Continuous Dopaminergic Stimulation by Pramipexole Is Effective to Treat EarlyMorning Akinesia in Animal Models ofParkinson’s Disease: A Pharmacokinetic-Pharmacodynamic Study Using in VivoMicrodialysis in Rats

摘要

Short-acting dopamine (DA) agonists are usually administered several times a day resulting in fluctuating plasma and brain levels. DA agonists providingcontinuous dopaminergic stimulation may achieve higher therapeutic benefit forexample by alleviating nocturnal disturbances as well as early morning akinesia. Inthe present study continuous release (CR) of pramipexole (PPX) was maintained by subcutaneous implantation of Alzet1 minipumps, whereas subcutaneous PPX injectionswere used to mimic PPX immediate release (IR) in male Wistar rats. In the catalepsybar test, PPX-CR (1 mg/kg/day) reversed the haloperidol-induced motor impairmentin the morning and over the whole observation period of 12h. In contrast, PPXIR(tid 1 mg/kg, pre-treatment the day before) was not effective in the morning but catalepsy was reduced for 6 h after PPX-IR (1 mg/kg) injection. In the reserpinemodel, early morning akinesia indicated by the first motor activity measurement in the morning was significantly reversed by PPX-R (2 mg/kg/day). Again, PPX-IR (tid0.3 mg/kg, pre-treatment the day before) was not able to antagonise early morningakinesia. These results are in agreement with in vivo microdialysis measurementsshowing a continuous decrease of extracellular DA levels and a continuous PPX exposurein the PPX-CR (1 mg/kg/day) group. In contrast, PPX-IR (0.3 mg/kg) produced atransient decrease of extracellular DA levels over 6 h and showed maximum PPX levels2 h after dosing which decreased over the following 6–8 h. The present study demonstratesthat PPX-CR may offer a higher therapeutic benefit than PPX-IR on earlymorning akinesia and confirms earlier reports that PPX-IR reverses motor impairment for several hours.