Chronic But Not Acute Treatment with a Metabotropic Glutamate 5 Receptor Antagonist Reverses the Akinetic Deficits in a Rat Model of Parkinsonism

Abstract

Metabotropic glutamate receptors (mGluRs) have recently been considered as potential pharmacological targets in the treatment of neurodegenerative disorders and particularly in parkinsonism. Within the basal ganglia, receptors of group I (mGluR1 and mGluR5) are widely expressed; the present study was thus aimed at blocking these receptors in a 6-hydroxydopamine (6-OHDA) model of Parkinson's disease in the rat. Considering the prominent expression of mGluR5, we have used the selective mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) to target these receptors. In rats trained to quickly depress a lever after a visual cue, bilateral lesions of the dopaminergic nerve terminals in the striatum produced severe akinetic deficits, which were expressed by increases in delayed responses and reaction times. Acute MPEP injection (1.5, 3, and 6 mg/kg, i.p.) had no effect, whereas chronic administration, ineffective in a control group, significantly reversed the akinetic deficits. Alleviation of these deficits was seen after 1 week of treatment, and the preoperative performance was fully recovered after a 3 week treatment of MPEP at all doses. Chronic MPEP also induced ipsilateral rotation in the unilateral 6-OHDA circling model. However, no effect was seen of MPEP (1.5, 3, or 6 mg/kg, i.p.) on haloperidol-induced catalepsy (1 mg/kg, i.p.). Altogether, these results suggest a specific role of mGluRs in the regulation of extrapyramidal motor functions and a potential therapeutic value for mGluR5 antagonists in the treatment of Parkinson's disease.

Simultaneous Blockade of Adenosine A2A and Metabotropic Glutamate mGlu5 Receptors Increase their Efficacy in Reversing Parkinsonian Deficits in Rats

“…Although this nonselective action cannot be ruled out the range of doses of MPEP below 10 mM used in the present study possess a better affinity for mGluR5 than for mGluR4 (Anderson et al, 2002). Nevertheless, as previously shown (Breysse et al, 2002) the range of doses alleviating 6-OHDA-induced deficits without inducing side effects is relatively narrow. To circumvent this problem we have therefore investigated the possible advantages of a coadministration of selective adenosine A 2A and mGlu 5 receptor antagonists.…”

“…The effect of the highest dose of MPEP (1.5 mg/ kg) was further tested in a sham-control group (n ¼ 6), since no effects were found with the lowest dose (MPEP 0.375 mg/kg) in 6-OHDA rats. Doses of MPEP were selected on the basis of our own previous study (Breysse et al, 2002).…”

“…Systemic or intrastriatal administration of group I mGluR (subtypes 1 and 5) antagonists reversed catalepsy induced by a DA receptor blockade or DA depletion (Konieczny et al, 1998;Dawson et al, 2000;Ossowska et al, 2001). In unilateral and bilateral 6-OHDA models of PD, a chronic but not acute treatment with MPEP induced ipsilateral circling behavior and produced a full recovery of akinesia in the RT task (Spooren et al, 2000;Breysse et al, 2002). The selectivity of MPEP action on mGluR5 has recently been questioned since it could act as an allosteric potentiator of mGluR4 (Mathiesen et al, 2003) and exert its effects through this group III mGluRs subtype.…”

“…Owing to their high level of expression in the basal ganglia structures: striatum, the internal pallidum and substantia nigra pars reticulata (Testa et al, 1994;Tallaksen-Greene et al, 1998), the group I metabotropic glutamate receptors play a major role in the regulation of these nuclei (Rouse et al, 2000). Indeed, recent studies in rats have emphasized the anti-Parkinsonian action of the selective mGluR antagonist of subtype 5 (mGlu 5 receptor) 2-methyl-6-(phenylethylnyl)-pyridine (MPEP) in 6-OHDA-lesioned rats (Spooren et al, 2000;Breysse et al, 2002Breysse et al, , 2003.…”

“…Here we provide evidence that subthreshold doses of the highly selective A 2A receptor antagonist, 8-(3-chlorostyryl)caffeine (CSC), when administered in combination to the mGlu 5 receptor antagonist MPEP, alleviate motor executive deficits in an operant task in rats. Partial bilateral 6-OHDA lesions of the striatum, which have previously been found to produce long-lasting deficits in movement initiation in a reaction time (RT) task, were used as a model of the early stage of PD (Amalric et al, 1995a;Breysse et al, 2002Breysse et al, , 2003.…”