D1-D2 interaction in feedback control of midbrain dopamine neurons

Abstract

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 (</=20 microg/kg) of quinpirole. Because low doses of D2 agonists preferentially act on DA autoreceptors, and because the D1 inhibition persisted in animals whose DA autoreceptors were blocked by intranigral application of raclopride, our results suggest that the expression of D1 feedback inhibition requires co-activation of D2-like receptors on DA target neurons, instead of DA neurons themselves. These results, together with the finding that chloral hydrate completely blocked the D1 inhibition, may explain why previous studies have failed to show a consistent D1 effect on DA cells and suggest that drugs designed to act specifically on one subtype of DA receptor may, via feedback pathways, influence the action of endogenous DA on other DA receptor subtypes as well.

Fig. 1.

Diagram illustrating the position of brainstem transection for the low cerveau isolé preparation.A, Sagittal view of a rat brain showing the site of transection between the pons and the medulla oblongata (1 mm posterior to the lambda, indicated by the thick line).B, Coronal view of the transected areas (shaded) through the cerebellum and the brainstem.Thick lines illustrate the initial and final positions of the transection knife (a flattened needle). See Materials and Methods for details. Figures are redrawn from the rat atlas of Paxinos and Watson (1997).

Fig. 2.

Systemic activation of D1-like receptors produces no consistent effect on the activity of SN DA cells in rats pretreated with low doses of a D2 agonist. A, Graph showing lack of a consistent effect of the D1 agonist SKF38393 on SN DA cells in rats pretreated with low doses of the D2 agonist quinpirole (5–20 μg/kg, i.v.). Open and filled circles represent, respectively, the firing rate of individual cells immediately before SKF38393 administration (10–20 mg/kg, i.v.) and after SKF38393 had produced a maximum effect. Straight lines link the data from individual cells. Of nine cells tested, seven were slightly excited or showed no response to SKF38393 (<10% change in baseline) and two were inhibited. Overall, the firing rate was decreased nonsignificantly from 56.5 ± 7.3 to 52.8 ± 9.4% of baseline (p = 0.757; n = 9; open and filed bars).B, Typical rate histogram showing lack of an effect of SKF38393 on the activity of an SN DA cell pretreated with a low dose of quinpirole. A single dose of quinpirole (QUIN, 10 μg/kg, i.v.) inhibited the firing of the cell to ∼40% of baseline. Subsequent administration of SKF38393 (SKF, 10 mg/kg, i.v.) did not significantly affect the remaining activity. In this and following figures, arrows indicate the times of drug injection, and the numbers above thearrows represent the doses of the drug injected.

Fig. 3.

Systemic activation of D1-like receptors consistently inhibits SN DA neurons in rats pretreated with high doses of a D2 agonist. A, Graph showing the inhibition of DA cells by the D1 agonist SKF38393 (5–20 mg/kg, i.v.) in rats pretreated with high doses of the D2 agonist quinpirole (40–160 μg/kg, i.v.).Open and filled circles represent the firing rate of individual cells before and after SKF38393 injection, respectively. Of 10 cells tested, nine were inhibited, and one showed no response to SKF38393. On average, the firing rate was significantly decreased from 39.3 ± 4.7 to 10.9 ± 4.1% of baseline (p < 0.0001; n = 10;open and filled bars). B, Typical rate histogram showing the inhibition by SKF38393 of a SN DA cell pretreated with a high dose of quinpirole (QUIN, 40 μg/kg). After the final dose of quinpirole, the firing rate of this cell was decreased to about 40% of baseline. Subsequent administration of SKF38393 (SKF) almost completely stopped the remaining activity. The selective D1 antagonist SCH23390 (SCH) reversed the inhibition induced by SKF38393. Haloperidol (HAL) further increased the firing rate to the predrug level. C, Typical rate histogram showing lack of an effect of the D1 antagonist SCH23390 on the inhibition induced by the D2 agonist quinpirole alone. After a cumulative dose of 80 μg/kg, quinpirole (QUIN) completely inhibited the activity of this cell. About 2 min later, the cell began to recover spontaneously. SCH23390 (SCH), up to 160 μg/kg, produced no effect on the recovery of the cell. Haloperidol (HAL), on the other hand, increased the activity to baseline.

