Sebastien Lopez

Electrophysiological and behavioral evidence that modulation of metabotropic glutamate receptor 4 with a new agonist reverses experimental parkinsonism

Developing nondopaminergic palliative treatments for Parkinsons disease represents a major challenge to avoid the debilitating side effects produced by l‐DOPA therapy. Increasing interest is addressed to the selective targeting of group III metabotropic glutamate (mGlu) receptors that inhibit transmitter release at presumably overactive synapses in the basal ganglia. Here we characterize the functional action of a new orthosteric group III mGlu agonist, LSP1–2111, with a preferential affinity for mGlu4 receptor. In mouse brain slices, LSP1– 2111 inhibits striatopallidal GABAergic transmission by selectively activating the mGlu4 receptor but has no effect at a synapse modulated solely by the mGlu7 and mGlu8 receptors. Intrapallidal LSP1–2111 infusion reverses the akinesia produced by nigrostriatal dopamine depletion in a reaction time task, whereas an mGlu8–receptor agonist has no effect. Finally, systemic administration of LSP1–2111 counteracts haloperidol‐induced catalepsy, opening promising perspectives for the development of antiparkinsonian therapeutic strategies focused on orthosteric mGlu4–receptor agonists.—Beurrier, C., Lopez, S., Révy, D., Selvam, C., Goudet, C., Lhérondel, M., Gubellini, P., Kerkerian‐LeGoff, L., Acher, F., Pin, J.‐P., Amalric, M. Electrophysiological and behavioral evidence that modulation of metabotropic glutamate receptor 4 with a new agonist reverses experimental parkinsonism. FASEB J. 23, 3619–3628 (2009). www.fasebj.org

Targeting Group III Metabotropic Glutamate Receptors Produces Complex Behavioral Effects in Rodent Models of Parkinson's Disease

Drugs activating group III metabotropic glutamate receptors (mGluRs) represent therapeutic alternatives to l-DOPA (l-3,4-dihydroxyphenylalanine) for the treatment of Parkinsons disease (PD). Their presynaptic location at GABAergic and glutamatergic synapses within basal ganglia nuclei provide a critical target to reduce abnormal activities associated with PD. The effects of selective group III mGluR agonists (1S,3R,4S)-1-aminocyclopentane-1,3,4-tricarboxylic acid (ACPT-I) and l-(+)-2-amino-4-phosphonobutyric acid (l-AP4) infused into the globus pallidus (GP) or the substantia nigra pars reticulata (SNr) were thus studied in rat models of PD. Bilateral infusions of ACPT-I (1, 2.5, and 5 nmol/μl) into the GP fully reverse the severe akinetic deficits produced by 6-hydroxydopamine nigrostriatal dopamine lesions in a reaction-time task without affecting the performance of controls. Similar results were observed after l-AP4 (1 nmol) or picrotoxin, a GABAA receptor antagonist, infused into the GP. In addition, intrapallidal ACPT-I counteracts haloperidol-induced catalepsy. This effect is reversed by concomitant administration of a selective group III receptor antagonist (RS)-α-cyclopropyl-4-phosphonophenylglycine. In contrast, ACPT-I (0.05, 0.1, and 0.25 nmol) infusions into the SNr enhance the lesion-induced akinetic deficits in control and lesioned rats and do not reverse haloperidol-induced catalepsy. l-AP4 (0.05 nmol) and picrotoxin in the SNr produce the same effects. Together, these results show that activation of group III mGluRs in the GP provides benefits in parkinsonian rats, presumably by modulating GABAergic neurotransmission. The opposite effects produced by group III mGluR activation in the SNr, also observed with a selective mGluR8 agonist, support the use of subtype-selective group III mGluR agonists as a potential antiparkinsonian strategy.

Spatial deficits in a mouse model of Parkinson disease

RationaleAccumulating evidence in humans demonstrated that visuo-spatial deficits are the most consistently reported cognitive abnormalities in Parkinson disease (PD). These deficits have been generally attributed to cortical dopamine degeneration. However, more recent evidence suggests that dopamine loss in the striatum is responsible for the visuo-spatial abnormalities in PD. Studies based on animal models of PD did not specifically address this question.ObjectivesThus, the first goal of this study was to analyze the role of dopamine within the dorsal striatum in spatial memory. We tested bilateral 6-OHDA striatal lesioned CD1 mice in an object–place association spatial task. Furthermore, to see whether the effects were selective for spatial information, we measured how the 6-OHDA-lesioned animals responded to a non-spatial change and learned in the one-trial inhibitory avoidance task.ResultsThe results demonstrated that bilateral (approximately 75%) dopamine depletion of the striatum impaired spatial change discrimination. On the contrary, no effect of the lesion was observed on non-spatial novelty detection or on passive avoidance learning.ConclusionsThese results confirm that dopamine depletion is accompanied by cognitive deficits and demonstrate that striatal dopamine dysfunction is sufficient to induce spatial information processing deficits.

