CHARACTERIZATION OF DOPAMINE-RECEPTORS MEDIATING INHIBITION OF ADENYLATE-CYCLASE ACTIVITY IN RAT STRIATUM

Abstract

In the presence of SCH 23390 [(R)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepin-7-ol (2)-2-butenedioate], 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 in basal enzyme activity and is reached with 100 .mu.M dopamine. The apparent IC50 of dopamine is 2.5 .mu.M. The inhibitory effect of dopamine is mimicked by various dopamine receptor agonists with the following rank order of potency: (-)-propylnorapomorphine .gtoreq. bromocriptine > (.+-.)-2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene = (-)-apomorphine > dopamine > LY 171555 [quinpirole hydrochloride] > l-noradrenaline [norepinephrine] > l-phenylephrine. Clonidine and l-isoproterenol are inactive at 100 .mu.M. Bromocriptine and LY 171555, 2 agents which stimulate selectively D2 receptors, inhibit striatal adenylate cyclase activity in the absence of SCH 23390. 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 .mu.M) and (-)-butaclamol (EC50 = 10 .mu.M). The inhibitory effect of dopamine on striatal adenylate cyclase activity is dependent on the presence of GTP, with half-maximal inhibition occurring at 1 .mu.M GTP. In the absence of SCH 23390, dopamine stimulates adenylate cyclase activity, reaching a maximum at 1 .mu.M 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 analog of GTP, has a biphasic effect on the striatal adenylate cyclase activity, inhibiting at low concentrations (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. In rat striatum dopamine inhibits adenylate cyclase activity by acting on postsynaptic dopamine receptors with pharmacological properties of D2 type.