Sensitization of dopamine-stimulated adenylyl cyclase in the striatum of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated rhesus monkeys and patients with idiopathic Parkinson's disease.
Dopamine-stimulated adenylyl cyclase activity was measured in striatal homogenates of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated rhesus monkeys and humans with idiopathic Parkinson's disease and compared with the activity in control tissue. No differences between parkinsonian and control tissue were found in the presence of 20 mM NaCl. However, when 120 mM NaCl was included in the assay medium, a significantly higher increase in the Vmax of dopamine-stimulated adenylyl cyclase activity was observed in the caudate of MPTP-parkinsonian rhesus monkeys and the putamen of patients with idiopathic Parkinson's disease. No such sensitization was seen in the MPTP-treated rhesus putamen or human Parkinson's disease caudate tissue. A role of D2 receptors in this sensitization could be ruled out by the concomitant use of the D2 antagonist l-sulpiride and by [3H]spiperone saturation analysis of the D2 receptor density, which was found at control level in the caudate tissue of MPTP-treated rhesus monkeys. Similarly, on the basis of saturation binding with the D1 selective ligand 125I-SCH 23982, there was no difference in caudate nucleus D1 receptor densities between control and MPTP-treated monkeys. Our results point to a region-specific functional sensitization of D1 receptors as a consequence of severe dopaminergic denervation of the striatum and suggest the possibility of a therapeutic potential of a D1 agonist with full intrinsic activity in Parkinson's disease.
Pifl
C
C
Institute of Biochemical Pharmacology, University of Vienna, Austria.
Nanoff
C
C
Schingnitz
G
G
Schütz
W
W
Hornykiewicz
O
O
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology*; D000262:Adenylyl Cyclases / Q000378:metabolism*; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001552:Benzazepines / Q000031:analogs & derivatives / Q000494:pharmacology; D003342:Corpus Striatum / Q000737:chemistry / Q000201:enzymology* / Q000648:ultrastructure; D004298:Dopamine / Q000032:analysis / Q000494:pharmacology*; D018492:Dopamine Antagonists; D005260:Female; D006801:Humans; D007457:Iodine Radioisotopes; D008253:Macaca mulatta; D008297:Male; D010300:Parkinson Disease / Q000201:enzymology* / Q000209:etiology / Q000503:physiopathology; D011699:Putamen / Q000737:chemistry / Q000201:enzymology / Q000648:ultrastructure; D011954:Receptors, Dopamine / Q000032:analysis / Q000187:drug effects / Q000502:physiology; D013004:Somatostatin / Q000494:pharmacology
C049558:8-iodo-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepine-7-ol; D001552:Benzazepines; D018492:Dopamine Antagonists; D007457:Iodine Radioisotopes; D011954:Receptors, Dopamine; D013004:Somatostatin; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000262:Adenylyl Cyclases; D004298:Dopamine