PHARMACOLOGICAL CHARACTERIZATION OF THE D2-DOPAMINE RECEPTOR NEGATIVELY COUPLED WITH ADENYLATE-CYCLASE IN RAT ANTERIOR-PITUITARY

  • 1 January 1983
    • journal article
    • research article
    • Vol. 23  (3) , 576-584
Abstract
In male and female rat anterior pituitary homogenates, dopamine inhibited basal adenylate cyclase by 30% and 50%, respectively. Dopamine inhibited vasoactive intestinal peptide-stimulated adenylate cyclase by 50% in both sexes. Sulpiride, a specific D2 antagonist, stereospecifically blocked with high affinity the dopamine inhibition in both males and females. RU 24,926 [N-(3-hydroxyphenethyl)-N-propyl-m-tyramine], a specific, non-catechol, non-ergot D2 agonist, inhibited basal adenylate cyclase of female pituitary with a higher apparent affinity than dopamine (Kdapp 20 nM and 450 nM, respectively). This effect was also stereospecifically antagonized by sulpiride. Apomorphine was more potent (Kdapp100 nM) than dopamine, whereas norepinephrine and SKF 38,393 [2,3,4,5-tetrahydro-7,8-dihydroxy-1phenyl-1H-3-benzazepine], a specific D1 agonist, were poorly active; isoproterenol and clonidine were inactive. Ergots derivatives such as CB 154 [2-bromo-.alpha.-ergocryptine], LY 14,865 [trans(.+-.)4,4a,5,6,7,8,8a,9-octa-hydro-5-propyl-2H-pyrazolo-[3,4-g]-quinoline dihydrochloride], pergolide, and lergotrile were potent agonists. .alpha.-Dihydroergocryptine was a partial agonist of the dopamine receptor negatively coupled with an adenylate cyclase. Because of the slow association kinetics of this drug with the dopamine receptor, its Kdapp (0.7 nM) for adenylate cyclase inhibition could be correctly determined only after a 30-min incubation period. All classical dopaminergic antagonists blocked dopamine inhibition of pituitary adenylate cyclase, pimozide (KI[inhibition constant]1 nM) and spiperone (KI 0.8 nM) being the more potent. There were good correlations between the affinities of a large series of agonists and antagonists for the anterior pituitary dopamine receptors negatively coupled with an adenylate cyclase, and for either D2 dopamine receptors labeled with [3H]dihydroergocryptine or [3H]spiroperidol in both putuitary and striatum, or D2 pituitary receptors involved in prolactin secretion. The pituitary dopamine receptors negatively coupled with an adenylate cyclase are evidently the classical D2 receptors involved in prolactin secretion.