D2-dopamine receptor-mediated inhibition of cyclic AMP formation in striatal neurons in primary culture

S Weiss, M Sebben, JA Garcia-Sainz and J Bockaert

Dopamine (DA) regulation of intracellular cyclic AMP formation in purified, intact striatal neurons in primary culture was examined. DA (EC50, 3 microM) and vasoactive intestinal polypeptide (VIP; EC50, 10 nM) stimulated cyclic AMP formation by 2- and 5-fold, respectively. In the presence of 0.1 microM forskolin (which was virtually ineffective alone), neurohormone efficacy was augmented; potency was unaffected. In the presence of 0.1 microM SCH 23390, a selective D1 antagonist, the DA dose-response curve was shifted rightward in a competitive manner. At low concentrations (0.01-1.0 microM), however, DA inhibited basal cyclic AMP formation. The inhibitory effect, but not the shift of the dose-response curve, was blocked by 5 microM l-sulpiride, a selective D2 antagonist. At saturating concentrations of VIP (0.1-1.0 microM), no other neurohormone can further augment cyclic AMP formation. Under these conditions, increasing concentrations of DA resulted in a dose- dependent (IC50, 0.5 microM) inhibition of VIP-stimulated cyclic AMP synthesis. This effect was augmented in the presence of 0.1 microM SCH 23390 and blocked by 5 microM 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 cyclic AMP formation suggests that it is of the D2 type. Furthermore, both DA and Met-enkephalin inhibition of cyclic AMP formation is lost after exposure of striatal neurons to islet activator protein. These findings suggest that a D2 receptor mediates the inhibition of intracellular cyclic AMP 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.

Volume 27, Issue 6, pp. 595-599, 06/01/1985
Copyright © 1985 by American Society for Pharmacology and Experimental Therapeutics

This article has been cited by other articles:

				S. Hernandez-Lopez, T. Tkatch, E. Perez-Garci, E. Galarraga, J. Bargas, H. Hamm, and D. J. Surmeier D2 Dopamine Receptors in Striatal Medium Spiny Neurons Reduce L-Type Ca2+ Currents and Excitability via a Novel PLC{beta}1-IP3-Calcineurin-Signaling Cascade J. Neurosci., December 15, 2000; 20(24): 8987 - 8995. [Abstract] [Full Text] [PDF]

				T. Blank, I. Nijholt, U. Teichert, H. Kugler, H. Behrsing, A. Fienberg, P. Greengard, and J. Spiess The phosphoprotein DARPP-32 mediates cAMP-dependent potentiation of striatal N-methyl-D-aspartate responses PNAS, December 23, 1997; 94(26): 14859 - 14864. [Abstract] [Full Text] [PDF]

				J. Kim, Jür. Wess, A. M. v. Rhee, T. Schöneberg, and K. A. Jacobson Site-directed Mutagenesis Identifies Residues Involved in Ligand Recognition in the Human A[IMAGE] Adenosine Receptor J. Biol. Chem., June 9, 1995; 270(23): 13987 - 13997. [Abstract] [Full Text] [PDF]