Stimulatory Action of Lisuride on Dopamine-Sensitive Adenylate Cyclase in the Rat Striatal Homogenate

Abstract

Abstract-Effect of lisuride, an ergot derivative of isolysergic structure, on dopamine sensitive adenylate cyclase was studied in the homogenate of rat corpus striatum. Stimulatory action of lisuride, similar to the actions of dopamine and apomorphine, on striatal adenylate cyclase was potentiated significantly by guanosine triphosphate (GTP) and by guanyl-5'-yl imidodiphosphate (GMP-PNP), although with lisuride alone, there was only a slight stimulation.The maximal stimulation attained in the presence of GTP corresponded to about 1.4 times the basal rate of cyclic AMP formation in the homogenate and was abolished by an addition of haloperidol.Lisuride at a concentration above 3 ,uM inhibited stimulation of cyclic AMP formation by dopamine. The effect of lisuride and the extent of potentiation by the guanyl nucleotides were almost comparable to the effects of apomorphine, under corresponding conditions. Thus, lisuride, like apomorphine, acts as a partial agonist-antagonist, and has the ability to stimulate the dopamine-sensitive adenylate cyclase in the rat corpus striatum.Drugs such as apomorphine stimulate dopaminergic receptors in the brain. Lisuride, a semi-synthetic ergot derivative of isolysergic structure (1), also exhibits potent dopaminergic actions in vivo, as demonstrated by enhancement of locomotor activity (2), induction of stereotyped behavior (2) and reduction in serum prolactin levels (3). Direct stimulatory action of lisuride on dopamine receptors of post synaptic membrane was suggested by the finding that the induction of stereotyped behavior was inhibited by haloperidol, a blocker of dopamine receptors, and not by a-methyl-p-tyrosine methyl ester, an inhibitor of dopamine synthesis (2). It was also reported that specific binding of 3H-spiroperidol and of 3H-lisuride was inhibited by lisuride (4) and (+)-butaclamol (5), respectively.Adenylate cyclase in some regions of the brain is stimulated by dopamine in vitro (6-8), hence, the possibility that adenylate cyclase plays an important role in the post synaptic membrane has been discussed in relation to dopamine-dependent brain functions (9, 10).In fact, after solubilization of the synaptic membrane of bovine caudate nuclei, the enzyme activity of dopamine-sensitive adenylate cyclase could be reconstituted with two protein fractions, the one necessary for dopamine binding and the other for the catalytic site (11).Though less efficient than dopamine, apomorphine does stimulate the adenylate cyclase

Medikamentöse Behandlung der idiopathischen Parkinson-Krankheit

“…Lisurid besitzt neben einer D2-Rezeptor-agonistischen Wirkung eine geringe stimulierende Wirkung auf D1-Rezeptoren und bindet außerdem an 5-HT1A-Rezeptoren [21]. Die Bioverfügbarkeit von Lisurid liegt bei 14%.…”