Dopamine transporter relation to levodopa-derived synaptic dopamine in a rat model of Parkinson's: an in vivo imaging study.
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 approximately 20-97%) were imaged with (11)C-dihydrotetrabenazine (VMAT2 marker), (11)C-methylphenidate (DAT marker) and (11)C-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 (11)C-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 approximately 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.
Sossi
Vesna
V
Pacific Parkinson's Research Centre, Wesbrook Mall, Vancouver, British Columbia, Canada.
Dinelle
Katherine
K
Topping
Geoffrey J
GJ
Holden
James E
JE
Doudet
Doris
D
Schulzer
Michael
M
Ruth
Thomas J
TJ
Stoessl
A Jon
AJ
de la Fuente-Fernandez
Raul
R
D000818:Animals; D004195:Disease Models, Animal; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism*; D007980:Levodopa / Q000378:metabolism*; D008297:Male; D010300:Parkinson Disease / Q000000981:diagnostic imaging / Q000378:metabolism*; D049268:Positron-Emission Tomography / Q000379:methods; D011485:Protein Binding / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013569:Synapses / Q000000981:diagnostic imaging / Q000378:metabolism*
D050483:Dopamine Plasma Membrane Transport Proteins; D007980:Levodopa