CSF dopamine, serotonin, and biopterin metabolites in patients with restless legs syndrome

Earley, Christopher J.; Hyland, Keith; Allen, Richard P.

doi:10.1002/1531-8257(200101)16:1<144::aid-mds1009>3.0.co;2-f

Cited by 62 publications

(22 citation statements)

References 42 publications

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“…As previously reported for both of these samples (9,18), the RLS patients were withdrawn from all RLS related medications for at least 2 weeks prior to the study. CSF was obtained from a lumbar puncture at 10 AM for group 1 and 10 PM for group 2, following procedures previously described (10).…”

Section: Methodsmentioning

confidence: 99%

Abnormally increased CSF 3-Ortho-methyldopa (3-OMD) in untreated restless legs syndrome (RLS) patients indicates more severe disease and possibly abnormally increased dopamine synthesis

et al. 2009

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Background-Abnormally high CSF 3-OMD occurs frequently for RLS patients indicating either increased L-dopa synthesis, limitations in L-dopa decarboxylation or increased MAT/COMT activity, or some combination of these. Increased tyrosine hydroxylase activity was found on both RLS autopsy and the rodent iron-deprivation model of RLS, suggesting increased DA synthesis in RLS. We, therefore, hypothesized elevated 3-OMD in RLS results from increased DA synthesis and that this should occur accordingly with increased HVA. It would then also reflect both more severe iron insufficiency pathology of RLS and greater clinical severity, shown by the objective measure of PLMS/hr.

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Section: Methodsmentioning

confidence: 99%

Abnormally increased CSF 3-Ortho-methyldopa (3-OMD) in untreated restless legs syndrome (RLS) patients indicates more severe disease and possibly abnormally increased dopamine synthesis

et al. 2009

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“…Cerebrospinal fluid (CSF) from individuals with RLS displays increased tetrahydrobiopterin (THB) and increased tyrosine hydroxylase (TH) activity [16]. CSF 3-ortho-methyldopa (3OMD) is increased in proportion to increased homovanillic acid (HVA), suggesting increased DA synthesis, release and turnover.…”

Section: The State Of the Daergic System In Rlsmentioning

confidence: 99%

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

Earley¹,

Uhl

Clemens

et al. 2017

Sleep Medicine

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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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“…CSF from RLS patients has significantly more 3-O-methyldopa (3-OMD) that correlates with the CSF homovanillic acid and RLS severity, indicating that increased dopamine production is proportional to the severity of RLS symptoms [15 • ]. CSF tetrahydrobiopterin is increased significantly more in the morning than night for RLS patients compared to normal controls [16] consistent with the larger circadian extracellular dopa-mine pattern in the iron-deprived rat.…”

Section: Pathology: Iron–dopamine Connectionmentioning

confidence: 99%

Update in restless legs syndrome

Salas

Gamaldo²,

Allen³

2010

Current Opinion in Neurology

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Purpose of review Although restless legs syndrome (RLS) is a disorder recognized in the medical literature since the 17th century, there have only recently been significant clinical and scientific advances in diagnosis, epidemiology and understanding the disorder, mainly due to the advent of dopaminergic treatment. Recent findings Recent discoveries have uncovered the iron–dopamine connection in RLS and the basic dopaminergic pathology related to the RLS symptoms. These have led to new understanding of the morbidity of RLS and the many conditions associated with RLS, which have also supported new approaches to treatment. These developments are each briefly described here. Summary Although there has been progress in understanding, diagnosing and treating RLS, it remains an underdiagnosed and undertreated condition severely impairing functioning of patients with moderate-to-severe disease. Much work is needed to improve on current, as well as other novel therapies.

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CSF dopamine, serotonin, and biopterin metabolites in patients with restless legs syndrome

Cited by 62 publications

References 42 publications

Abnormally increased CSF 3-Ortho-methyldopa (3-OMD) in untreated restless legs syndrome (RLS) patients indicates more severe disease and possibly abnormally increased dopamine synthesis

Abnormally increased CSF 3-Ortho-methyldopa (3-OMD) in untreated restless legs syndrome (RLS) patients indicates more severe disease and possibly abnormally increased dopamine synthesis

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

Update in restless legs syndrome

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