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Metabolic–dopaminergic mapping of the 6-hydroxydopamine rat model for Parkinson’s disease

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European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Purpose

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 [18F]-fluoro-2-deoxy-D-glucose (FDG) and [18F]-FECT {2′-[18F]-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 × 10−6). DAT binding was severely decreased in the ipsilateral caudate-putamen, nucleus accumbens and substantia nigra (all p < 5 × 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 × 10−5), while cerebellar glucose metabolism was inversely correlated to the level of DAT impairment (p < 3 × 10−4).

Conclusions

In vivo cerebral mapping of 6-OHDA-lesioned rats using [18F]-FDG and [18F]-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.

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Acknowledgements

The authors acknowledge Peter Vermaelen and Frea Coun for their invaluable assistance in animal preparation and data acquisition. We also thank the PET radiopharmacy staff (M. Bex, T. de Groot ScD, D. Vanderghinste PharmD) for their expert support. KVL is Senior Clinical Researcher and VB a Postdoctoral Researcher for the Fund for Scientific Research Flanders (FWO), Belgium. Financial support of the Research Council of the Katholieke Universiteit Leuven (OT/05/58), the Fund for Scientific Research, Flanders, Belgium (FWO/G.0548.06), and the Institute for Science and Technology SBO project 030238 (AniMoNe) is gratefully acknowledged. This work was funded in part by the European Community FP6 Network-of-Excellence DIMI (LSHB-CT-2005-512146). This experiment was approved by the local Animal Ethics Committee and was according to European Ethics Committee guidelines (decree 86/609/EEC).

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Authors and Affiliations

  1. Division of Nuclear Medicine, KU Leuven and University Hospital Leuven, Leuven, Belgium

    Cindy Casteels & Koen Van Laere

  2. Molecular Small Animal Imaging Center (MOSAIC), KU Leuven, Leuven, Belgium

    Cindy Casteels, Guy Bormans & Koen Van Laere

  3. Laboratory for Neurobiology and Gene Therapy, KU Leuven, Leuven, Belgium

    Erwin Lauwers & Veerle Baekelandt

  4. Laboratory for Radiopharmacy, KU Leuven, Leuven, Belgium

    Guy Bormans

  5. Division of Nuclear Medicine, KU Leuven and University Hospital Gasthuisberg, Herestraat 49, 3000, Leuven, Belgium

    Cindy Casteels

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  1. Cindy Casteels
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Correspondence to Cindy Casteels.

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Casteels, C., Lauwers, E., Bormans, G. et al. Metabolic–dopaminergic mapping of the 6-hydroxydopamine rat model for Parkinson’s disease. Eur J Nucl Med Mol Imaging 35, 124–134 (2008). https://doi.org/10.1007/s00259-007-0558-3

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  • DOI: https://doi.org/10.1007/s00259-007-0558-3

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