Dopamine Receptors in Restless Legs Syndrome and Augmentation: A Novel Perspective Focused on D1 and D3 Receptor Dynamics

Restless legs syndrome (RLS) is a common neurological disorder with a prevalence of up to 10% in the general population. The condition is defined by an urge to move the legs, transient relief with movement, and symptom worsening at night. It is more common in women than in men, with a prevalence ratio of 2:1, and it can have a negative impact on sleep and quality of life.

Despite its high prevalence, the underlying pathophysiology of RLS is not fully understood. There are multiple identified central nervous system (CNS) abnormalities but, pathologically, disruptions in iron‐related neural homeostasis are a robust hallmark of RLS. RLS is often familial and associated with specific genetic predispositions, ¹ , ² although no highly penetrant genes have been identified, and except for a gene that encodes ferroportin, no strong links between iron metabolism and genetic risk factors for RLS have been identified. ²

RLS is initially highly responsive to low‐dose treatment with dopaminergics, in particular those targeting the D2/D3 receptor subtypes. These G protein‐coupled receptors are part of the D2‐like receptor class (D2, D3, and D4) that reduce activation of cyclic AMP (cAMP)‐mediated second messenger cascades and decrease cellular excitability. In contrast, drugs that stimulate the D1‐like receptor class (D1 and D5) by activating cAMP‐mediated pathways have been shown to worsen RLS‐like symptoms in animal models. ³ All receptor subtypes express different binding affinities to dopamine, with D2‐like receptors generally having a higher affinity than D1‐like receptors. ⁴ The strong initial efficacy of D3 receptor agonists suggests that RLS pathophysiology is associated with increased cellular excitabilities, and it points to a potential causative role for a dopamine‐related dysfunction in RLS. There is some evidence of physiological dopaminergic abnormalities in RLS, ⁵ but there is no evidence of dopamine deficiency, and no consensus as to whether dopamine‐related mechanisms in themselves primarily cause RLS or whether these abnormalities are secondary to other pathologies. Recent evidence suggests that a reduction of brain iron content may lead to a dysfunction of mesolimbic and nigrostriatal dopaminergic pathways that in turn promote a dysregulation of sensorimotor networks. ⁶

Importantly, although initially highly effective, prolonged exposure to dopaminergics that target D3 receptors with a higher affinity than D2 receptors commonly leads to a gradual worsening of baseline severity, termed augmentation, which increases the intensity, anatomy, and duration of the symptoms, often dramatically. ¹ , ⁷ , ⁸ In addition, D3 receptor activation can lead to a potentiation of D2 receptor‐mediated outcomes. ⁹ In contrast, the D2‐receptor‐specific agonist sumanirole alone failed to improve RLS symptoms in a randomized, double‐blind, placebo‐controlled study. ¹⁰ Even during augmentation, D3‐receptor‐preferring agonists continue to improve immediate RLS symptoms, but require increased and more frequent dosing, before they are eventually discontinued in many cases. Due to this risk of drug‐induced augmentation, the American Academy of Sleep Medicine recently recommended against the use of D3 receptor agonists as primary treatments for RLS. ¹¹

We here present an updated model that can explain the pathophysiological underpinnings of both the dopamine response in RLS and augmentation, and that integrates the established contributions of the associated genetic mutations and the different response profiles to D2/D3 receptor drugs, acutely and chronically, in animal models and humans. This model is based on predicted changes to the D1 receptor system in RLS patients that may be afflicted by the genetic mutations observed in genome‐wide association studies (GWAS), and on the established consequences of long‐term treatment with D3‐receptor‐preferring agonists on D1 receptor expression in animal models.

1. Genetics Point to a Contributing Role of Dopamine and the Dopamine D1 Receptor in RLS

GWAS have identified changes in four genes that present the highest risks associated with RLS (MEIS1, BTBD9, MAP2K5, and PTPRD), with odds ratios (ORs) of 1.47–1.92 (MEIS1), ¹² , ¹³ 1.38–1.84 (BTBD9), ¹⁴ 1.24–1.27 (MAP2K5), ¹³ , ¹⁴ and 1.31–1.68 (PTPRD). ¹⁴ , ¹⁵ Based on these data, several transgenic animal models have been developed in which these putative RLS‐associated genes were silenced or knocked out, and in each of these models some aspects of RLS‐like behavior were observed. Together, the data support the concept that these genes may be involved in RLS symptomatology.

