Brain Advance Access originally published online on May 16, 2008
Brain 2008 131(6):1574-1587; doi:10.1093/brain/awn085
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Sprouting of dopamine terminals and altered dopamine release and uptake in Parkinsonian dyskinaesia
1Brain Injury and Repair, Howard Florey Institute, University of Melbourne, Parkville, VIC, 3010, 2The Mental Health Research Institute of Victoria, 155 Oak Street, Locked Bag 11, Parkville, VIC, 3052, 3Faculty of Education, Australian Catholic University, 115 Victoria Pde, Fitzroy, VIC and 4Department of Pharmacology, Bosch Institute and School of Medical Sciences, Bosch Building, University of Sydney, NSW, 2006, Australia and 5Centre for Neuroscience, University of Melbourne, Parkville, VIC, 3010, Australia
Correspondence to: Malcolm K. Horne, Howard Florey Institute, Level 2 Alan Gilbert Building, 161 Barry St, Carlton Sth, 3053, Australia E-mail: malcolm.horne{at}florey.edu.au
Failed storage capacity, leading to pulsatile delivery of dopamine (DA) in the striatum, is used to explain the emergence of ‘wearing off’ and dyskinaesia in Parkinson's disease. In this study, we show that surviving DA neurons in 6-OHDA lesioned rats sprout to re-innervate the striatum, and maintain terminal density until 
60% of neurons are lost. We demonstrate that DA terminal density correlates with baseline striatal DA concentration ([DA]). Electrochemical and synaptosome studies in 6-OHDA lesioned rats and primates suggest that impaired striatal DA re-uptake and increased DA release from medial forebrain bundle fibres contribute to maintaining striatal DA levels. In lesioned rats where terminal density fell by 60% or more, L-DOPA administration increased striatal DA levels markedly. The striatal [DA] produced by L-DOPA directly correlated with the extent of dyskinaesia, suggesting that dyskinaesia was related to high striatal [DA]. While sprouting and decreased dopamine uptake transporter function would be expected to contribute to the marked increase in L-DOPA induced [DA], the increased [DA] was most marked when DAergic fibres were >60% denervated, suggesting that other release sites, such as serotonergic fibres might be contributing. In conclusion, the extent of dyskinaesia was directly proportional to the extent of DA terminal denervation and levels of extra-synaptic striatal DA. We propose that sprouting of DA terminals and decreased dopamine uptake transporter function prevent the appearance of Parkinsonian symptoms until about 60% loss of nigral neurons, but also contribute to dysregulated striatal DA release that is responsible for the emergence of dyskinaesia and ‘wearing off’.
Key Words: dopamine uptake transporter; levodopa; Parkinson's disease; striatum; voltammetry
Abbreviations: AIM, abnormal involuntary movement; AUC, area under curve; DA, dopamine; DAT, dopamine reuptake transporter; HPLC, high-performance liquid chromatography; IAS, index of arbour size; MFB, medial forebrain bundle; SERT, serotonin re-uptake transporter; TH, tyrosine hydroxylase
Received January 8, 2008. Revised March 5, 2008. Accepted April 14, 2008.
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