Distribution and roles of metabotropic glutamate receptors in the basal ganglia motor circuit: implications for treatment of Parkinson's Disease and related disorders

Susan T. Rouse, Michael J. Marino, Stefania R. Bradley, Hazar Awad,

Available online 30 April 2001.

Abstract

The basal ganglia (BG) are a set of interconnected subcortical structures that play a critical role in motor control. The BG are thought to control movements by a delicate balance of transmission through two BG circuits that connect the input and output nuclei: the direct and the indirect pathways. The BG are also involved in a number of movement disorders. Most notably, the primary pathophysiological change that gives rise to the motor symptoms of Parkinson's Disease (PD) is the loss of dopaminergic neurons of the substantia nigra pars compacta (SNc) that are involved in modulating function of the striatum and other BG structures.

This ultimately results in an increase in activity of the indirect pathway relative to the direct pathway and the hallmark PD symptoms of rigidity, bradykinesia, and akinesia.

A great deal of effort has been dedicated to finding treatments for this disease. The current pharmacotherapies are aimed at replacing the missing dopamine, while the current surgical treatments are aimed at reducing transmission through the indirect pathway. Dopamine replacement therapy has proven to be helpful, but is associated with severe side effects that limit treatment and a loss of efficacy with progression of the disease. Recently developed surgical therapies have been highly effective, but are highly invasive, expensive, and assessable to a small minority of patients.

For these reasons, new effort has been dedicated to finding pharmacological treatment options that will be effective in reducing transmission through the indirect pathway. Members of the metabotropic glutamate receptor (mGluR) family have emerged as interesting and promising targets for such a treatment.

This review will explore the most recent advances in the understanding of mGluR localization and function in the BG motor circuit and the implications of those findings for the potential therapeutic role of mGluR-targeted compounds for PD.

FULL ARTICLE:

http://www.sciencedirect.com/science...aa7f454ba3dda8

"The direct and indirect pathways of the BG act as a fine-tuning mechanism in movement control (Alexander et al., 1986). The balance of transmission through the direct and indirect pathways is tightly regulated by a major modulatory projection from dopaminergic neurons in the substantia nigra pars compacta (SNc). This dopamine input to the striatum regulates the direct and indirect pathways differentially, due to the presence of different postsynaptic dopamine receptors on the two populations of medium spiny neurons. D1 receptors are primarily expressed on medium spiny neurons that project directly to SNr, while D2 receptors are primarily expressed on the medium spiny neurons that constitute the indirect pathway (Gerfen et al., 1990). Because of this differential expression, the release of dopamine in the striatum has a net excitatory effect on the direct pathway, and an inhibitory influence on the indirect pathway."

...the primary pathological change giving rise to the motor symptoms of PD is the selective death of dopaminergic neurons in the SNc. The loss of this important modulatory input results in a decrease in activity through the direct pathway and an increase in activity through the indirect pathway (Albin and Wichmann). These changes lead to increased inhibition of thalamocortical neurons, which is believed to underlie the hallmark symptoms of the disease: rigidity, bradykinesia, and akinesia. The right panel of Fig. 1 schematically illustrates the activity changes in BG-thalamocortical circuitry that are thought to occur in PD.....

....there has been a major focus on developing novel treatment strategies that are aimed at acting downstream of the lost dopaminergic neurons to restore balance to the direct and indirect pathways. This effort has led to development of highly effective surgical treatments, such as pallidotomy (Baron and Laitinen) or high-frequency stimulation of the SNT (Limousin et al., 1995), that are aimed at reducing activity through the indirect pathway. .....

Metabotropic glutamate receptors provide novel therapeutic targets for treatment of movement disorders

That part is complicated!