Modulation of Dopaminergic and Glutamatergic Brain Function: PET Studies on Parkinsonian Rats

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 D 2 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 mg/2 mL of 6-hydroxydopamine (n 5 6) or saline solution (n 5 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 11 C-2b-carbomethoxy-3b-(4-fluorophenyl)-tropane (CFT), as well as dopamine D 2 receptor and mGluR 5 modulation using 11 C-raclopride and 2-11 C-methyl-6-(2-phenylethynyl)-pyridine ( 11 C-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 mGluR 5 expression. Results: PET images showed decreased 11 C-CFT binding on the lesioned side, including the structures of the striatum, hippocampus, and cortex, compared with the contralateral intact side. Interestingly, dopamine D 2 receptors and mGluR 5 upregulation were observed in the right striatum, hippocampus, and cortex, using 11 C-raclopride and 11 C-MPEP, respectively. A negative correlation was also found between the percentage change in mGluR 5 expression and DAT function. Finally, tyrosine hydroxylase immunoreactivity confirmed both dopamine fiber loss (t 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.

Metabotropic Glutamate Receptors 5 Blockade Reverses Spatial Memory Deficits in a Mouse Model of Parkinson's Disease

“…Although mGluR5 upregulation was observed in different brain regions, such as hippocampus and frontal cortex, it was more robust in the striatum. Further, in this structure it was accompanied by enhanced mGluR5 expression, as assessed by western blot analysis (Pellegrino et al, 2007). These findings support the existence compensatory mechanisms, at the striatal level, after nigrostriatal DA degeneration.…”

Enhanced binding of metabotropic glutamate receptor type 5 (mGluR5) PET tracers in the brain of parkinsonian primates

“…The synthesis and labeling of these tracers has been described by us (Brownell et al, 2003;Pellegrino et al, 2007;Wang et al, 2007). Regions of interest (ROIs) were delineated based on MRI high resolution anatomical images acquired on a Siemens 3T Trio system, as previously reported by our group (Jenkins et al, 2004;Sanchez-Pernaute et al, 2007) and anatomical atlas (Fig.…”

“…In two animals imaging studies of mGluR5 and DAT were done in different session to avoid background activity, since [ 18 F] FPEB has long retention time. After administration of [ 18 F]FPEB (3-[ 18 F]fluoro-5-(2-pyridinylethynyl)benzonitrile) (0.8-1.2 mCi i.v., specific activity 1900 mCi/µmol) dynamic volumetric data were acquired for 120min followed by transmission imaging and data reconstruction as above.The synthesis and labeling of these tracers has been described by us (Brownell et al, 2003;Pellegrino et al, 2007;Wang et al, 2007). Regions of interest (ROIs) were delineated based on MRI high resolution anatomical images acquired on a Siemens 3T Trio system, as previously reported by our group (Jenkins et al, 2004;Sanchez-Pernaute et al, 2007) and anatomical atlas (Fig.…”

Diffusion tensor imaging in a rat model of Parkinson's disease after lesioning of the nigrostriatal tract

“…So far, the most widely used non-invasive experimental and clinical tool to evaluate PD severity is positron emission tomography (PET) or single photon emission tomography (SPECT) (14). In vivo studies of the nigrostriatal dopaminergic projection have also been performed in the 6-OHDA model using radiotracers with high affinity and specificity for the plasma membrane dopamine transporter (DAT) (15)(16)(17)(18). Quantification of PET images of patients or animal models showed a decrease of DAT binding that can be related to nigrostriatal degeneration.…”