Characterization of dopamine receptors mediating inhibition of adenylate cyclase activity in rat striatum

P Onali, MC Olianas and GL Gessa

In the presence of SCH 23390, a potent blocker of D1 dopamine receptors, dopamine inhibits adenylate cyclase activity of synaptic plasma membranes isolated from rat striatum. Maximal inhibition corresponds to a 20-25% decrease of basal enzyme activity and is reached with 100 microM dopamine. The apparent IC50 of dopamine is 2.5 microM. The inhibitory effect of dopamine is mimicked by various dopamine receptor agonists with the following rank order of potency: (- )-propylnorapomorphine greater than or equal to bromocriptine greater than (+/-)-2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene = (-)- apomorphine greater than dopamine greater than LY 171555 greater than l- noradrenaline greater than l-phenylephrine. Clonidine and l- isoproterenol are inactive at 100 microM. Bromocriptine and LY 171555, two agents which stimulate selectively D2 receptors, inhibit striatal adenylate cyclase activity in the absence of SCH 23390. However, bromocriptine behaves like a partial agonist. A variety of neuroleptic drugs antagonize the dopamine inhibition with a rank order of potency which qualitatively correlates with their relative affinity for D2 receptors. l-Sulpiride (EC50 = 210 nM) and (+)-butaclamol (EC50 = 130 nM) are severalfold more potent than d-sulpiride (EC50 = 5 microM) and (-)-butaclamol (EC50 = 10 microM). The inhibitory effect of dopamine on striatal adenylate cyclase activity is dependent on the presence of GTP, with half-maximal inhibition occurring at 1 microM GTP. In the absence of SCH 23390, dopamine stimulates adenylate cyclase activity, reaching a maximum at 1 microM GTP. At higher concentrations of the nucleotide, the dopamine-stimulated enzyme activity decreases, and this decline is antagonized by the D2 receptor blocker l-sulpiride. Guanyl- 5'-yl imidodiphosphate, a stable analogue of GTP, has a biphasic effect on the striatal adenylate cyclase activity, inhibiting at low concentration (from 1 to 100 nM) and stimulating at higher concentrations. Selective activation of D2 receptors by LY 171555 does not increase the extent of enzyme inhibition elicited by guanyl-5'-yl imidodiphosphate. Sodium chloride amplifies the inhibition of striatal adenylate cyclase activity by LY 171555 and reduces the potency of the D2 agonist by a factor of 4. The dopamine-inhibited enzyme activity is lost following intrastriatal injection of kainic acid. The results indicate that in rat striatum dopamine inhibits adenylate cyclase activity by acting on postsynaptic dopamine receptors with pharmacological properties of D2 type.

Volume 28, Issue 2, pp. 138-145, 08/01/1985
Copyright © 1985 by American Society for Pharmacology and Experimental Therapeutics

This article has been cited by other articles:

				K.-W. Lee, J.-H. Hong, I. Y. Choi, Y. Che, J.-K. Lee, S.-D. Yang, C.-W. Song, H. S. Kang, J.-H. Lee, J. S. Noh, et al. Impaired D2 Dopamine Receptor Function in Mice Lacking Type 5 Adenylyl Cyclase J. Neurosci., September 15, 2002; 22(18): 7931 - 7940. [Abstract] [Full Text] [PDF]

				G. Cai, H.-Y. Wang, and E. Friedman Increased Dopamine Receptor Signaling and Dopamine Receptor-G Protein Coupling in Denervated Striatum J. Pharmacol. Exp. Ther., September 1, 2002; 302(3): 1105 - 1112. [Abstract] [Full Text] [PDF]

				D. M. Mottola, J. D. Kilts, M. M. Lewis, H. S. Connery, Q. D. Walker, S. R. Jones, R. G. Booth, D. K. Hyslop, M. Piercey, R. M. Wightman, et al. Functional Selectivity of Dopamine Receptor Agonists. I. Selective Activation of Postsynaptic Dopamine D2 Receptors Linked to Adenylate Cyclase J. Pharmacol. Exp. Ther., June 1, 2002; 301(3): 1166 - 1178. [Abstract] [Full Text] [PDF]

				J. M. Brown, G. R. Hanson, and A. E. Fleckenstein Cocaine-Induced Increases in Vesicular Dopamine Uptake: Role of Dopamine Receptors J. Pharmacol. Exp. Ther., September 1, 2001; 298(3): 1150 - 1153. [Abstract] [Full Text] [PDF]

				E. S. Vizi Role of High-Affinity Receptors and Membrane Transporters in Nonsynaptic Communication and Drug Action in the Central Nervous System Pharmacol. Rev., March 1, 2000; 52(1): 63 - 90. [Abstract] [Full Text] [PDF]

				C. MISSALE, S. R. NASH, S. W. ROBINSON, M. JABER, and M. G. CARON Dopamine Receptors: From Structure to Function Physiol Rev, January 1, 1998; 78(1): 189 - 225. [Abstract] [Full Text] [PDF]

				A. Nishi, G. L. Snyder, and P. Greengard Bidirectional Regulation of DARPP-32 Phosphorylation by Dopamine J. Neurosci., November 1, 1997; 17(21): 8147 - 8155. [Abstract] [Full Text] [PDF]

				P. Drolet, L. Bilodeau, A. Chorvatova, L. Laflamme, N. Gallo-Payet, and M. D. Payet Inhibition of the T-Type Ca2+ Current by the Dopamine D1 Receptor in Rat Adrenal Glomerulosa Cells: Requirement of the Combined Action of the G{beta}{gamma} Protein Subunit and Cyclic Adenosine 3',5'-Monophosphate Mol. Endocrinol., April 1, 1997; 11(4): 503 - 514. [Abstract] [Full Text]

				J. L. Waddington Functional interactions between D-1 and D-2 dopamine receptor systems: their role in the regulation of psychomotor behaviour, putative mechanisms, and clinical relevance J Psychopharmacol, January 1, 1989; 3(2): 54 - 63. [PDF]