Increases in striatal preproenkephalin gene expression are associated with nigrostriatal damage but not L-DOPA-induced dyskinesias in the squirrel monkey.
Changes in preproenkephalin expression in the caudate and putamen have been linked to the development of L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesias in primate models of Parkinson's disease, although not all investigators have been able to confirm this association. Because nigrostriatal damage per se is associated with increases in striatal preproenkephalin mRNA levels, it is difficult to know if changes in transcript levels are a result of lesioning or concurrent L-DOPA treatment and resulting dyskinesias. To circumvent these difficulties, we measured striatal preproenkephalin mRNA levels in monkeys with L-DOPA-induced dyskinesias both with and without lesions of the nigrostriatal system. The latter model is not confounded by morphological and biochemical changes resulting from nigrostriatal damage. Monkeys were gavaged with L-DOPA (15 mg/kg) twice daily for a 2-week period and killed 3 days after treatment. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment alone resulted in an increase in preproenkephalin mRNA levels as previously shown. However, striatal transcript levels were similarly elevated in dyskinetic MPTP-lesioned animals treated with L-DOPA. In unlesioned animals, preproenkephalin mRNA levels were also similar in control and L-DOPA-treated dyskinetic monkeys. Because drug-induced changes in mRNA may not be sustained for a prolonged period after treatment, a second series of experiments were done in which animals were killed 3-4 h after the last dose of L-DOPA, but the results were similar to those obtained after 3 days. These data show that, while elevations in striatal preproenkephalin mRNA levels are associated with nigrostriatal damage, they are not linked to the development of L-DOPA-induced dyskinesias. These results thus question the importance of preproenkephalin mRNA in the pathogenesis of this disabling complication of L-DOPA therapy in Parkinson's disease.
The Parkinson's Institute, 1170 Morse Avenue, Sunnyvale, CA 94089, USA. mquik@parkinsonsinstitute.org
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Langston
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Di Monte
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D000818:Animals; D001345:Autoradiography; D003342:Corpus Striatum / Q000378:metabolism*; D015259:Dopamine Agents / Q000494:pharmacology*; D050483:Dopamine Plasma Membrane Transport Proteins; D020820:Dyskinesias / Q000209:etiology / Q000378:metabolism; D004745:Enkephalins / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D017403:In Situ Hybridization; D007980:Levodopa / Q000494:pharmacology*; D008297:Male; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins; D011498:Protein Precursors / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D012453:Saimiri; D013378:Substantia Nigra / Q000378:metabolism*; D013997:Time Factors
D015259:Dopamine Agents; D050483:Dopamine Plasma Membrane Transport Proteins; D004745:Enkephalins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D011498:Protein Precursors; D012333:RNA, Messenger; D007980:Levodopa; C033660:preproenkephalin; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine