Dopamine receptor changes in untreated and (+)-PHNO-treated MPTP parkinsonian primates.
Fifteen monkeys (Macaca fascicularis) were utilized in this study. Seven naive animals received no treatment and served as controls. Eight animals were rendered parkinsonian with serial injections of MPTP. Three of the parkinsonian monkeys were treated with (+)-4-propyl-9-hydroxynaphthoxasine [(+)-PHNO], a selective dopamine D2 agonist. (+)-PHNO (2-5 micrograms/kg/h) was administered continuously using subcutaneous osmotic pumps. All animals were given weekly scored neurologic examinations throughout the study. Their movement was quantitated in an activity box. The animals were sacrificed 30-120 days after their last MPTP injection by an overdose of sodium pentobarbital. The brains were removed, frozen and cut into 20-microns sections. The density of D1 and D2 receptors was studied in the basal ganglia of these animals at the level of the anterior commissure. For the D2 assay, total binding was determined using various concentrations of [3H]spiperone in buffer containing 300 nm mianserine. For the D1 assay, total binding was determined using various concentrations of [3H]SCH-23390. Tissue isotope concentration was determined from the autoradiographs. The parkinsonian animals demonstrated 90-97% dopamine depletion in the striatum. There was a 75-90% decrease in free movement in the untreated parkinsonian monkeys and their composite clinical score was 8.9 on a scale of 0-16 (zero being normal). Control monkey scores averaged 0.6. The untreated parkinsonian monkeys demonstrated an increase in the number of D2 sites as compared to controls. This increase was greatest at the lateral putamen. The (+)-PHNO-treated monkeys demonstrated increased activity, a neurologic score of 3.4, and a 40-70% decreased in D2 sites in both caudate and putamen. There was no change in the number of D1 binding sites in both the untreated and the (+)-PHNO-treated parkinsonian monkeys as compared to controls.
Department of Neurology, Jefferson Medical College, Philadelphia, PA 19107.
G M
GM
Alexander
D L
DL
Brainard
S W
SW
Gordon
M
M
Hichens
J R
JR
Grothusen
R J
RJ
Schwartzman
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000818:Animals; D015259:Dopamine Agents / Q000627:therapeutic use*; D008252:Macaca fascicularis; D008297:Male; D010078:Oxazines / Q000627:therapeutic use*; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000188:drug therapy*; D011954:Receptors, Dopamine / Q000187:drug effects*
D015259:Dopamine Agents; D010078:Oxazines; D011954:Receptors, Dopamine; C042631:naxagolide; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine