Molecular basis of levodopa-induced dyskinesias

A series of experiments were performed in the 1-methyl-4-phenyl-1,2,3,6-tet rahydropyridine (MPTP) model of parkinsonism for the purpose of understandi ng the mechanism of dopaminergic dyskinesias. Dyskinesias can be induced in this model by de novo treatment with levodopa, or selective D1 or D2 agoni sts, provided the drugs are short acting and administered in the pulsatile mode. Biochemical analysis of the brains revealed several alterations in do pamine receptor-binding and messenger RNA message following denervation and dopaminergic treatment, but none that clearly correlated with the presence of dyskinesias. On the other hand, gamma-aminobutyric acid (GABA)(A) bindi ng was increased in the internal segment of the globus pallidus of dyskinet ic MPTP monkeys. This was observed consistently and could be associated wit h an exaggerated response to GABAergic inhibitory inputs in this strategic structure. Increased preproenkephalin message was also found to correlate w ith dyskinesias and may be linked co changes in GABA receptors. Treatments chat caused dyskinesias induced, in the striatum, chronic Fos proteins of t he Delta FosB family which, when coupled with Jun-D, form AP-1 complexes th at can affect several genes, including enkephalin and N-methyl-D-aspartate receptor. We suggest that levodopa-induced dyskinesias represent a form of pathological learning, which results from deficient gating of glutamatergic inputs to the striatum by dopamine.