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Interaction of Pergolide with Central Dopaminergic Receptors (Parkinsonism/Adenylate Cyclase) MENEK GOLDSTEIN*, ABRAHAM LIEBERMAN*, Jow Y

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Interaction of Pergolide with Central Dopaminergic Receptors (Parkinsonism/Adenylate Cyclase) MENEK GOLDSTEIN*, ABRAHAM LIEBERMAN*, Jow Y Proc. Natl. Acad. Sci. USA Vol. 77, No. 6, pp. 3725-3728, June 1980 Neurobiology Interaction of pergolide with central dopaminergic receptors (parkinsonism/adenylate cyclase) MENEK GOLDSTEIN*, ABRAHAM LIEBERMAN*, Jow Y. LEW*, TAKU ASANO*, MYRNA R. ROSENFELDt, AND MAYNARD H. MAKMANt *New York University Medical Center, Departments of Psychiatry and Neurology, 560 First Avenue, New York, New York 10016; and tAlbert Einstein College of Medicine, Departments of Biochemistry and Molecular Pharmacology, Bronx, New York 10461 Communicated by Michael Heidelberger, February 12,1980 ABSTRACT The activity of pergolide, an N-propylergoline MATERIALS AND METHODS derivative, has been tested for stimulation of central dopa- minergic receptors. Binding to dopamine receptors shows that Materials. [3H]Dopamine (8.4 Ci/mmol), [3H]Spiroperidol pergolide acts as an agonist with respect to these receptors. GTP ([3H]Spi) (23 Ci/mmol), N-n-[3H]propylnorapomorphine decreases the potencies of dopamine agonists and of pergolide, ([3H]NPA) (75 Ci/nmol) were purchased from New England but not of bromocriptine, to displace [3HJspiroperidol {43HSpi) Nuclear (1 Ci = 3.7 X 1010 becquerels). Pergolide was a gift from striatal membrane sites. The GTP-sensitive site labeled from Eli Lilly, and bromocriptine from Sandoz Pharmaceu- by [3HJSpi seems to be localized on intrastriatal dopamine re- tical. ceptors. The potency of dopamine agonists and of pergolide to Binding Assay. Preparation of bovine or rat membranes and displace [3HJSpi from striatal receptor sites is reduced in membranes exposed to higher temperatures. Pergolide, but not the ensuing binding assay were carried out as described (13). hitherto-tested dopaminergic ergots, stimulates do amine- For routine assay each tube contained 1.8 ml. of membrane sensitive adenylate cyclase in striatal homogenates. Thus, per- suspension (5 mg of wet tissue), 0.1 ml of radioactive ligand (2.5 golide, unlike other dopaminergic ergots, acts as an agonist on nM [3H]dopamine, 0.5 nM [3H]Spi, or 0.5 nM [3H]NPA), and, GTP-sensitive components of [3HJSpi binding and stimulates when indicated, various concentrations of drugs dissolved in dopamine receptors linked to dopamine-sensitive adenylate 0.1% ascorbic acid. Ergot compounds were dissolved in ap- cyclase. The drug also induces turning behavior in rats with proximately 25 ,l of glacial acetic acid and brought up to 1 mM 6-OH-dopamine lesions and relieves tremor in monkeys with with a solution containing 50% (vol/vol) ethanol in 0.01 M HCG ventromedial tegmental lesions for a longer time at a lower dose The in were incubated for 10 min than other tested dopaminergic ergots. Other studies have tubes, triplicate, at 37°C shown that it is effective in the treatment of patients with ad- when [3H]dopamine was used, or 15 min with [3H]Spi or vanced parkinsonism. [3H]NPA, then cooled to 0WC, and filtered. Radioactivity was measured in the filters. Saturable and specific binding of It is now established that the major abnormality in parkinsonism [3H]dopamine, [3H]NPA, and [3H]Spi was measured as the is the degeneration of the nigrostriatal 3,4-dihydroxyphenyl- excess over "blanks" measured in the presence of 1 1uM apo- ethylamine (dopamine) neurons. The effectiveness of 3,4- morphine (for [3H]dopamine or [3H]NPA) or of 0.1 ,uM (+)- dihydroxyphenylalanine (L-dopa) in parklnsonism is dependent butaclamol (for [3H]Spi). on the capacity of the remaining nigrostriatal dopamine neu- Values for the mean inhibitory concentration, ICso, were rons to from It has derived by log probit analysis. Values for the dissociation con- synthesize dopamine administered L-dopa. stant, Kd, for each radioactive ligand were determined from become apparent that therapeutic response diminishes after the corresponding Scatchard plots, and values for the inhibitor prolonged treatment with L-dopa (1, 2). This decrease might constant, Ki, were determined according to the equation Ki = be due to progressive degeneration of the nigrostriatal dopa- IC50/(I + C/Kd), in which C represents the concentration of mine neurons or to a decreased sensitivity of dopamine recep- the radioactive ligand. tors in the striatum. It was therefore of interest to investigate Dopamine-Sensitive Adenylate Cyclase. Male Sprague- the effectiveness of drugs that directly stimulate dopamine Dawley rats were sacrificed by decapitation, and striata were receptors in the brain. Among various dopamine agonists tested, rapidly dissected. The activity of adenylate cyclase was de- certain ergot alkaloids were found to stimulate dopamine re- termined in triplicate for each assay as described (14). The