Fig. 4.

D1-mediated feedback inhibition persists after DA autoreceptors are blocked. A, Graph showing inhibition by the D1 agonist SKF38393 of DA cells with blocked DA autoreceptors. Before testing for the D1 response, raclopride was introduced locally just above the SN (2–8 μg) to block DA autoreceptors, and high doses of quinpirole (40–640 μg/kg, i.v.) were administered to activate D2-like receptors on DA target neurons. Open andfilled circles represent the firing rate of individual cells before and after SKF38393 injection (5–10 mg/kg, i.v.), respectively. In 17 of 18 cells, SKF38393 produced a clear further inhibition. On average, the firing rate was reduced significantly from 47.9 ± 5.1 to 16.1 ± 5.1% of baseline (openand filled bars; p < 0.0001;n = 18). B, Typical rate histogram showing the inhibition by SKF38393 of an SN DA cell treated locally with raclopride (8 μg). A cumulative dose of 40 μg/kg of quinpirole (QUIN) produced a 50% inhibition of firing. Injection of SKF38393 (SKF) produced a clear further inhibition. The D1 antagonist SCH39166 (SCH) reversed the inhibition induced by SKF38393. The D2 antagonist raclopride (Rac) brought the activity back to baseline.

Fig. 5.

The new D1 agonist DHX mimics the effect of SKF38393 and inhibits the activity of DA cells treated with high doses of the D2 agonist quinpirole. A, Graph showing the inhibition induced by DHX (0.5–1 mg/kg) of seven SN DA cells in rats pretreated with raclopride (4–10 μg, locally in the SN) and with quinpirole (160 μg/kg, i.v.). Open and filled circles represent the firing rate of individual cells before and after DHX injection, respectively. All cells showed an inhibitory response to DHX. On average, the firing rate was reduced from 45.0 ± 7.0 to 13.8 ± 4.1% of baseline (open andfilled bars; p < 0.001).B, Typical rate histogram showing the inhibition by DHX of an SN DA cell pretreated locally with raclopride (10 μg). Quinpirole (QUIN, 160 μg/kg) inhibited the firing rate of this cell to 65% of baseline. DHX further inhibited the activity to 35%. SCH39166 (SCH) reversed the inhibition induced by DHX. Raclopride further returned the activity to predrug baseline (data not shown).

Fig. 6.

The anesthetic chloral hydrate blocks the D1-mediated feedback inhibition of SN DA neurons. A, Graph showing lack of an effect of a D1 agonist on SN DA cells in chloral hydrate-anesthetized animals (400 mg/kg, i.p.). Before testing for the effect of SKF38393, rats were pretreated with a high dose of quinpirole (40–160 μg/kg, i.v.). Open andfilled circles represent the firing rate of individual cells before and after SKF38393 injection (10–20 mg/kg, i.v.), respectively. No significant D1 effect was observed in any of the seven cells tested. The average firing rate of the cells was slightly increased from 33.7 ± 4.0 to 35.8 ± 4.0% of baseline after SKF38393 injection (open and filled bars;p = 0.082). B, Typical rate histogram showing lack of an effect of SKF38393 (20 mg/kg) on an SN DA cell in a chloral hydrate-anesthetized animal (400 mg/kg, i.p.). The firing rate of the cell was reduced to about 30% of baseline after a high dose of quinpirole (QUIN, 80 μg/kg, i.v.). Subsequent administration of SKF38393 (SKF) and SCH23390 (SCH) produced no effect on the remaining activity. Haloperidol (HAL) returned the firing rate to baseline.