Connectome and molecular pharmacological dopaminergic differences in RLS: plastic changes and neuroadaptations that may contribute to augmentation

Publication date: Available online 27 June 2016
Source:Sleep Medicine
Author(s): Christopher Earley, George R. Uhl, Stefan Clemens, Sergi Ferré
Restless Legs Syndrome (RLS) is primarily treated with levodopa and dopaminergics that target the inhibitory dopamine receptor subtypes D3 and D2. The initial success of this therapy led to the idea of a hypo-dopaminergic state as the mechanistic origin underlying RLS. However, multiple lines of evidence suggest that this simplified concept of a reduced dopamine function as the basis of RLS is incomplete. Moreover, long-term medication with the D2/D3 agonists leads to a reversal of the initial benefits of dopamine agonists and augmentation, which is a worsening of symptoms under therapy. The recent findings on the state of the dopamine system in RLS that support the notion that a dysfunction in the dopamine system may in fact give rise to a hyper-dopaminergic state is summaraized. Based on this data, the concept of a dynamic nature of the dopamine effects in a circadian context, is presented. The possible interactions of cell-adhesion molecules expressed by dopaminergic systems and their possible impact on RLS and augmentation are discussed. Genome-wide association studies (GWAS) indicate a significantly increased risk for RLS in populations with genomic variants of the cell adhesion molecule receptor type protein tyrosine phosphatase D (PTPRD), and PTPRD is abundantly expressed by dopamine neurons. PTPRD may play a role in the reconfiguration of neural circuits, including shaping the interplay of G protein-coupled receptor (GPCR) homomers and heteromers that mediate dopaminergic modulation. Recent animal model data support the concept that interactions between functionally-distinct dopamine receptor subtypes can re-shape behavioral outcomes and change with normal aging. Additionally, long-term activation of one dopamine receptor subtype can increase receptor expression of a different receptor subtype with opposing modulatory actions. Such dopamine receptor interactions at both spinal and supra-spinal levels appear to play important roles in RLS. In addition, these interactions can also extend to the adenosine A2A receptor, which is also prominently expressed in the striatum. Interactions between A2A and dopamine receptors and dopaminergic cell adhesion molecules, including PTPRD, may provide new pharmacological targets in treating RLS. In summary, new treatment options for RLS that include recovery from augmentation will have to take into account dynamic changes to the dopamine system that occur during the circadian cycle, plastic changes that can develop as a function of treatment or with aging, changes to the connectome based on alterations to cell adhesion molecules, and receptor interactions that may reach beyond the dopamine system itself.



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