Pathophysiology and biochemistry of dyskinesia: clues for the development of non-dopaminergic treatments.

Abstract

Levodopa-induced dyskinesia is a major therapeutic problem in the long-term treatment of Parkinson's disease. The development of dyskinesia is dependent on the extent of nigral denervation but can be induced through both D-1 and D-2 dopamine receptors. Short-acting dopamine agonists producing pulsatile receptor stimulation are more likely to induce dyskinesia than long-acting drugs that produce continuous receptor stimulation. However, there are no consistent changes in dopamine receptors which explain the occurrence of dyskinesia. Rather, dyskinesia may originate from an imbalance between the major striatal output pathways. Indeed, levodopa and dopamine agonist drugs show a differential ability to alter striatal output as judged by mRNA for colocalised neuropeptides. The involvement of striatal output pathways raises the possibility of utilising a range of non-dopaminergic receptors within the striatum and in output nuclei as targets for novel drug therapies which may be antiparkinsonian without eliciting dyskinesia. For example, the A2a adenosine antagonist KW6002 reverses motor deficits in primates treated with MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) without provoking an established dyskinesia. Similarly, manipulation of muscarinic cholinergic receptors in the striatum can alter the intensity and components of dyskinesia. Neurotrophic therapies diminish dyskinesia since glial cell line-derived neurotrophic factor (GDNF) produces a decrease in motor disability in MPTP-treated primates associated with a reduced intensity of levodopa-induced dyskinesia. The mechanisms underlying the manifestations and the priming process for dyskinesia remain unknown, but non-dopaminergic approaches to therapy may provide an effective way of preventing, or limiting, the expression of involuntary movements in Parkinson's disease.