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

被引:52
作者
De Leonibus, Elvira [1 ,2 ]
Manago, Francesca [1 ,2 ]
Giordani, Francesco [1 ,2 ]
Petrosino, Francesco [3 ]
Lopez, Sebastien [4 ]
Oliverio, Alberto [1 ,2 ]
Amalric, Marianne [4 ,5 ]
Mele, Andrea [1 ,2 ,5 ]
机构
[1] Univ Roma La Sapienza, Dipartimento Genet & Biol Mol C Darwin, I-00185 Rome, Italy
[2] Univ Roma La Sapienza, Ctr Ric Neurobiol D Bovet, I-00185 Rome, Italy
[3] Univ Roma La Sapienza, Dipartimento Fisiol Umane & Farmacol, I-00185 Rome, Italy
[4] Univ Aix Marseille, Lab Neurobiol Cognit, CNRS, UMR6155, Marseille, France
[5] CERC, CNR, Ist Neurosci, Rome, Italy
关键词
visuo-spatial discrimination; Parkinson's disease; mGluR5; antagonist; mice; rotational behavior; ANTAGONIST 2-METHYL-6-(PHENYLETHYNYL)-PYRIDINE MPEP; FUNCTIONAL INTERACTION; ADENOSINE A(2A); WORKING-MEMORY; RAT MODEL; 6-HYDROXYDOPAMINE-LESIONED RATS; MGLUR5; ANTAGONISTS; AGONIST CHPG; WATER MAZE; GROUP-I;
D O I
10.1038/npp.2008.129
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Visuo-spatial deficits are the most consistently reported cognitive abnormalities in Parkinson's disease (PD), and they are frequently associated to motor symptoms in the early stages of the disease when dopamine loss is moderate and still restricted to the caudate putamen. The metabotropic glutamate receptor 5 (mGluR5) antagonist, 2-methyl-6-(phenylethynyl)-pyridine (MPEP), has beneficial effects on motor symptoms in animal models of PD. However, the effects of MPEP on the cognitive deficits of the disease have never been investigated. Thus, the purpose of this study was to explore its therapeutic potentials by investigating its effects on the visuo-spatial deficits induced by 6-hydroxydopamine (6-OHDA) lesions of dorsal striatum in CD1 mice. The results demonstrated that systemic injections of MPEP (6, 12, and 24 mg/kg, i.p.) impair visuo-spatial discrimination in intact mice at high concentrations, whereas lower doses (1.5 and 3 mg/kg, i.p.) were void of effects. Nevertheless, when an ineffective dose (MPEP 3 mg/kg) was injected, either acutely or subchronically (8 days), it antagonized the visuo-spatial discrimination deficit induced by bilateral dopamine lesion of the striatum. Furthermore, the same treatment increased contralateral turning induced by L-DOPA in mice bearing unilateral 6-OHDA lesion. These results confirm the therapeutic potential of mGluR5 blockade on motor symptoms induced by reduced striatal dopamine function. Further, they demonstrate that mGluR5 blockade may also have beneficial effects on cognitive deficits induced by dopamine depletion.
引用
收藏
页码:729 / 738
页数:10
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