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Effects of chronic treatment of MPTP monkeys with bromocriptine alone or in combination with SKF 38393
C Rouillard1, P J Bédard, T Di Paolo
1School of Pharmacy, Laval University, Québec, Canada.
Abstract:
Eight monkeys developed a severe parkinsonian syndrome after i.v. administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Treatment with bromocriptine (5 mg/kg) relieved the parkinsonian symptoms, but the efficacy of this treatment appeared to decrease slightly with time. The addition of SKF38393 (5 mg/kg) to the bromocriptine treatment in four monkeys prevented and even reversed the tendency to decreased efficacy with an increased response in three out of four animals. Neither of these two treatments induced dyskinesia in these monkeys. Dopamine D1 and D2 receptors, assayed in the caudate nucleus, the putamen and nucleus accumbens with [3H]SCH 23390 and [3H]spiperone binding respectively, were not significantly different in MPTP monkeys treated with bromocriptine or with bromocriptine plus SKF38393. Monkeys in the two treatment groups had a similar extent of denervation of the striatum and accumbens as assessed by the content of dopamine and its metabolites. These results suggest that in MPTP monkeys, the behavioral response to the D2 agonist bromocriptine can be enhanced by concomitant activation of the D1 receptors while this combination of agonists does not induce dyskinesia. The addition of the D1 agonist does not appear to cause further alteration of the D1 or D2 receptors.
Insights
MPTP-induced parkinsonism in monkeys improved with bromocriptine, a dopamine D2 agonist. Adding SKF38393, a D1 agonist, enhanced bromocriptine
Area of Science:
- Neuroscience
- Pharmacology
- Primate Models
Background:
- 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes severe parkinsonian syndrome in monkeys.
- Bromocriptine, a dopamine D2 receptor agonist, provides symptomatic relief but efficacy can wane over time.
Purpose of the Study:
- To investigate the efficacy of combining a D1 receptor agonist (SKF38393) with a D2 receptor agonist (bromocriptine) for treating MPTP-induced parkinsonism.
- To assess whether this combination therapy prevents or reverses the decrease in treatment efficacy and if it induces dyskinesia.
Main Methods:
- MPTP was administered to eight monkeys to induce parkinsonism.
- Monkeys were treated with bromocriptine alone or in combination with SKF38393.
- Dopamine D1 and D2 receptor binding assays were performed on brain tissue.
- Dopamine and metabolite levels were measured to assess denervation.
Main Results:
- Bromocriptine treatment improved parkinsonian symptoms, but efficacy decreased over time.
- The addition of SKF38393 prevented the decrease in efficacy and improved response in most animals.
- Neither treatment induced dyskinesia, and receptor binding and dopamine levels remained similar between groups.
Conclusions:
- Concomitant activation of dopamine D1 and D2 receptors enhances behavioral response to D2 agonists in MPTP-treated monkeys.
- This combination therapy is effective in improving parkinsonian symptoms without inducing dyskinesia.
- D1 receptor activation does not appear to further alter D1 or D2 receptor levels in this model.
