The Selective mGlu5 Receptor Agonist CHPG Inhibits Quinpirole-Induced Turning in 6-Hydroxydopamine-Lesioned Rats and Modulates the Binding Characteristics of Dopamine D2 Receptors in the Rat Striatum Interactions with Adenosine A2a Receptors

Popoli, Patrizia; Pézzola, Antonella; Torvinen, Maria; Reggio, Rosaria; Pintor, Annita; Scarchilli, Laura; Fuxé, Kjell; Ferré, Sergi

doi:10.1016/s0893-133x(01)00256-1

Cited by 136 publications

(121 citation statements)

References 41 publications

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“…Recent evidence have shown that agonists acting at A 2A and group I mGlu receptors were able to reduce either separately or in costimulation the high-affinity state of the DA D2 receptor binding sites (Ferré et al, 1999). A functional antagonistic relationship of D 2 with A 2A and mGlu 5 receptors is further supported by a recent study showing that the mGlu5 receptor agonist, CHPG, inhibit the D 2 -induced turning behavior in unilateral 6-OHDA-lesioned animals, an effect greatly potentiated by a joint administration with the A 2A receptor agonist CGS 21680 (Popoli et al, 2001). It might then be suggested that the complete recovery of DA-induced deficits observed in the present study after a concomitant blockade of mGlu 5 and A 2A receptors result from a normalization of the overactive striatopallidal GABA pathway.…”

Section: Functional Interaction Between a 2a And Mglu 5 Receptorsmentioning

confidence: 79%

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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Section: Functional Interaction Between a 2a And Mglu 5 Receptorsmentioning

confidence: 79%

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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“…Such a mechanism was recently proposed for the induction of LTD in the cerebral cortex (Otani et al, 1999). Another possibility would be that mGluR5 and dopamine receptors functionally interact via direct protein-protein interactions, a phenomenon that has been characterized for other G-protein-coupled receptors in the CNS including dopamine and adenosine receptors with group I mGluRs (Ciruela et al, 2001;Popoli et al, 2001;Ferre et al, 2002). The fact that mGluR5 and dopamine receptors display a similar pattern of subsynaptic distribution relative to dopaminergic synapses (Yung et al, 1995) supports the possibility of functional interactions between these receptors.…”

Section: Discussionmentioning

confidence: 93%

Group I Metabotropic Glutamate Receptors in the Monkey Striatum: Subsynaptic Association with Glutamatergic and Dopaminergic Afferents

2003

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Group I metabotropic glutamate receptors (mGluRs) are involved in long-term synaptic plasticity and neuroprotection in the striatum, but the specific role(s) of mGluR1 and mGluR5 remain poorly understood. In this study, we used electron-microscopic immunocytochemistry to compare the pattern of subsynaptic and subcellular distribution of mGluR1a and mGluR5 in relation to putative glutamatergic and dopaminergic inputs to the monkey striatum. At the light-microscopic level, both group I mGluRs are expressed in the striatal neuropil. In addition, numerous perikarya of striatal output neurons are immunostained for mGluR5, but much less frequently for mGluR1a. At the electron-microscopic level, immunoreactivity for both receptor subtypes is primarily expressed postsynaptically in dendrites and spines, although presynaptic mGluR1a labeling of glutamatergic thalamostriatal boutons and, less frequently, dopaminergic and corticostriatal terminals is also seen. In contrast to mGluR1a, mGluR5 immunoreactivity is rarely encountered presynaptically. In postsynaptic elements, 40 -70% of immunoreactivity for both receptor subtypes is expressed intracellularly, whereas 30 -60% is apposed to the plasma membrane. More than 80% of the labeling apposed to the plasma membrane is extrasynaptic. The remaining 20% is located at the edges of putative glutamatergic synapses or in the active zone of symmetric synapses. In mGluR5-, but not mGluR1a-immunostained sections, ϳ70% of dopaminergic symmetric synapses are labeled perisynaptically.These data emphasize the differential pattern of subsynaptic localization of the two group I mGluRs and provide various presynaptic and postsynaptic sites whereby mGluR1 and mGluR5 could mediate different, but complementary, effects on glutamatergic and dopaminergic transmission in the primate striatum.

