Molecular basis of levodopa-induced dyskinesias.
A series of experiments were performed in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of parkinsonism for the purpose of understanding the mechanism of dopaminergic dyskinesias. Dyskinesias can be induced in this model by de novo treatment with levodopa, or selective D1 or D2 agonists, provided the drugs are short acting and administered in the pulsatile mode. Biochemical analysis of the brains revealed several alterations in dopamine 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 binding was increased in the internal segment of the globus pallidus of dyskinetic MPTP monkeys. This was observed consistently and could be associated with an exaggerated response to GABAergic inhibitory inputs in this strategic structure. Increased preproenkephalin message was also found to correlate with dyskinesias and may be linked to changes in GABA receptors. Treatments that caused dyskinesias induced, in the striatum, chronic Fos proteins of the deltaFosB family which, when coupled with Jun-D, form AP-1 complexes that 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.
Calon
F
F
Centre de Recherches en Endocrinologie Moléculaire, Le Centre Hospitalier Universitaire de Québec, and Faculty of Pharmacy, Laval University, Québec, Canada.
Grondin
R
R
Morissette
M
M
Goulet
M
M
Blanchet
P J
PJ
Di Paolo
T
T
Bédard
P J
PJ
D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects / Q000235:genetics*; D015259:Dopamine Agents / Q000009:adverse effects*; D004409:Dyskinesia, Drug-Induced / Q000235:genetics*; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007980:Levodopa / Q000009:adverse effects*; D010300:Parkinson Disease / Q000188:drug therapy*
D015259:Dopamine Agents; D007980:Levodopa