Factors influencing the onset and persistence of dyskinesia in MPTP-treated primates.
The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treated primate model of Parkinson's disease provides a unique opportunity to study factors influencing the onset and persistence of dyskinesia induced by levodopa or dopamine agonist treatment. Contrary to popular belief, denervation is not essential for the induction of dyskinesia, and both D1 and D2 dopamine agonist drugs are able to initiate dyskinetic movements. However, their ability to do so is currently attributed to their pharmacokinetic and pharmacodynamic properties rather than to their receptor selectivity, although this view is challenged in this article. Short-acting pulsatile dopamine agonists are more likely to induce dyskinesia than drugs that have a long duration of effect and produce continuous receptor stimulation. The induction of dyskinesia does not seem to be associated with any obvious change in the number or sensitivity of post-synaptic dopamine receptors, but rather to downstream events associated with the indirect and direct output pathways. Currently, there is evidence for the involvement of both pathways in the genesis of dyskinesia and so there is no clear explanation for the onset of involuntary movements or for the priming process that initiates dyskinesia. However, a variety of therapeutic strategies primarily related to the use of non-dopaminergic agents may be able to prevent dyskinesia from occurring, and the actions of neurotropic factors, such as glial-derived neurotropic factor, may be effective in reversing established involuntary movements.
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Neurodegenerative Diseases Research Centre, Division of Pharmacology & Therapeutics, Guy's, King's & St Thomas' School of Biomedical Sciences, King's College London, UK.
D000818:Animals; D015259:Dopamine Agents / Q000009:adverse effects*; D004409:Dyskinesia, Drug-Induced / Q000503:physiopathology*; D007980:Levodopa / Q000009:adverse effects*; D020267:MPTP Poisoning / Q000188:drug therapy* / Q000503:physiopathology; D011323:Primates
D015259:Dopamine Agents; D007980:Levodopa