MEIS1: Meis1 is a transcription factor that plays an important role in the early development of several organs, including the CNS. ¹⁶ Importantly, Meis1 knockout mice express RLS‐like motor restlessness and increased striatal dopamine turnover, ¹⁷ and D1 receptor protein levels are upregulated in adult animals. ¹⁸

BTBD9: Btbd9 is a protein‐coding gene that is extensively expressed in the CNS but whose precise function is unknown. In animal models, members of the BTB protein family have been implicated in multiple aspects of synaptic plasticity and transmission. ¹⁹ Btbd9 knockout causes rest‐phase‐specific motor restlessness, sleep disturbance, and increased thermal sensation, ²⁰ consistent with RLS‐like behaviors. In addition, while activities of dopamine neurons in the substantia nigra were not altered, the D1 receptor pathway was potentiated in Btbd9 knockouts. ²¹

MAP2K5: Map2k5 is a member of the MAPK (mitogen‐activated protein kinase) family that is associated with various diseases including CNS disorders and RLS. ²² Map2k5 is crucial for dopaminergic neuron survival, and a knockout of this gene is associated with decreased dopaminergic cell survival and tyrosine hydroxylase levels in the nigrostriatal pathway. ²²

PTPRD: The protein tyrosine phosphatase D (Ptprd) gene encodes for a cell adhesion molecule likely to influence development and connections of addiction, locomotion, and sleep‐related brain circuits where it is expressed. ²³ , ²⁴ Variations in the expression of the Ptprd gene have been associated with altered connectivities within the dopamine system. ²⁴

The observed upregulation or potentiation of the D1 receptor in two GWAS‐derived models, together with evidence from two additional models showing alterations in the dopamine system, suggests a potential convergence on a common dopaminergic mechanism in RLS patients with these mutations. Specifically, these findings point to a dysregulation of dopaminergic signaling, possibly mediated by altered D1 receptor function or expression. Support for a crucial role of the D1 receptor in RLS arises also from studies on dopamine D3 receptor knockout mice. There, silencing of the D3 receptor system is associated with RLS‐like behaviors including increased locomotor activities and reflex excitability, and an upregulation of the D1 receptor system in the spinal cord. ¹⁸ , ²⁵ In addition, in RLS animal models based on iron deprivation, D1 receptor mRNA expression is increased in the spinal cord ²⁶ and the striatum, where it is thought to lead to a hyperdopaminergic striatal state by means of a disinhibited D1 receptor activation. ²⁷ Together, these data support the concept that the emergence of RLS symptoms might be driven by a functional increase in D1 receptor expression (Fig. 1).

FIG. 1.

Hypothesized model of the different states of a model neuron under control conditions, in restless legs syndrome (RLS), and in RLS after short‐ and long‐term treatment. The assumption is that the D1 receptor mediates excitatory actions while the D3 receptor subtype mediates inhibitory actions. (A) Healthy control neuron. In this model, excitatory actions mediated by D1 receptors and inhibitory actions mediated by D3 receptors are in a homeostatic balance, and the postsynaptic neuron fires at a low tonic rate. (B) In the “RLS” neuron, D1 receptors are functionally upregulated, leading to a net increase in excitability that then manifests itself in an increased firing rate and the emergence of RLS symptoms. (C) Short‐term exposure to D3 receptor agonists decreases the firing rate and re‐establishes a (temporary) balance between D1 and D3 receptor physiology, which explains the initial benefits of these drugs. (D) In contrast, long‐term exposure to D3 receptor agonists drives an additional increase in D1 receptor expression, which overrides the initial effect of the D3 receptor agonists and which may be the mechanism underlying augmentation. [Color figure can be viewed at wileyonlinelibrary.com]

2. The Potential Interplay of D1 and D3 Receptors in the Pathophysiology of RLS and Augmentation

Treatment of RLS has been historically focused on D2/D3 receptor agonists, which all have their highest affinity for D3 receptors. Our model suggests that the immediate efficacy of the D3 receptor agonists stems from reducing the overall excitability of an increased D1 receptor function (Fig. 1C). In this model, the application of D3 agonists re‐establishes a (temporary) balance between D1 and D3 receptor physiology and re‐establishes an excitability equilibrium (cf. Fig. 1A). Importantly, such an interplay between excitatory and inhibitory dopamine receptors is well established in basal ganglion circuitry. However, due to the basal ganglia indirect and direct circuitry, stimulation of D1 and D2 pathways results in grossly similar basal ganglia output through the globus pallidus internus. Consequently, both D1‐ and D3‐specific receptor agonists can improve motor features in Parkinson's disease. ²⁸ , ²⁹ This contrasts with the outcomes of dopamine modulation in the spinal cord, where stimulation of D1‐ or D2/D3 receptors has opposite physiological effects. For example, activation of D1 receptors promotes excitability and lowers pain threshold, while activation of D3 and D2‐like receptors decreases excitability and increases pain threshold. ²⁶ , ³⁰ , ³¹