final ceptors (3, 4), and their therapeutic effectiveness in parkin- dilution of tissue was 1:300, 3',5'-cyclic AMP (cAMP) was sonism was investigated (5, 6). measured by a protein-binding assay (15), and protein was We now describe dopamine agonist properties of a semi- measured by the method of Lowry et al. (16). synthetic ergoline derivative, pergolide (8fl-[8-(methylthio)- Surgical Lesions. Unilateral 6-OH-dopamine lesions were methyl]-6-propylergoline), tested both in vitro and in two an- induced in and decortication was performed on male imal models that simulate certain features of parkinsonism. The Sprague-Dawley rats weighing 150-200 g (17, 18). Green potency of pergolide was compared with that of bromocriptine monkeys (Cercopithecus sabeus) weighing 3-4 kg were used (2-bromo-a-ergocriptine), another ergot derivative currently for placing unilateral radiofrequency ventromedial tegmental used in the treatment of parkinsonism (7, 8). The long duration (VMT) lesions in the brain stem (19). The animals developed of action of pergolide as an agonist (9, 10) prompted us to in- hypokinesia and resting tremor (4-6 cycles per sec) 1-2 weeks vestigate its therapeutic effectiveness in parkinsonism patients. after surgery (20). Preliminary reports on this study have been presented (9, 11, Turning Behavior. The turning behavior in rats was mea- 12). sured in a transparent plastic cage and the number of 3600 turns was recorded for 3 min every 15 min (17). The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "ad- Abbreviations: Spi, spiroperidol; NPA, N-n-propylnorapomorphine; vertisement" in accordance with 18 U. S. C. §1734 solely to indicate cAMP, 3',5'-cyclic AMP; AIM, abnormal involuntary movements; this fact. VMT, ventromedial tegmental. 3725 Downloaded by guest on October 1, 2021 3726 Neurobiology: Goldstein et al. Proc. Natl. Acad. Sci. USA 77 (1980) Table 1. Affinities of pergolide and of other drugs at bovine Table 3. Effect of unilateral decortication on binding of [3H]Spi striatal dopamine receptor binding sites to rat striatal membrane sites in the presence and absence of GTP Ki, nM Receptor binding, Drug [3H]dopamine [3H]NPA [3H]Spi pmol/g tissue Conc., Control side Lesion side Pergolide 12.8 I 0.8 41.1 ± 5.5 34.2 ± 2.5 Drug OM -GTP +GTP -GTP +GTP Bromocriptine 49.0 3.5 54.7 I 7.0 1.8 + 0.2 Dopamine 12.5 ± 1.0 50.9 ± 8.0 D-Butaclamol 0.1 19.6 17.4 12.2 10.9 Apomorphine 6.6 ± 0.4 3.5 ± 0.5 42.8 ± 5.5 Bromocriptine 0.05 13.9 12.9 8.5 7.6 Spi 6.5 1.0 0.3 + 0.05 Pergolide 0.05 6.6 4.6 3.6 0.4 Haloperidol 135 ± 18.0 32.8 ± 4.5 5.5 ± 0.9 Binding to receptor was measured 2-3 weeks after decortication Binding was assayed in presence of four to six concentrations of in intact and decorticated striatum. The specific binding (excess over each compound in triplicate. The values are the mean : SEM from blanks in the presence of the drug) was determined in the absence and at least three experiments. The Kd and maximal binding, B,, were presence of 50 ,uM GTP. The results are the mean of two experiments; obtained from Scatchard analysis of the saturation data. Kd (nM): SEM was +3-10%o. [3H]Spi = 0.41 : 0.03, [3H]dopamine =S14.80 + 0.8, [3H]NPA = 0.35 ± 0.05 and 1.30 I 0.20. B... (pmol/g oftissue): [3H]Spi = 27.0 ± 1.2, cyclase with high affinity for agonists are localized on in- [3H]dopamine = 22.3 + 1.1, [3H]NPA = 12.4 I 0.8 and 27.0 1 1.5. The trastriatal neurons (18). To determine whether removal of two values for [3H]NPA indicate high- and low-affinity binding sites, corticostriatal dopamine receptors alters receptor binding af- respectively. finity of pergolide or of bromocriptine we have measured their capacity to displace [3H]Spi in decorticated rat striatum. Tremor and Abnormal Involuntary Movements (AIM). In agreement with previously reported findings (18), Tremor was recorded on an electroencephalograph and AIM decortication results in a decrease of [3H]Spi binding dis- were observed visually (20). placeable by D-butaclamol in striatum (Table 3). Pergolide- and bromocriptine-displaceable [3H]Spi binding is also decreased RESULTS on the decorticated side of the striatum. GTP inhibits more Dopamine receptor binding studies effectively the displacement of [3H]Spi by pergolide in the decorticated striatum than in the intact striatum, indicating that Affinities for Agonist and Antagonist Sites. The capacity GTP-sensitive sites labeled by [3H]Spi are localized on the in- DA and antago- of Pergolide to displace radiolabeled agonists trastriatal neurons and that Pergolide interacts with these do- nists from bovine striatal membrane sites was investigated (Table 1). Pergolide effectively displaces [3H]dopamine, pamine receptors. [3H]NPA, and [3H]Spi from striatal membrane sites and has a Thermal Exposure of Striatal Membranes. Thermal ex- higher affinity for [3H]dopamine binding sites and a lower posure of striatal membranes decreases the number of binding affinity for [3H]Spi binding sites than does bromocriptine.
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