Blockade of the metabotropic glutamate receptor subtype 5 (mGluR5) produces antiparkinsonian-like effects in rats

Ossowska, Krystyna; Konieczny, Jolanta; Wolfarth, S; Wierońska, Joanna M.; Pilc, Andrzej

doi:10.1016/s0028-3908(01)00083-1

Cited by 109 publications

(64 citation statements)

References 34 publications

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“…However, it would be very difficult to explain these effects by motor impairment, because MPEP tended to increase ambulatory locomotor activity. This finding is in agreement with previous reports, showing no decrease in spontaneous locomotion by the MPEP dose range used here (Ossowska et al, 2001;Henry et al, 2002). Unlike the other subjects, the group of rats given MPEP injections also decreased their reinstatement baseline during injections, suggesting that MPEP might have had long-term effects on this behavior.…”

Section: Discussionsupporting

confidence: 93%

“…Together, these data suggest that generalized disruption of motor function most likely did not contribute to decreased reinstatement. These findings are in agreement with previous data on the effects of these drugs on locomotion (Dalia and Wallace, 1995;Bristow et al, 1996;Mead and Stephens, 1999;Ossowska et al, 2001). Measurement of spontaneous locomotor activity may, however, have only limited value as control of drug-induced changes in reinstatement behavior, because habituated animals have relatively low basal activity levels.…”

Section: Discussionsupporting

confidence: 92%

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Ionotropic and Metabotropic Glutamate Receptor Antagonism Attenuates Cue-Induced Cocaine Seeking

Bäckström

Hyytiä

2005

Neuropsychopharmacol

161

121

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Neuroanatomical and pharmacological evidence implicates glutamate transmission in drug-environment conditioning that partly controls drug seeking and relapse. Glutamate receptors could be targets for pharmacological attenuation of the motivational properties of drugpaired cues and for relapse prevention. The purpose of the present study was therefore to investigate the involvement of ionotropic and metabotropic glutamate receptor subtypes in cue-induced reinstatement of cocaine-seeking behavior. Rats were trained to selfadminister cocaine using a second-order schedule of reinforcement (FR4(FR5:S)) under which a compound stimulus (light and tone) associated with cocaine infusions was presented contingently. Following extinction, the effects of the competitive NMDA receptor antagonist CGP 39551 (0, 2.5, 5, 10 mg/kg intraperitoneally (i.p.)), two competitive AMPA/kainate antagonists, CNQX (0, 0.75, 1.5, 3 mg/ kg i.p.) and NBQX (0, 1.25, 2.5, 5 mg/kg i.p.), the NMDA/glycine site antagonist L-701,324 (0, 0.63, 1.25, 2.5 mg/kg i.p.), and the mGluR5 antagonist MPEP (0, 1.25, 2.5, 5 mg/kg i.p.) on cue-induced reinstatement of cocaine seeking were examined. The AMPA/kainate receptor antagonists CNQX and NBQX, the NMDA/glycine site antagonist L-701,324, and the mGluR5 antagonist MPEP attenuated significantly cue-induced reinstatement. The NMDA antagonist CGP 39551 failed to affect reinstatement. Additional control experiments indicated that attenuation of cue-induced reinstatement by CNQX, NBQX, L-701,324, and MPEP was not accompanied by significant suppression of spontaneous locomotor activity. These results suggest that conditioned influences on cocaine seeking depend on glutamate transmission. Accordingly, drugs with antagonist properties at various glutamate receptor subtypes could be useful in prevention of relapse induced by conditioned stimuli.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 92%

Ionotropic and Metabotropic Glutamate Receptor Antagonism Attenuates Cue-Induced Cocaine Seeking

Bäckström

Hyytiä

2005

Neuropsychopharmacol

161

121

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“…Thus, blockade of mGluR5 activity in the STN can be beneficial in treating PD pathophysiology. Indeed, there are reports demonstrating that systemic administration of MPEP ameliorates parkinsonian-like symptoms in rodent models of the disease (Ossowska et al, 2001;Spooren et al, 2001) (for review, see Breysse et al, 2002). Our findings provide support for another mechanism by which silencing mGluR5 in the GP may also be beneficial in PD.…”

