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Dopamine receptor changes in untreated and (+)-PHNO-treated MPTP parkinsonian primates
G M Alexander1, D L Brainard, S W Gordon
1Department of Neurology, Jefferson Medical College, Philadelphia, PA 19107.
Abstract:
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.
Insights
MPTP-induced parkinsonian monkeys treated with a dopamine D2 agonist showed improved movement and reduced D2 receptor density. This suggests D2 receptor modulation may be a therapeutic strategy for Parkinson's disease.
Area of Science:
- Neuroscience
- Pharmacology
- Primate Models
Background:
- Parkinson's disease is characterized by dopamine depletion and motor deficits.
- Dopamine receptor alterations, particularly D2 receptors, are implicated in Parkinson's pathophysiology.
- MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) is a neurotoxin used to create parkinsonian models in non-human primates.
Purpose of the Study:
- To investigate the effects of a selective dopamine D2 receptor agonist, (+)-PHNO, on motor function and D2 receptor density in MPTP-induced parkinsonian monkeys.
- To examine changes in D1 and D2 receptor binding in the basal ganglia of parkinsonian monkeys with and without (+)-PHNO treatment.
Main Methods:
- MPTP was administered to induce parkinsonism in eight cynomolgus monkeys (Macaca fascicularis).
- Three parkinsonian monkeys received continuous subcutaneous infusion of (+)-PHNO (2-5 µg/kg/h) via osmotic pumps.
- Neurologic examinations and movement quantification in an activity box were performed weekly.
- Post-mortem analysis of brain tissue assessed D1 and D2 receptor densities in the basal ganglia using radioligand binding assays ([3H]spiperone for D2, [3H]SCH-23390 for D1).
Main Results:
- MPTP-induced parkinsonian monkeys exhibited significant dopamine depletion (90-97%) and motor deficits (75-90% decrease in movement, clinical score 8.9).
- Untreated parkinsonian monkeys showed an upregulation of D2 receptors in the striatum, particularly the lateral putamen.
- (+)-PHNO treatment improved motor activity (neurologic score 3.4) and decreased D2 receptor density by 40-70% in the caudate and putamen.
- No significant changes in D1 receptor density were observed in either untreated or treated parkinsonian monkeys compared to controls.
Conclusions:
- Selective dopamine D2 receptor agonism with (+)-PHNO can ameliorate motor deficits in an MPTP-induced parkinsonian model.
- The therapeutic effect of (+)-PHNO is associated with a normalization of D2 receptor density in the basal ganglia.
- Dopamine D2 receptor modulation represents a potential therapeutic avenue for Parkinson's disease, while D1 receptors appear unaffected in this model.