Presynaptic dopaminergic compartment determines the susceptibility to L-DOPA-induced dyskinesia in rats.
Drug-induced dyskinesias in dopamine-denervated animals are known to depend on both pre- and postsynaptic changes of the nigrostriatal circuitry. In lesion models used thus far, changes occur in both of these compartments and, therefore, it has not been possible to dissect the individual contribution of each compartment in the pathophysiology of dyskinesias. Here we silenced the nigrostriatal dopamine neurotransmission without affecting the anatomical integrity of the presynaptic terminals using a short-hairpin RNA-mediated knockdown of tyrosine hydroxylase enzyme (shTH). This treatment resulted in significant reduction (by about 70%) in extracellular dopamine concentration in the striatum as measured by on-line microdialysis. Under these conditions, the animals remained nondyskinetic after chronic L-DOPA treatment, whereas partial intrastriatal 6-hydoxydopamine lesioned rats with comparable reduction in extracellular dopamine levels developed dyskinesias. On the other hand, apomorphine caused moderate to severe dyskinesias in both groups. Importantly, single-dose L-DOPA challenge in apomorphine-primed shTH animals failed to activate the already established abnormal postsynaptic responses. Taken together, these data provide direct evidence that the status of the presynaptic, DA releasing compartment is a critical determinant of both the induction and maintenance of L-DOPA-induced dyskinesias.
Ulusoy
Ayse
A
Brain Repair and Imaging in Neural Systems, Department of Experimental Medical Science, Lund University, BMC D11, 22184 Lund, Sweden.
Sahin
Gurdal
G
Kirik
Deniz
D
D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D000229:Dependovirus / Q000235:genetics; D004198:Disease Susceptibility; D004298:Dopamine / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects; D004409:Dyskinesia, Drug-Induced / Q000378:metabolism* / Q000473:pathology; D005260:Female; D055785:Gene Knockdown Techniques; D007980:Levodopa; D017551:Microdialysis; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000201:enzymology; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011995:Recombination, Genetic / Q000235:genetics; D013378:Substantia Nigra / Q000187:drug effects / Q000201:enzymology; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
C483820:Fosb protein, rat; D016760:Proto-Oncogene Proteins c-fos; D034741:RNA, Small Interfering; D007980:Levodopa; D014446:Tyrosine 3-Monooxygenase; D001058:Apomorphine; D004298:Dopamine