Connectome and molecular pharmacological differences in the dopaminergic system in restless legs syndrome (RLS): plastic changes and neuroadaptations that may contribute to augmentation

Highlights

• Long-term treatment of RLS with dopamine D2/D3 receptor agonists leads to augmentation.

• Augmentation may result from a hyperdopaminergic state.

• Protein tyrosine phosphatase D (PTPRD) may play a role in the reconfiguration of neural circuits.

• Alterations in direct and indirect interactions between D1 and D3 receptors might be involved.

• New treatment options for RLS may extend beyond the dopamine system itself.

Abstract

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 hypodopaminergic state as the mechanism 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 induce a hyperdopaminergic state are summarized. On the basis of these 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 the dopaminergic systems and their possible effects 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 reshape behavioral outcomes and change with normal aging. Additionally, long-term activation of one dopamine receptor subtype can increase the receptor expression of a different receptor subtype with opposite modulatory actions. Such dopamine receptor interactions at both spinal and supraspinal levels appear to play important roles in RLS. In addition, these interactions can extend to the adenosine A₁ and A_2A receptors, which are also prominently expressed in the striatum. Interactions between adenosine and dopamine receptors and dopaminergic cell adhesion molecules, including PTPRD, may provide new pharmacological targets for treating RLS. In summary, new treatment options for RLS that include recovery from augmentation will have to consider dynamic changes in the dopamine system that occur during the circadian cycle, plastic changes that can develop as a function of treatment or with aging, changes in the connectome based on alterations in cell adhesion molecules, and receptor interactions that may extend beyond the dopamine system itself.

Introduction

Levodopa and dopamine D_2/3 receptor (D2/3R) agonists significantly improve the primary symptom of restless legs syndrome (RLS), which is defined as focal, akathisia involving the lower extremities [1], [2]. Dopamine (DA) antagonists, on the contrary, can trigger or worsen akathisia [3], [4], [5]. From these findings, it has been deduced that the dopaminergic system is involved in the development of RLS/akathisia and that decreased DA function is at the heart of RLS [6], [7], [8]. The concept of decreased DA function in RLS has been the rationale for the proposed use of 6-hydroxydopamine (6-OHDA) lesions and D3R knockouts to model RLS [9], [10], [11], [12]. The simplistic concept of “decreased DA function,” however, cannot fully account for many other clinical features seen in RLS. How does “decreased DA function” account for the intensification of RLS/akathisia with chronic use of DA agonists or the distinct circadian presentation of the disease? As Parkinson’s disease exemplifies the ultimate state of “decreased DA function,” why do all patients with Parkinson’s disease not develop RLS [13], [14]? Despite often dramatic improvement in both RLS and periodic limb movement disorder (PLMD) with acute DA agonist treatment, polysomnographic data still show persistent abnormalities in other sleep measures [15]. Defining the underlying pathology of RLS as simply “decreased DA function” thus ignores obvious dynamic issues and clinical conundrums.