Metabolic-dopaminergic mapping of the 6-hydroxydopamine rat model for Parkinson's disease.
OBJECTIVE
The unilateral 6-hydroxydopamine (6-OHDA) lesion rat model is a well-known acute model for Parkinson's disease (PD). Its validity has been supported by invasive histology, behavioral studies and electrophysiology. Here, we have characterized this model in vivo by multitracer imaging [glucose metabolism and dopamine transporter (DAT)] in relation to behavioral and histological parameters.


METHODS
Eighteen female adult Wistar rats (eight 6-OHDA-lesioned, ten controls) were investigated using multitracer [(18)F]-fluoro-2-deoxy-D: -glucose (FDG) and [(18)F]-FECT {2'-[(18)F]-fluoroethyl-(1R-2-exo-3-exe)-8-methyl-3-(4-chlorophenyl)-8-azabicyclo(3.2.1)-octane-2-carboxylate} small animal positron emission tomography (PET). Relative glucose metabolism and parametric DAT binding images were anatomically standardized to Paxinos space and analyzed on a voxel-basis using SPM2: , supplemented by a template-based predefined volumes-of-interest approach. Behavior was characterized by the limb-use asymmetry test; dopaminergic innervation was validated by in vitro tyrosine hydroxylase staining.


RESULTS
In the 6-OHDA model, significant glucose hypometabolism is present in the ipsilateral sensory-motor cortex (-6.3%; p = 4 x 10(-6)). DAT binding was severely decreased in the ipsilateral caudate-putamen, nucleus accumbens and substantia nigra (all p < 5 x 10(-9)), as confirmed by the behavioral and histological outcomes. Correlation analysis revealed a positive relationship between the degree of DAT impairment and the change in glucose metabolism in the ipsilateral hippocampus (p = 3 x 10(-5)), while cerebellar glucose metabolism was inversely correlated to the level of DAT impairment (p < 3 x 10(-4)).


CONCLUSIONS
In vivo cerebral mapping of 6-OHDA-lesioned rats using [(18)F]-FDG and [(18)F]-FECT small animal PET shows molecular-functional correspondence to the cortico-subcortical network impairments observed in PD patients. This provides a further molecular validation supporting the validity of the 6-OHDA lesion model to mimic multiple aspects of human PD.
Casteels
Cindy
C
Division of Nuclear Medicine, KU Leuven and University Hospital Leuven, Leuven, Belgium. cindy.casteels@uz.kuleuven.be
Lauwers
Erwin
E
Bormans
Guy
G
Baekelandt
Veerle
V
Van Laere
Koen
K
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003042:Cocaine / Q000031:analogs & derivatives / Q000378:metabolism; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000032:analysis / Q000378:metabolism; D005260:Female; D019788:Fluorodeoxyglucose F18 / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006801:Humans; D016627:Oxidopamine / Q000633:toxicity*; D010300:Parkinson Disease / Q000000981:diagnostic imaging / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D049268:Positron-Emission Tomography; D051381:Rats; D017208:Rats, Wistar; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
C095071:2'-fluoroethyl 8-methyl-3-(4-chlorophenyl)-8-azabicyclo(3.2.1)octane-2-carboxylate; D050483:Dopamine Plasma Membrane Transport Proteins; D019788:Fluorodeoxyglucose F18; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase; D003042:Cocaine; D005947:Glucose; D004298:Dopamine