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

Vallano, Antonio; Fernández-Dueñas, Víctor; García-Negredo, Gloria; Quijada, M.A.; Simon, Céline; Cuffi, M.L.; Carbonell, L.; Sánchez, Sílvia; Arnau, Josep Maria; Ciruela, Francisco

doi:10.2174/18715273113129990115

Cited by 9 publications

(8 citation statements)

References 107 publications

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“…mGluR5 also has been shown to play a role in dyskinesia, and unlike 5-HT1B, mGluR5 appears to potentiate abnormal involuntary movements after dopamine replacement therapy (21,22). Striatal medium spiny projection neurons and cholinergic interneurons express mGluR5 receptors, and pharmacologic inhibition of mGluR5 is antidyskinetic (23,24); thus, our finding that genetic inhibition of p11 is antidyskinetic could be consistent with this mechanism.…”

Section: Discussionsupporting

confidence: 63%

Gene therapy blockade of dorsal striatal p11 improves motor function and dyskinesia in parkinsonian mice

Marongiu

Arango-Lievano

Francardo

et al. 2016

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

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Complications of dopamine replacement for Parkinson's disease (PD) can limit therapeutic options, leading to interest in identifying novel pathways that can be exploited to improve treatment. p11 (S100A10) is a cellular scaffold protein that binds to and potentiates the activity of various ion channels and neurotransmitter receptors. We have previously reported that p11 can influence ventral striatal function in models of depression and drug addiction, and thus we hypothesized that dorsal striatal p11 might mediate motor function and drug responses in parkinsonian mice. To focally inhibit p11 expression in the dorsal striatum, we injected an adeno-associated virus (AAV) vector producing a short hairpin RNA (AAV.sh.p11). This intervention reduced the impairment in motor function on forced tasks, such as rotarod and treadmill tests, caused by substantia nigra lesioning in mice. Measures of spontaneous movement and gait in an open-field test declined as expected in control lesioned mice, whereas AAV.sh.p11 mice remained at or near normal baseline. Mice with unilateral lesions were then challenged with L-dopa (levodopa) and various dopamine receptor agonists, and resulting rotational behaviors were significantly reduced after ipsilateral inhibition of dorsal striatal p11 expression. Finally, p11 knockdown in the dorsal striatum dramatically reduced L-dopa-induced abnormal involuntary movements compared with control mice. These data indicate that focal inhibition of p11 action in the dorsal striatum could be a promising PD therapeutic target to improve motor function while reducing L-dopa-induced dyskinesias.gene therapy | p11 | Parkinson's disease | dyskinesia | striatum

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Section: Discussionsupporting

confidence: 63%

Gene therapy blockade of dorsal striatal p11 improves motor function and dyskinesia in parkinsonian mice

Marongiu

Arango-Lievano

Francardo

et al. 2016

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

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“…The association between smoking and low mGluR5 DVR might represent a mechanism underlying the improvement of extrapyramidal side effects through nicotine consumption given that the specific pharmacological blocking of mGluR5 has emerged as one of the most attractive non-dopaminergic-based strategies in the management of motor symptoms in Parkinson's Disease (Vallano et al, 2013). Previously, we reported on a positive correlation between anxiety-related symptoms and mGluR5 DVR (Akkus et al, 2014).…”

Section: Discussionmentioning

confidence: 90%

Metabotropic glutamate receptor 5 neuroimaging in schizophrenia

Akkus

Treyer

Ametamey

et al. 2017

Schizophrenia Research

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The metabotropic glutamate receptor 5 (mGluR5) is a promising drug target for the treatment of schizophrenia. In this study, we compared mGluR5 distribution volume ration (DVR) in subjects with schizophrenia and healthy controls. Given our previous findings, we matched samples for gender, age, and smoking status. Binding to mGluR5 was determined using positron emission tomography and [ 11 C]ABP688, which binds to an allosteric site with high selectivity. DVR in the 15 individuals with schizophrenia did not differ from that of the 15 controls. In both groups, smoking was associated with marked global reductions in mGluR5 availability (on average 23.8%). In nonsmoking subjects with schizophrenia, there was a positive correlation between mGluR5 DVR in the medial orbitofrontal cortex and the use of antipsychotic drugs (r = 0.9, p =0.019). Because antipsychotic drugs such as clozapine appeared to have indirect effects on mGluR5 signaling, our findings may be clinically relevant. They also provide promising leads for elucidating the high comorbidity between schizophrenia and tobacco addiction. Low mGluR5 DVR in smokers my represent a risk factor for schizophrenia. Alternatively, smoking may counteract the potential upregulation of mGluR5 by antipsychotic drugs.

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“…Based on these findings, mGlu5 receptor ligands may provide important adjuncts to behavioural addiction treatment. Such drugs are already in clinical trial for other disorders, including schizophrenia (Lindsley and Stauffer, ) and Parkinson's disease (Duty, ; Vallano et al ., ). They are now being considered as potential treatments for addiction, although the cognitive effects of mGlu5 are complex, especially as they are also important for extinction (Cleva et al ., ).…”

Section: Animal Models Can Elucidate How Cues Mediate Drug‐seeking Bementioning

confidence: 97%

Role of cues and contexts on drug‐seeking behaviour

Perry

Zbukvic

Kim

et al. 2014

British J Pharmacology

106

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Environmental stimuli are powerful mediators of craving and relapse in substance‐abuse disorders. This review examined how animal models have been used to investigate the cognitive mechanisms through which cues are able to affect drug‐seeking behaviour. We address how animal models can describe the way drug‐associated cues come to facilitate the development and persistence of drug taking, as well as how these cues are critical to the tendency to relapse that characterizes substance‐abuse disorders. Drug‐associated cues acquire properties of conditioned reinforcement, incentive motivation and discriminative control, which allow them to influence drug‐seeking behaviour. Using these models, researchers have been able to investigate the pharmacology subserving the behavioural impact of environmental stimuli, some of which we highlight. Subsequently, we examine whether the impact of drug‐associated stimuli can be attenuated via a process of extinction, and how this question is addressed in the laboratory. We discuss how preclinical research has been translated into behavioural therapies targeting substance abuse, as well as highlight potential developments to therapies that might produce more enduring changes in behaviour. Linked Articles This article is part of a themed section on Animal Models in Psychiatry Research. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-20

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

Cited by 9 publications

References 107 publications

Gene therapy blockade of dorsal striatal p11 improves motor function and dyskinesia in parkinsonian mice

Gene therapy blockade of dorsal striatal p11 improves motor function and dyskinesia in parkinsonian mice

Metabotropic glutamate receptor 5 neuroimaging in schizophrenia

Role of cues and contexts on drug‐seeking behaviour

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