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 Parkinsons 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.

Metabotropic glutamate 7 receptor subtype modulates motor symptoms in rodent models of Parkinson's disease

Metabotropic glutamate (mGlu) receptors modulate synaptic transmission in the central nervous system and represent promising therapeutic targets for symptomatic treatment of Parkinsons disease (PD). Among the eight mGlu receptor subtypes, mGlu7 receptor is prominently expressed in the basal ganglia, but its role in restoring motor function in animal models of PD is not known. The effects of N,N′-dibenzhydrylethane-1,2-diamine dihydrochloride (AMN082), the first selective allosteric activator of mGlu7 receptors, were thus tested in different rodent models of PD. Here, we show that oral (5 mg/kg) or intrastriatal administration (0.1 and 0.5 nmol) of AMN082 reverses haloperidol-induced catalepsy in rats. AMN082 (2.5 and 5 mg/kg) reduces apomorphine-induced rotations in unilateral 6-hydroxydopamine (6-OHDA)-lesioned rats. In a more complex task commonly used to evaluate major akinetic symptoms of PD patients, 5 mg/kg AMN082 reverses the increased reaction time to respond to a cue of bilateral 6-OHDA-lesioned rats. In addition, AMN082 reduces the duration of haloperidol-induced catalepsy in a mGlu7 receptor-dependent manner in wild-type but not mGlu7 receptor knockout mice. Higher doses of AMN082 (10 and 20 mg/kg p.o.) have no effect on the same models of PD. Overall these findings suggest that mGlu7 receptor activation can reverse motor dysfunction associated with reduced dopamine activity. Selective ligands of mGlu7 receptor subtypes may thus be considered as promising compounds for the development of antiparkinsonian therapeutic strategies.

Haloperidol Regulates the State of Phosphorylation of Ribosomal Protein S6 via Activation of PKA and Phosphorylation of DARPP-32

Administration of typical antipsychotic drugs, such as haloperidol, promotes cAMP-dependent signaling in the medium spiny neurons (MSNs) of the striatum. In this study, we have examined the effect of haloperidol on the state of phosphorylation of the ribosomal protein S6 (rpS6), a component of the small 40S ribosomal subunit. We found that haloperidol increases the phosphorylation of rpS6 at the dual site Ser235/236, which is involved in the regulation of mRNA translation. This effect was exerted in the MSNs of the indirect pathway, which express specifically dopamine D2 receptors (D2Rs) and adenosine A2 receptors (A2ARs). The effect of haloperidol was decreased by blockade of A2ARs or by genetic attenuation of the Gαolf protein, which couples A2ARs to activation of adenylyl cyclase. Moreover, stimulation of cAMP-dependent protein kinase A (PKA) increased Ser235/236 phosphorylation in cultured striatal neurons. The ability of haloperidol to promote rpS6 phosphorylation was abolished in knock-in mice deficient for PKA activation of the protein phosphatase-1 inhibitor, dopamine- and cAMP-regulated phosphoprotein of 32 kDa. In contrast, pharmacological or genetic inactivation of p70 rpS6 kinase 1, or extracellular signal-regulated kinases did not affect haloperidol-induced rpS6 phosphorylation. These results identify PKA as a major rpS6 kinase in neuronal cells and suggest that regulation of protein synthesis through rpS6 may be a potential target of antipsychotic drugs.

Activation of Metabotropic Glutamate 4 Receptors Decreases L-DOPA-Induced Dyskinesia in a Mouse Model of Parkinson's Disease

Group III metabotropic glutamate (mGlu) receptors modulate glutamatergic and GABAergic transmission in the basal ganglia. In this study, we examined a novel orthosteric agonist at the mGlu4 receptor, LSP1-2111, for its ability to affect L-DOPA-induced dyskinesia (LID), in a mouse model. In 6-OHDA-lesioned mice treated with L-DOPA, chronic co-administration of LSP1-2111 significantly attenuated the development of abnormal involuntary movements, which are regarded as a marker of dyskinesia. In contrast, a single injection of LSP1-2111 did not modify the expression of LID, once this condition had been established by previous administration of L-DOPA. LSP1-2111 did not affect L-DOPA-induced cAMP and extracellular signal-regulated protein kinase signaling, which have been previoulsy implicated in dyskinesia. These results indicate that co-administration of LSP1-2111 may improve the efficacy of standard L-DOPA therapy by attenuating its liability for dyskinesia.