L-DOPA-induced dyskinesia in the rat is associated with striatal overexpression of prodynorphin- and glutamic acid decarboxylase mRNA.
Rats sustaining unilateral near-complete 6-hydroxydopamine lesions of the mesostriatal dopamine pathway received daily injections of 3, 4 dihydroxyphenyl-l-alanine (L-DOPA, 8 mg/kg plus 15 mg/kg benserazide) for 3 weeks. During this period, about 50% of the rats gradually developed abnormal involuntary movements, lasting for 2-3 h following each L-DOPA dose. Rats were killed 3 days after the last L-DOPA injection, and sections through the striatum were processed for in situ hybridization histochemistry. Within the L-DOPA-treated group, levels of preproenkephalin (PPE) mRNA, glutamic acid decarboxylase (GAD67) mRNA, and prodynorphin (PDyn) mRNA in the dopamine-denervated caudate-putamen, as well as GAD67 mRNA expression in the globus pallidus ipsilateral to the 6-hydroxydopamine (6-OHDA) lesion, were higher in dyskinetic than non-dyskinetic animals, and positively correlated with the rats' dyskinesia scores. By contrast, striatal preprotachykinin mRNA expression and D2 receptor-radioligand binding were not significantly associated with dyskinesia. Among all these markers, PDyn mRNA levels showed the most pronounced treatment-dependence (three times higher in the L-DOPA-treated group than in saline-injected lesion-only controls), and the strongest correlation with the rats' dyskinesia scores (r2 = 0.82). However, a multiple regression equation including the three factors, GAD67 mRNA levels in the GP, GAD67 mRNA in the lateral CPu, and striatal PDyn mRNA, gave a better fit for dyskinesia scores than PDyn mRNA alone (r2 = 0.92). The results show that L-DOPA-induced dyskinesia is associated with overexpression of PDyn and GAD67 mRNA in the striatal projection neurons, and GAD67 mRNA levels in the globus pallidus. Due to its treatment-dependent expression, and strong correlation with the associated dyskinetic symptoms, striatal PDyn mRNA, in particular, may play a role in the mechanisms of behavioural sensitization brought about by the drug.
Wallenberg Neuroscience Center, Institute of Physiology and Neuroscience, University of Lund, 223 62 Lund, Sweden. Angela.Cenci_Nilsson@mphy.lu.se
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Lee
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Björklund
D000818:Animals; D001345:Autoradiography; D001522:Behavior, Animal / Q000187:drug effects; D003342:Corpus Striatum / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D004409:Dyskinesia, Drug-Induced / Q000378:metabolism*; D004745:Enkephalins / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D005968:Glutamate Decarboxylase / Q000235:genetics*; D017403:In Situ Hybridization; D007980:Levodopa / Q000494:pharmacology*; D016627:Oxidopamine / Q000494:pharmacology; D011498:Protein Precursors / Q000235:genetics*; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D015320:Tachykinins / Q000235:genetics
D004745:Enkephalins; D011498:Protein Precursors; D012333:RNA, Messenger; D017448:Receptors, Dopamine D2; D015320:Tachykinins; C044206:preprotachykinin; D007980:Levodopa; D016627:Oxidopamine; C033660:preproenkephalin; D005968:Glutamate Decarboxylase