期刊
JOURNAL OF NEUROCHEMISTRY
卷 109, 期 1, 页码 85-92出版社
WILEY
DOI: 10.1111/j.1471-4159.2009.05904.x
关键词
dopamine kinetics; dopamine transporter; Parkinson's disease; positron emission tomography; rat model; regulatory changes
资金
- CIHR
- NSERC
- MSFHR
- CRC
- James A. Moore Chair
- TRIUMF Life Science
Studies showed that the dopamine (DA) transporter (DAT) modulates changes in levodopa-derived synaptic dopamine levels (Delta(DA)) in Parkinson's disease (PD). Here we evaluate the relationship between DAT and Delta(DA) in the 6-hydroxydopamine model of Parkinson's disease to investigate these mechanisms as a function of dopaminergic denervation and in relation to other denervation-induced regulatory changes. 27 rats with a unilateral 6-hydroxydopamine lesion (denervation similar to 20-97%) were imaged with C-11-dihydrotetrabenazine (VMAT2 marker), C-11-methylphenidate (DAT marker) and C-11-raclopride (D2-type receptor marker). For denervation < 75%Delta(DA) was significantly correlated with a combination of relatively preserved terminal density and lower DAT. For denervation < 90%, Delta(DA) was significantly negatively correlated with DAT with a weaker dependence on VMAT2. For the entire data set, no dependence on pre-synaptic markers was observed; Delta(DA) was significantly positively correlated with C-11-raclopride binding-derived estimates of DA loss. These findings parallel observations in humans, and show that (i) regulatory changes attempt to normalize synaptic DA levels (ii) a lesion-induced functional dependence of Delta(DA) on DAT occurs up to similar to 90% denervation (iii) for denervation < 75% relative lower DAT levels may relate to effective compensation; for higher denervation, lower DAT levels likely contribute to oscillations in synaptic DA associated with dyskinesias.
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