VMAT2 binding is elevated in dopa-responsive dystonia: visualizing empty vesicles by PET.
Dopa-responsive dystonia (DRD) is a lifelong disorder in which dopamine deficiency is not associated with neuronal loss and therefore it is an ideal human model for investigating the compensatory changes that occur in response to this biochemical abnormality. Using positron emission tomography (PET), we examined the (+/-)-alpha-[(11)C]dihydrotetrabenazine ([(11)C]DTBZ) binding potential of untreated DRD patients and normal controls. Two other PET markers of presynaptic nigrostriatal function, d-threo-[(11)C]methylphenidate ([(11)C]MP) and 6-[(18)F]fluoro-L-dopa ([(18)F]-dopa), and [(11)C]raclopride were also used in the study. We found increased [(11)C]DTBZ binding potential in the striatum of DRD patients. By contrast, no significant changes were detected in either [(11)C]MP binding potential or [(18)F]-dopa uptake rate constant. In addition, we found evidence for increased dopamine turnover in one DRD patient by examining changes in [(11)C]raclopride binding potential in relation to levodopa treatment. We propose that the increase in [(11)C]DTBZ binding likely reflects the dramatic decrease in the intravesicular concentration of dopamine that occurs in DRD; upregulation of vesicular monoamine transporter type 2 (VMAT2) expression may also contribute. Our findings suggest that the striatal expression of VMAT2 (as estimated by [(11)C]DTBZ binding) is not coregulated with dopamine synthesis. This is in keeping with a role for VMAT2 in other cellular processes (i.e., sequestration and release from the cell of potential toxic products), in addition to its importance for the quantal release of monoamines.
De La Fuente-Fernández
Raúl
R
Pacific Parkinson's Research Centre, University of British Columbia, Vancouver, B.C., Canada.
Furtado
Sarah
S
Guttman
Mark
M
Furukawa
Yoshiaki
Y
Lee
Chong S
CS
Calne
Donald B
DB
Ruth
Thomas J
TJ
Stoessl
A Jon
AJ
D000293:Adolescent; D000328:Adult; D002250:Carbon Radioisotopes; D003342:Corpus Striatum / Q000000981:diagnostic imaging / Q000378:metabolism*; D022162:Cytoplasmic Vesicles / Q000378:metabolism / Q000648:ultrastructure; D004298:Dopamine / Q000172:deficiency* / Q000378:metabolism*; D015259:Dopamine Agents; D020821:Dystonic Disorders / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005462:Fluorine Radioisotopes; D006801:Humans; D007980:Levodopa / Q000627:therapeutic use; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D026901:Membrane Transport Proteins; D008774:Methylphenidate; D008875:Middle Aged; D009479:Neuropeptides; D010300:Parkinson Disease / Q000378:metabolism; D020891:Raclopride; D013747:Tetrabenazine / Q000031:analogs & derivatives*; D014055:Tomography, Emission-Computed; D050492:Vesicular Biogenic Amine Transport Proteins; D050493:Vesicular Monoamine Transport Proteins
D002250:Carbon Radioisotopes; D015259:Dopamine Agents; D005462:Fluorine Radioisotopes; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009479:Neuropeptides; C493452:SLC18A2 protein, human; D050492:Vesicular Biogenic Amine Transport Proteins; D050493:Vesicular Monoamine Transport Proteins; D008774:Methylphenidate; C032811:dihydrotetrabenazine; D020891:Raclopride; D007980:Levodopa; D004298:Dopamine; D013747:Tetrabenazine