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“…For instance, intrastriatal injection of nonselective or group I mGlu receptor agonists induced delayed contralateral turning behavior, which is possibly mediated by the potentiation of action of adenosine A 2A receptors in striatopallidal neurons followed by the disinhibition of subthalamic nucleus neurons, with the consequent increase in output of dopaminergic nigrostriatal neurons (28). In 6-hydroxydopamine-lesioned rats, the intracerebroventricular injection of an mGlu5 agonist counteracted the contralateral turning behavior elicited by a dopamine D2 agonist, which could be explained by the potentiation of reciprocal interaction between adenosine A 2A and dopamine D2 receptors (30). Recently, Chiamulera et al (11) reported that mice lacking the mGlu5 receptor do not self-administer cocaine and show no increased locomotor activity after cocaine treatment, despite the increase in dopamine release in nucleus accumbens.…”

Section: Discussionmentioning

confidence: 99%

Metabotropic mGlu5 receptors regulate adenosine A _2A receptor signaling

Nishi

Liu

Matsuyama

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

133

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D opamine-and cAMP-regulated phosphoprotein of M r 32,000 (DARPP-32) is a signal transduction molecule that is selectively enriched in medium-sized spiny neurons in neostriatum, and plays an obligatory role in dopaminergic signaling. Mice lacking DARPP-32 exhibit profound deficits in their molecular, electrophysiological, and behavioral responses to dopamine, drugs of abuse and antipsychotic medication, demonstrating the importance of DARPP-32 in most of the actions of dopamine (1).When DARPP-32 is phosphorylated by cAMP-dependent protein kinase (PKA) on Thr-34, it is converted into a potent inhibitor of protein phosphatase-1, and thereby controls the phosphorylation state and activity of many downstream physiological effectors, including various neurotransmitter receptors and voltage-gated ion channels (for review, see ref.2). Phosphorylation and dephosphorylation of DARPP-32 at Thr-34 are regulated by dopamine, adenosine, glutamate, serotonin, and other neurotransmitters. For example, dopamine, by activating dopamine D1-type receptors (3), and adenosine, by activating adenosine A 2A receptors (4), stimulate the phosphorylation of DARPP-32 at Thr-34.Metabotropic glutamate (mGlu) receptors are subdivided into three groups on the basis of agonist pharmacology, sequence homology, and G-protein effector coupling: group I (mGlu1 and mGlu5 receptors), group II (mGlu2 and mGlu3 receptors), and group III (mGlu4, mGlu6, mGlu7, and mGlu8 receptors; ref. 5). Group I mGlu receptors are coupled to the phospholipase C (PLC) pathway (6), the extracellular signal-regulated kinase (ERK) pathway (7), and the p38 pathway (8); group II and III mGlu receptors are negatively coupled to adenylyl cyclase (9). Individual subtypes of mGlu receptors are assumed to mediate distinct facilitatory (group I) or inhibitory (group II and III) actions on neuronal transmission (10). Recently, mGlu receptors were shown to be involved in cocaine self-administration (11) and methamphetamine-induced neurotoxicity (12). However, the molecular mechanisms underlying the actions of mGlu receptors are not clearly understood. In this study, we investigated the regulation of DARPP-32 phosphorylation at Thr-34 by mGlu receptors by using neostriatal slices. The results obtained indicate that the actions of mGlu5 receptors are linked to A 2A adenosine receptors by means of a mechanism involving the ERK cascade.

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The Selective mGlu5 Receptor Agonist CHPG Inhibits Quinpirole-Induced Turning in 6-Hydroxydopamine-Lesioned Rats and Modulates the Binding Characteristics of Dopamine D2 Receptors in the Rat Striatum Interactions with Adenosine A2a Receptors

Abstract: In 6-hydroxydopamine-lesioned rats, the selective mGlu 5 receptor agonist (1)(2)(3)(4)(5)(6)

Cited by 136 publications

References 41 publications

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

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

Group I Metabotropic Glutamate Receptors in the Monkey Striatum: Subsynaptic Association with Glutamatergic and Dopaminergic Afferents

Metabotropic mGlu5 receptors regulate adenosine A _2A receptor signaling

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The Selective mGlu5 Receptor Agonist CHPG Inhibits Quinpirole-Induced Turning in 6-Hydroxydopamine-Lesioned Rats and Modulates the Binding Characteristics of Dopamine D2 Receptors in the Rat Striatum Interactions with Adenosine A2a Receptors

Abstract: In 6-hydroxydopamine-lesioned rats, the selective mGlu 5 receptor agonist (1)(2)(3)(4)(5)(6)

Cited by 136 publications

References 41 publications

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

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

Group I Metabotropic Glutamate Receptors in the Monkey Striatum: Subsynaptic Association with Glutamatergic and Dopaminergic Afferents

Metabotropic mGlu5 receptors regulate adenosine A 2A receptor signaling

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Metabotropic mGlu5 receptors regulate adenosine A _2A receptor signaling