Therapeutic Exploration of Metabotropic Glutamate Receptor Antagonists in Parkinson’s Disease by Positron Emission Tomography

Therapeutic Exploration of Metabotropic Glutamate Receptor Antagonists in Parkinson’s Disease by Positron Emission Tomography

Brownell Anna-Liisa , Sanchez-Pernaute Rosario

US Neurology, 2010;5(2):21-5

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Abstract
Metabotropic glutamate receptors (mGluR)s are G-protein-coupled receptors that function as modulators of synaptic function and glutamate transmission. Post-synaptically localized subtype 5 mGlu5 receptors are co-localized with adenosine A2a, dopamine, and N-methyl-D-aspartate (NMDA) receptors and regulate local protein synthesis and messenger RNA (mRNA) translation at synapses, and are thus ideally positioned to control synaptic plasticity. Aberrant synaptic plasticity appears to be involved in a number of developmental and degenerative neuropsychiatric disorders, including Parkinson’s disease. Pharmacological modulation of mGluR5 could potentially open new therapeutic avenues for the treatment of such disorders, for both symptomatic and neuroprotective purposes. In this review, we summarize a series of in vivo studies we performed in order to delineate the anatomical basis and functional role of mGluR5 antagonists in Parkinson’s disease models, taking advantage of high-resolution positron emission tomography (PET) and the recent development of novel specific radiopharmaceuticals. Our findings of a prevalent distribution of mGluR5 in the striatum and limbic structures and a significant binding enhancement following dopamine lesions support the role of mGlu5 receptors in modulating dopamine- and glutamate-dependent signaling and synaptic plasticity within the basal ganglia cortico–subcortical loops.

Keywords
Metabotropic glutamate receptor (mGluR), mGluR5, dopamine, Parkinson’s disease (PD), positron emission tomography (PET), FPEB, MPEP

Disclosure: This research was supported by National Institutes of Health (NIH) grants NIBIB-EB001850 and NINDS-NS39793. The authors have no conflicts of interest to declare.
Received: February 5, 2009 Accepted: July 17, 2009
Correspondence: Anna-Liisa Brownell, PhD, Associate Professor, Department of Radiology, Bartlett Hall 504R, Massachusetts General Hospital, Boston, MA 02114. E: abrownell@partners.org

There is great interest in developing pharmacological compounds that function through metabotropic glutamate receptors (mGluRs) as modulators of synaptic function and that could consequently become effective therapeutic agents for several developmental and degenerative neuropsychiatric disorders. mGluRs are located perisynaptically, acting as sensors and modulators of glutamate transmission.1 This functional specificity makes them attractive pharmacological targets. In particular, subtype 5 receptors (mGluR5) regulate local protein synthesis and messenger RNA (mRNA) translation at synapses, and are thus ideally positioned to control synaptic plasticity.2–5 A number of studies have explored the therapeutic potential of drugs acting at the mGluR5 for a variety of conditions, including Parkinson’s disease (PD), addiction, chronic pain, mood disorders, epilepsy, and fragile X, among others.6,7 Despite their diversity, these disorders may share common mechanisms involving aberrant brain plasticity.

Regarding PD, the loss of dopamine (DA)-mediated inhibition in the striatum results in excess excitatory transmission. It is therefore possible that mGluR5 modulation can improve PD symptoms directly8–10 or through modulation of cholinergic interneurons,11,12 although in vivo off-target effects of mGluR5 antagonists, particularly on N-methyl-D-aspartate (NMDA) and mGluR1s, have to be taken into account.13 Furthermore, mGluR5 antagonists appear particularly promising for the treatment of levodopa-induced dyskinesia,14–16 a frequent, invalidating complication of DA replacement therapy that represents an abnormal form of synaptic plasticity.17 Finally, pharmacological manipulation of mGluR5s could open new modalities of neuroprotection for PD and other degenerative diseases of the nervous system, by decreasing excitotoxicity,18 modulating signaling pathways, or, perhaps, through local translation of trophic factors. We have explored the anatomical basis and functional role of mGluR5 antagonists in models of PD, taking advantage of high-sensitivity positron emission tomography (PET) and the recent development of novel specific radiopharmaceuticals in a series of studies briefly reviewed here.

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Keywords:
Metabotropic glutamate receptor (mGluR), mGluR5, dopamine, Parkinson’s disease (PD), positron emission tomography (PET), FPEB, MPEP, Parkinson’s disease tremor, Parkinson’s disease deep brain stimulation, Parkinson’s disease treatment,

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