Modulation of dopaminergic and glutamatergic brain function: PET studies on parkinsonian rats

Daniela Pellegrino, Francesca Cicchetti, Xukui Wang, Aijun Zhu, Mexiang Yu, Martine Saint-Pierre, Anna Liisa Brownell

Research output: Contribution to journalArticle

51 Scopus citations

Abstract

Degeneration of dopaminergic neurons of the substantia nigra pars compacta is a cardinal feature of Parkinson's disease (PD). Although uncertain, the pathology has been suggested to derive from a malfunction of the complex interaction between dopaminergic and metabotropic glutamate receptors (mGluRs). To further address this issue, we investigated the imaging profile and expression of dopamine D2 receptors and mGluRs in a classic parkinsonian rodent model induced by the toxin 6-hydroxydopamine. Methods: Adult male Sprague-Dawley rats (250-300 g) received a stereotaxic injection of 8 μg/2 μL of 6-hydroxydopamine (n = 6) or saline solution (n = 4) in the right medial forebrain bundle. Small-animal PET was performed on all rats 4 wk after the surgical procedure to assess dopamine transporter (DAT) status using 11C-2β-carbomethoxy-3β-(4-fluorophenyl)-tropane (CFT), as well as dopamine D2 receptor and mGluR5 modulation using 11C-raclopride and 2-11C-methyl-6-(2-phenylethynyl)- pyridine(11C-MPEP), respectively. Behavioral studies were also conducted 6 wk after lesioning by D-amphetamine challenge. Immunohistochemistry and Western blotting were carried out at 8 wk after lesioning to confirm dopamine fiber, neuronal loss, and level of striatal mGluR5 expression. Results: PET images showed decreased 11C-CFT binding on the lesioned side, including the structures of the striatum, hippocampus, and cortex, compared with the contralateral intact side. Interestingly, dopamine D2 receptors and mGluR5 upregulation were observed in the right striatum, hippocampus, and cortex, using 11C-raclopride and 11C-MPEP, respectively. A negative correlation was also found between the percentage change in mGluR5 expression and DAT function. Finally, tyrosine hydroxylase immunoreactivity confirmed both dopamine fiber loss (f test, P < 0.01) and neuronal loss (t test, P < 0.01) on the lesioned side. These changes were accompanied by a strongly enhanced mGluR 5 expression in the right striatum of the lesioned side analyzed by Western plot. Conclusion: These findings support the existence of compensatory mechanisms in nigrostriatal dopamine degeneration and provide new insights that help further dissect some of the pathways underlying neurodegeneration. In addition, these results reconfirm that PET is a valuable tool for multilevel receptor studies, significantly contributing to the understanding of pathogenic mechanisms and ultimately opening new avenues in the study of neuroprotective approaches toward PD.

Original languageEnglish (US)
Pages (from-to)1147-1153
Number of pages7
JournalJournal of Nuclear Medicine
Volume48
Issue number7
DOIs
StatePublished - Jul 2007

Keywords

  • Dopamine receptors
  • Dopamine transporter
  • Glutamate receptors
  • Neurology
  • Parkinson's disease
  • PET

ASJC Scopus subject areas

  • Radiological and Ultrasound Technology

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