presents evidence for a new, non-DA-mediated effect of psychostimulants on VTA DA neurons. Thus, as previously observed with D-amphetamine, all psychostimulants tested, including cocaine, methamphetamine, and methylphenidate, had two opposing effects on firing rate of DA neurons: a DA-mediated inhibition and a non-DA-mediated excitation. The latter effect was normally masked by the DA-mediated inhibition and was revealed when the inhibition was blocked by a DA antagonist. Using spectral analysis, this study further showed that during psychostimulant-induced excitation, DA cells exhibited not only an increase in firing rate and bursting but also a low-frequency rhythmic oscillation (0.5-1.5 Hz) in their firing activity. The oscillatory response was unique to psychostimulants since it was not observed with the GABA A agonist muscimol, which also increased DA cell firing, and not mimicked by the nonpsychostimulant DA agonist L-dopa. Results further suggest that the effect requires activation of adrenergic a 1 receptors and depends on intact forebrain inputs to DA neurons. Further understanding of this novel effect may provide important insights into both the mechanism of action of psychostimulants and the neuronal circuitry that controls the activity of DA neurons in the brain.

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.

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.