Continuous intracerebroventricular infusion of dopamine and dopamine agonists through a totally implanted drug delivery system in animal models of Parkinson's disease.
We studied the effect of intracerebroventricular infusion of dopamine and dopamine agonists in animal models of dopamine deficiency as an experimental approach to the treatment of levodopa induced fluctuations in Parkinson's disease. Dopamine deficiency was produced in rats by unilateral lesion of the nigrostriatal pathway or by chronic treatment with reserpine. Monkeys were lesioned by intravenous injection of MPTP. The animals were treated with intracerebral infusions of dopamine (with or without associated intraperitoneal administration or intracerebroventricular infusion of pargyline), lisuride and pergolide. The intracerebroventricular infusion of these drugs was performed with osmotic minipumps in rats and with infusaid pumps in the monkeys. The infusion of dopamine or dopamine agonists in rats with unilateral lesions by 6-OH-dopamine produced a persistent rotation contralateral to the lesioned and implanted side. The infusion of dopamine reversed reserpine-induced akinesia only when pargyline was associated. In the range of concentration used, maximum allowed by solubility of compounds, the effects of dopamine were more potent than those of the agonists. In spite of the stability of dopamine "in vitro" when dissolved in antioxidants and at low pH, a pigment, product of autooxidation, was found in the brains of the animals infused with dopamine. The monkeys were implanted with infusaid pumps and infused for up to 3 weeks. The pump was not well tolerated due to its huge size for the animals. One monkey showed reversal of the MPTP-induced akinesia while the other, whose catheter had moved from the correct implantation site, remained unchanged. In both monkeys there was evidence of autooxidation of dopamine. Intracerebral infusion of dopamine agonists may be a possible experimental alternative to the treatment of levodopa induced fluctuations in Parkinson's disease but stable and soluble dopamine agonists and suitable delivery systems are needed.
de Yebenes
J G
JG
Centro Ramon y Cajal, Madrid, Spain.
Fahn
S
S
Jackson-Lewis
V
V
Jorge
P
P
Mena
M A
MA
Reiriz
J
J
D000818:Animals; D001927:Brain Diseases / Q000139:chemically induced / Q000188:drug therapy; D002404:Catheterization; D002552:Cerebral Ventricles; D004195:Disease Models, Animal; D004298:Dopamine / Q000008:administration & dosage* / Q000502:physiology / Q000627:therapeutic use; D004355:Drug Stability; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy; D007260:Infusion Pumps; D008781:Methyltyrosines / Q000008:administration & dosage / Q000627:therapeutic use; D010300:Parkinson Disease / Q000188:drug therapy*; D014677:Pharmaceutical Vehicles; D012110:Reserpine; D012995:Solubility; D019805:alpha-Methyltyrosine
D008781:Methyltyrosines; D014677:Pharmaceutical Vehicles; D019805:alpha-Methyltyrosine; D012110:Reserpine; D004298:Dopamine