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. 2012 Apr 1;2(2):221-232.
doi: 10.2217/nmt.12.6.

Therapeutic potential of targeting metabotropic glutamate receptors for Parkinson's disease

Jonathan W Dickerson  1 , P Jeffrey Conn
Affiliations

Therapeutic potential of targeting metabotropic glutamate receptors for Parkinson's disease

Jonathan W Dickerson et al. Neurodegener Dis Manag. .

Abstract

Parkinson's disease (PD) is a progressive neurological disorder predominantly characterized by motor symptoms including bradykinesia and resting tremor. The gold standard of treatment for PD remains dopamine replacement therapy, which eventually fails due to continued progression of the disease and the development of debilitating side effects. Recent breakthroughs are providing the first major advances in the development of fundamentally new pharmacological strategies for the treatment of PD that do not rely on dopamine replacement strategies, but rather aim to reduce the overactive indirect pathway within the basal ganglia. In this article, we will review the role of metabotropic glutamate receptors within the basal ganglia and discuss the potential for modulation of metabotropic glutamate receptors as a treatment for PD.

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Figures

Figure 1
Figure 1. Potential targets for metabotropic glutamate receptor modulation within the basal ganglia
Group I mGluRs are widely distributed throughout the basal ganglia. When activated, group I mGluRs counteract the response of the basal ganglia to dopamine (both directly in medium spiny neurons and indirectly via other nuclei within the basal ganglia). Antagonists of group I mGluRs (specifically mGlu5) have antiparkinsonian effects in animal models of Parkinson’s disease, which is thought to be due to reduced output from the STN and/or activity of the striatopallidal synapse. Group II mGluRs are localized presynaptically to corticostriatal terminals, STN–SNr synapses and STN–SNc synapses. Agonists of group II mGluRs may have antiparkinsonian effects due to reduced corticostriatal glutamate release and reduced activation of the STN. Group III mGluRs are also expressed in multiple basal ganglia nuclei. Electrophysiological and behavioral studies have revealed that activation of mGlu4 at the striatopallidal synapse has profound antiparkinsonian effects. Activation of mGlu4 also modulates the corticostriatal, STN–SNr and intrastriatal GABAergic synapses. While mGlu7 is expressed in many of the same nuclei as mGlu4, current data only support effects of mGlu7 at SNr synapses. Red neuron: GABAergic; green neuron: glutamatergic; blue neuron: dopaminergic. GPe: Globus pallidus pars externa; GPi: Globus pallidus pars interna; mGluR: Metabotropic glutamate receptor; SNc: Substantia nigra pars compacta; SNr: Substantia nigra pars reticulata; STN: Subthalamic nucleus.
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