Alterations in striatal neuropeptide mRNA produced by repeated administration of L-DOPA, ropinirole or bromocriptine correlate with dyskinesia induction in MPTP-treated common marmosets.
Chronic administration of L-DOPA to MPTP-treated common marmosets induces marked dyskinesia while repeated administration of equivalent antiparkisonian doses of ropinirole and bromocriptine produces only mild involuntary movements. The occurrence of dyskinesia has been associated with an altered balance between the direct and indirect striatal output pathways. Using in situ hybridisation histochemistry, we now compare the effects of these drug treatments on striatal preproenkephalin-A (PPE-A) and adenosine A(2a) receptor mRNA expression as markers of the indirect pathway and striatal preprotachykinin (PPT) mRNA and preproenkephalin-B (PPE-B, prodynorphin) mRNA expression as markers of the direct pathway.The equivalent marked losses of specific [3H]mazindol binding in the striatum of all drug treatment groups confirmed the identical nature of the nigral cell loss produced by MPTP treatment. MPTP-induced destruction of the nigro-striatal pathway markedly increased the level of PPE-A mRNA in the caudate nucleus and putamen and decreased the levels of PPT and PPE-B mRNA relative to normal animals. Repeated treatment with L-DOPA for 30 days produced marked dyskinesia but had no effect on the MPTP-induced increase in PPE-A mRNA in the caudate nucleus and putamen. In contrast, L-DOPA treatment normalised the MPTP-induced decrease in the level of PPT and PPE-B mRNA. Repeated treatment with ropinirole produced little or no dyskinesia but markedly reversed the MPTP-induced elevation in PPE-A mRNA in the caudate nucleus and putamen. However, it had no effect on the decrease in PPT or PPE-B mRNA. Similarly, bromocriptine treatment which induced only mild dyskinesia attenuated the MPTP-induced elevation in PPE-A mRNA in the caudate nucleus and putamen with no effect on reduced striatal PPT or PPE-B mRNA. Neither MPTP treatment nor treatment with L-DOPA, bromocriptine or ropinirole had any effect on adenosine A(2a) receptor mRNA in the striatum. These patterns of alteration in striatal PPE-A and PPT and PPE-B mRNA produced by L-DOPA, bromocriptine and ropinirole show differential involvement of markers of the direct and indirect striatal output pathways related to improvement of locomotor activity and mirror the relative abilities of the drugs to induce dyskinesia.
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Neurodegenerative Disease Research Centre, Guy's, King's and St. Thomas' School of Biomedical Sciences, King's College, SE1 1UL, London, UK.
Zeng
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Cannizzaro
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Pearce
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RK
Rose
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Jenner
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D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology*; D001971:Bromocriptine / Q000494:pharmacology; D002144:Callithrix; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D004409:Dyskinesia, Drug-Induced / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D004745:Enkephalins / Q000235:genetics; D005260:Female; D007211:Indoles / Q000494:pharmacology; D007980:Levodopa / Q000494:pharmacology; D008297:Male; D008454:Mazindol / Q000494:pharmacology; D017072:Neostriatum / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D009434:Neural Pathways / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D009479:Neuropeptides / Q000235:genetics*; D020734:Parkinsonian Disorders / Q000188:drug therapy*; D011498:Protein Precursors / Q000235:genetics; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D018047:Receptors, Purinergic P1 / Q000235:genetics; D015320:Tachykinins / Q000235:genetics
D000978:Antiparkinson Agents; D018765:Dopamine Uptake Inhibitors; D004745:Enkephalins; D007211:Indoles; D009479:Neuropeptides; D011498:Protein Precursors; D012333:RNA, Messenger; D018047:Receptors, Purinergic P1; D015320:Tachykinins; C044206:preprotachykinin; C046649:ropinirole; D001971:Bromocriptine; D007980:Levodopa; C033660:preproenkephalin; D008454:Mazindol