Importantly, dopamine D1 and D3 receptors can form functional heteromers in both brain and spinal cord that work synergistically ³² , ³³ or in an opposing manner, ³⁴ and there is evidence that the D3 receptor can modulate movement disorders by targeting D1 receptor‐mediated striatal signaling. ³⁵ , ³⁶

The clinical development of augmentation suggests that D3 agonists shift the D1R/D3R ratio over time. In rodent models, chronic treatment with pramipexole increased spinal D1 affinity in iron‐deprived mice with lesions to the posterior hypothalamic A11 region, a dopaminergic region with projections into the spinal cord, ³⁷ potentially mimiking augmentation. ³ , ³⁸ In addition, long‐term exposure to D3 receptor agonists lead to an upregulation of D1 receptor levels, both in isolate cells in vitro and in vivo. ³⁴ , ³⁹ Together, these data suggest that the long‐term treatment of RLS with D3 receptor agonists might lead to an additional upregulation of the D1 receptor system, and we postulate that this upregulation of the D1 receptor system then overrides the initial inhibitory effect of the D3 receptor drugs, thereby causing augmentation (Fig. 1D). Interestingly, animal studies have shown that normal aging is associated with a gradual change in D1 and D3 receptor expression in brain and spinal cord, which increases expression of the D1 receptor subtype over time. ⁴⁰

Based on this concept of changing D1 and D3 receptor dynamics, we predict that a novel and alternate treatment approach antagonizing the D1 receptor could emerge as a de novo treatment for both RLS and treatment‐induced augmentation, and that this approach would directly target the underlying biological basis of the pathophysiologies for both disorders.

3. D1 Receptors: A Novel Target for the Treatment of RLS and Augmentation?

Treatment of RLS has been focused on D2/D3 receptor agonists, which have been very successful in quickly controlling symptoms (Fig. 1C). However, this approach has severe long‐term limitations, and it may not address the underlying cause of the RLS symptomatology. A small, exploratory study showed the potential promise of the D1‐specific antagonist ecopipam for patients with augmented RLS. In this 10 subject crossover trial, not powered to demonstrate statistical changes, RLS diaries, the international RLS rating scale, and clinical global impressions all numerically favored ecopipam over placebo. ⁴¹ There are currently no human data on non‐augmented RLS, but a large multicenter, placebo‐controlled study of ecopipam as “adjunct thereapy” to either dopaminergics and/or gabapentinoids is in development. This will include non‐augmented subjects.

Ecopipam has also improved tics in Tourette's syndrome. ⁴² , ⁴³ Tourette's represents a hyperdopaminergic state, although the exact mechanisms are debated. ⁴⁴ , ⁴⁵ Non‐specific dopamine antagonists also improve tics, whereas they worsen RLS, suggesting that actions of the D1 antagonist likely take place in the direct pathway of the basal ganglia, and are not directly related to our proposed pathophysiology in RLS.

Taken together, we present a heuristic model regarding the pathophysiology and the treatment outcomes of RLS that focuses on a possible interplay of dopamine D1 and D3 receptors. ⁴⁶ We suggest that both RLS and D3 receptor agonist‐induced augmentation may result from altered ratios of D1:D3 receptor systems. The predicted increase of the D1 receptor expression or function in RLS may be the result of genetic and other factors, and while the treatment with D3 receptor‐preferring agonists initially dampens the increased neuronal excitabilities, over time this approach leads to an additional upregulation of the D1 receptor and results in an additional increased excitability.This novel concept: (1) is consistent with genetic associations of the key genes altered in RLS; (2) reflects changes in dopamine D1 receptor expression that are in line with findings from genetic deletion studies in RLS animal models; (3) can explain the bimodal opposing outcomes in the treatment of RLS with D3 receptor agonists; and (4) points to a novel target in treating the disorder. Importantly, our hypothesis can be tested in clinical trials of ecopipam, which will assess both subjects with dopaminergic augmentation and those without dopaminergic augmentation. This could determine if D1 blockade only helps in patients with artificially upregulated D1 receptors or if it improves all RLS patients.

Author Roles

(1) Research Project: A. Conception, B. Organization, C. Execution. (2) Conduct Literature Review: A. Design, B. Execution, C. Review and Critique. (3) Manuscript: A. Writing of the First Draft, B. Review and Critique, C. Final Approval of the Version to be Published.

S.C.: 1A, 1B, 1C, 2A, 2B, 2C, 3A, 3B, 3C.

W.G.O.: 1B, 2A, 2B, 2C, 3B, 3C.

W.P.: 1B, 2A, 2B, 2C, 3B, 3C.

Data Availability Statement

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.