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 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 mug/2 muL 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 (11)C-2beta-carbomethoxy-3beta-(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.


CONCLUSIONS
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.
Pellegrino
Daniela
D
Experimental PET Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.
Cicchetti
Francesca
F
Wang
Xukui
X
Zhu
Aijun
A
Yu
Mexiang
M
Saint-Pierre
Martine
M
Brownell
Anna-Liisa
AL
D000818:Animals; D002250:Carbon Radioisotopes; D003042:Cocaine / Q000031:analogs & derivatives; D003342:Corpus Striatum / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D006624:Hippocampus / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D007150:Immunohistochemistry; D008297:Male; D009410:Nerve Degeneration / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D016627:Oxidopamine; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology; D049268:Positron-Emission Tomography / Q000379:methods; D011725:Pyridines; D020891:Raclopride; D051381:Rats; D017207:Rats, Sprague-Dawley; D064529:Receptor, Metabotropic Glutamate 5; D017448:Receptors, Dopamine D2 / Q000096:biosynthesis*; D018094:Receptors, Metabotropic Glutamate / Q000096:biosynthesis*; D013378:Substantia Nigra / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D002250:Carbon Radioisotopes; D050483:Dopamine Plasma Membrane Transport Proteins; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D017448:Receptors, Dopamine D2; D018094:Receptors, Metabotropic Glutamate; D020891:Raclopride; C021279:(1R-(exo,exo))-3-(4-fluorophenyl)-8-methyl-8- azabicyclo(3.2.1)octane-2-carboxylic acid, methyl ester; C121465:6-methyl-2-(phenylethynyl)pyridine; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase; D003042:Cocaine