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Opposing Roles of Dopamine D1 and D2 Receptors in Nigral γ-[3H]Aminobutyric Acid Release?

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Address correspondence and reprint requests to Dr. M. Starr at MRC Neuropharmacology Group, Department of Pharmacology, The School of Pharmacy, 29–39 Brunswick Square, London WC1N 1AX, U.K.

Abstract

Abstract: This study examined the effects of dopamine D1and D2 receptor agonists and antagonists on the spontaneous and calcium-dependent, K+-induced release of γ-[3H]-aminobutyric acid ([3H]GABA) accumulated by slices of rat substantia nigra. SKF 38393 (D1 agonist) and dopamine (dual D1/D2 agonist) were without effect on [3H]GABA efflux by themselves (1–40 μM), or in the presence of the phosphodiesterase inhibitor isobutylmethylxanthine (IBMX) (0.5 μM), but potentiated evoked release in the presence of forskolin (0.5 μM), an adenylate cyclase activator. These increases in release were prevented by the D1 antagonist SCH 23390 (0.5 μM), but not by the D2 antagonist metoclopramide (0.5 μM), Higher concentrations of forskolin (10–40 μM) augmented stimulus-evoked [3H]GABA release directly, whereas dibutyryl cyclic AMP (100–200 μM) depressed it. Apomorphine, noradrenaline, and 5-hy-droxytryptamine (1–40 μM) had no effect. The D2 stimulants lisuride, RU 24213, LY 171555, and bromocriptine dose-dependently inhibited depolarisation-induced but not basal [3H]GABA outflow. These inhibitory responses were not modified by the additional presence of SKF 38393 (10 μM) or SCH 23390 (1 μM), or by injection of 6-hydroxydopamine into the medial forebrain bundle 42 days earlier, but were attenuated by metoclopramide (0.5 μM). Higher amounts (10 μM) of SCH 23390, metoclopramide, or other D2 antagonists (loxapine, haloperidol) reduced evoked GABA release by themselves, probably by nonspecific mechanisms. These results suggest D1 and D2 receptors may have opposing effects on nigral GABA output and could explain the variable effects of mixed D1/D2 dopaminomimetics in earlier release and electrophysiological experiments.

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