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

Abstract

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 caudateputamen. 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.

Targeting Striatal Metabotropic Glutamate Receptor Type 5 in Parkinson`s Disease: Bridging Molecular Studies and Clinical Trials

“…Moreover, in partially lesioned rats chronic systemic MPEP treatment was shown to be neuroprotective and to reverse the abnormal firing activity of dopaminergic neurons [91]. Interestingly, in addition to the MPEP-mediated cognitive and behavioural effects, the same treatment also increased contralateral turning induced by L-DOPA in mice bearing unilateral 6-OHDA lesion [90], thus confirming the therapeutic potential of mGlu 5 receptor blockade on motor symptoms produced by reduced striatal dopaminergic transmission (for review see [92]). On the other hand, the MPTP animal model of PD, mainly used in nonhuman primates and mice (rats are resistant to MPTP) [93], also seed some light about the potential therapeutic usage of mGlu 5 receptor antagonists in PD.…”

“…Interestingly, it was demonstrated that the chronic instead the acute treatment with 2-methyl-6-(phenylethynyl)-pyridine (MPEP), a mGlu 5 receptor antagonist, reversed these akinetic deficits [88,89], therefore suggesting that MPEP treatment might alleviate PDassociated motor executive deficits in an operant task. Also, the effects of MPEP on parkinsonian cognitive deficits has been studied and thus demonstrated that MPEP, either acutely or subchronically, antagonized the visuo-spatial discrimination deficit induced by bilateral 6-OHDA lesion of the striatum [90]. Moreover, in partially lesioned rats chronic systemic MPEP treatment was shown to be neuroprotective and to reverse the abnormal firing activity of dopaminergic neurons [91].…”

Pharmacological Modulation of Glutamate Transmission in a Rat Model of l-DOPA-Induced Dyskinesia: Effects on Motor Behavior and Striatal Nuclear Signaling

“…Genetic ablation of mGluR5 has produced adverse effects in hippocampal-dependent memory tasks in rodents (Lu et al, 1997). However, pharmacological blockade of mGluR5 improves spatial memory deficits in rodent models of PD (De Leonibus et al, 2009). Thus, although blockade of mGluR5 in a normal brain may negatively affect cognition, the same treatment would ameliorate cognitive deficits in situations where this receptor is overstimulated, which is the case in LID (Samadi et al, 2008b).…”

Understanding cognitive deficits in Parkinson’s disease: lessons from preclinical animal models

“…On the other hand, when tested for their spatial memory, mice injected with 6-OHDA in the striatum were impaired in both the short-and the long-term SOR, suggesting a predominant role of dopamine in modulating acquisition and maintenance of spatial information (De Leonibus et al 2007). The same authors successively showed that this deficit is restored by the administration of the mGluR5 selective antagonist MPEP, suggesting the possibility of a presynaptic modulatory action of mGluR5 receptors on the dopamine release from the residual nerve terminals (De Leonibus et al 2009). Thy1-aSyn transgenic mice fail in both short-and long-term SOR tests (Magen et al 2012).…”