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

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.