Section: Mglur5 Antagonists and Parkinson's Diseasesupporting

confidence: 71%

Distinct Functional Roles of the Metabotropic Glutamate Receptors 1 and 5 in the Rat Globus Pallidus

Poisik¹,

Mannaioni²,

Traynelis³

et al. 2003

J. Neurosci.

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Group I metabotropic glutamate receptors (mGluRs) 1 and 5 frequently colocalize in the same neurons throughout the CNS. Because both receptors can couple to the same effector systems, the purpose of their cellular coexpression remains unclear. Here, we report that group I mGluR1 and mGluR5 have distinct functional roles in type II neurons of the rat globus pallidus (GP). Type II GP neurons form a large population of GABAergic projection neurons that are characterized by the presence of inwardly rectifying current I h , low-threshold voltage-activated calcium current I t , and activity at rest. Although immunocytochemical analysis reveals a high degree of neuronal colocalization of the two group I mGluRs in the GP, activation of mGluR1 only directly depolarizes type II GP neurons. Interestingly, blockade of mGluR5 by a highly selective antagonist, methylphenylethynylpyridine, leads to the potentiation of the mGluR1-mediated depolarization in this neuronal subpopulation. Metabotropic GluR1 desensitizes during repeated activation with the agonist in type II GP neurons, and blocking mGluR5 prevents the desensitization of the mGluR1-mediated depolarization. Elimination of the activity of protein kinase C (PKC) by an application of 1 M bisendolylmaleimide or 1 M chelerythrine, both protein kinase C inhibitors, potentiates the mGluR1-mediated response and prevents the desensitization of mGluR1 in type II GP neurons, suggesting that the effect of mGluR5 on mGluR1 signaling may involve PKC. Together, these data illustrate a novel mechanism by which mGluR1 and mGluR5, members of the same family of G-protein-coupled receptors, can interact to modulate neuronal activity in the rat GP.

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“…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).…”

Section: Metabotropic Glutamate 5 Receptors Antagonism As Anti-parkinmentioning

confidence: 95%

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

Coccurello

Breysse

Amalric

2004

Neuropsychopharmacol

119

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Recent evidence suggest that antagonism of adenosine A 2A receptors represent an alternative therapeutic approach to Parkinson's disease (PD). Coactivation of A 2A and the glutamate subtype 5 metabotropic receptors (mGlu 5 ) synergistically stimulates DARPP-32 phosphorylation and c-fos expression in the striatum. This study therefore tested the effects of a joint blockade of these receptors to alleviate the motor dysfunction in a rat model of PD. 6-Hydroxydopamine infusions in the striatum produced akinetic deficits in rats trained to release a lever after a stimulus in a reaction time (RT) task. At 2 weeks after the lesion, A 2A and mGlu 5 receptors selective antagonists 8-(3-chlorostyryl)caffeine (CSC) and 2-methyl-6-(phenylethynyl)-pyridine (MPEP) were administered daily for 3 weeks either as a single or joint treatment. Injections of CSC (1.25 mg/kg) and MPEP (1.5 mg/kg) separately or in combination reduced the increase of delayed responses and RTs induced by 6-OHDA lesions, while the same treatment had no effect in controls. Furthermore, coadministration of lower doses of 0.625 mg/kg CSC and 0.375 mg/kg MPEP noneffective as a single treatment promoted a full and immediate recovery of akinesia, which was found to be more efficient than the separate blockade of these receptors. These results demonstrate that the combined inactivation of A 2A and mGlu 5 receptor potentiate their beneficial effects supporting this pharmacological strategy as a promising anti-Parkinsonian therapy.

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Blockade of the metabotropic glutamate receptor subtype 5 (mGluR5) produces antiparkinsonian-like effects in rats

Cited by 109 publications

References 34 publications

Ionotropic and Metabotropic Glutamate Receptor Antagonism Attenuates Cue-Induced Cocaine Seeking

Ionotropic and Metabotropic Glutamate Receptor Antagonism Attenuates Cue-Induced Cocaine Seeking

Distinct Functional Roles of the Metabotropic Glutamate Receptors 1 and 5 in the Rat Globus Pallidus

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

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