D-2-DOPAMINE RECEPTOR-MEDIATED INHIBITION OF CYCLIC-AMP FORMATION IN STRIATAL NEURONS IN PRIMARY CULTURE

  • 1 January 1985
    • journal article
    • research article
    • Vol. 27  (6) , 595-599
Abstract
Dopamine (DA) regulation of intracellular cAMP formation in purified, intact striatal neurons (from mice) in primary culture was examined. DA (EC50, 3 .mu.M) and vasoactive intestinal polypeptide (VIP; EC50, 10 nM) stimulated cAMP formation by 2- and 5-fold, respectively. In the presence of 0.1 .mu.M forskolin (which was virtually ineffective alone), neurohormone efficacy was augmented; potency was unaffected. In the presence of 0.1 .mu.M SCH 23390 [(R)-(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepin-7-ol-hemimaleate] a selective D1 antagonist, the DA dose-response curve was shifted rightward in a competitive manner. At low concentrations (0.01-1.0 .mu.M), however, DA inhibited basal cAMP formation. The inhibitory effect, but not the shift of the dose-response curve, was blocked by 5 .mu.M l-sulpiride, a selective D2 antagonist. At saturating concentrations of VIP (0.1-1.0 .mu.M), no other neurohormone can further augment cAMP formation. Under these conditions, increasing concentrations of DA resulted in a dose-dependent (IC50, 0.5 .mu.M) inhibition of VIP-stimulated cAMP synthesis. This effect was augmented in the presence of 0.1 .mu.M SCH 23390 and blocked by 5 .mu.M l-sulpiride. Sulpiride antagonism was stereospecific, with the l-isomer being 30-fold more potent than the d-isomer. The rank order of potency for a series of dopaminergic agonists and antagonists at the receptor mediating attenuation of cAMP formation suggests that it is of the D2 type. Furthermore, both DA and Met-enkephalin inhibition of cAMP formation is lost after exposure for striatal neurons to islet activator protein. These findings suggest that a D2 receptor mediates the inhibition of intracellular cAMP formation by DA in striatal neurons in primary culture, and may do so by an interaction with the inhibitory guanine nucleotide regulatory protein of adenylate cyclase.

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