Metabotropic glutamate receptors 5 blockade reverses spatial memory deficits in a mouse model of Parkinson's disease.
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.
De Leonibus
Elvira
E
Dipartimento di Genetica e Biologia Molecolare C.Darwin, Università degli Studi di Roma La Sapienza, Rome, Italy.
Managò
Francesca
F
Giordani
Francesco
F
Petrosino
Francesco
F
Lopez
Sebastien
S
Oliverio
Alberto
A
Amalric
Marianne
M
Mele
Andrea
A
D000818:Animals; D001245:Association Learning / Q000187:drug effects; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D007980:Levodopa / Q000494:pharmacology; D008297:Male; D008569:Memory Disorders / Q000188:drug therapy*; D051379:Mice; D009068:Movement / Q000187:drug effects; D016627:Oxidopamine; D010300:Parkinson Disease / Q000188:drug therapy* / Q000523:psychology; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology*; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors*; D013028:Space Perception / Q000187:drug effects; D014786:Vision Disorders / Q000188:drug therapy
D018691:Excitatory Amino Acid Antagonists; C578936:Grm5 protein, mouse; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D007980:Levodopa; C121465:6-methyl-2-(phenylethynyl)pyridine; D016627:Oxidopamine