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Movement Disorders Restless Legs Syndrome Neurochemistry of Idiopathic Restless Legs Syndrome Félix Javier Jiménez-Jiménez, 1 Hortensia Alonso-Navarro, 2 Elena García-Martín 3 and José AG Agúndez 4 1. Chairman of the Section of Neurology; Professor of Neurology, Hospital Universitario del Sureste, Arganda del Rey, Madrid,Spain; 2. Consultant Neurologist, Section of Neurology, Hospital Universitario del Sureste, Arganda del Rey, Madrid, Spain; 3. Professor of Pharmacology, Universidad de Extremadura, Cáceres, Spain; 4. Full Professor of Pharmacology, Universidad de Extremadura, Cáceres, Spain. Abstract The pathogenesis of idiopathic restless legs syndrome (iRLS) is not well established, but the most important hypothesis suggests dopaminergic dysfunction and iron deficiency. However, recent reports suggest a possible role for several neurotransmitters or neuromodulators, such as aspartate, glutamate, gamma-hydroxybutyric acid (GABA) and opiates, as well as relation with vitamin D deficiency. In this review, we summarise the studies related to neurochemical findings in iRLS. Keywords Restless legs syndrome, pathogenesis, neurochemistry, neurotransmitters, dopaminergic dysfunction, iron deficiency Disclosures: Félix Javier Jiménez-Jiménez, Hortensia Alonso-Navarro, Elena García-Martín and José AG Agúndez have no conflicts of interest to declare. Research at the authors’ laboratories is financed by grants PI12/00241, PI12/00324 and RETICS RD12/0013/0002 from Fondo de Investigación Sanitaria, Instituto de Salud Carlos III, Spain, Innovation and GR10068 from Junta de Extremadura, Spain. Financed in part by FEDER funds from the European Union. No funding was received for the publication of this article. Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any non-commercial use, distribution, adaptation and reproduction provided the original author(s) and source are given appropriate credit. Received: 26 January 2015 Accepted: 6 March 2015 Citation: European Neurological Review, 2015;10(1):35–44 Correspondence: Félix Javier Jiménez-Jiménez, C/Marroquina 14, 3º B, E-28030 Madrid, Spain E:; First described by Willis in 1672 and described in more detail by Ekbom in 1945, restless legs syndrome (RLS) or Willis–Ekbom disease (WED) is defined as a sensorimotor disorder in which the initial sensory symptom consists of an irresistible urge to move the legs (or both the legs and the arms) and is accompanied by or causes unpleasant sensations, appearing or worsening during rest, improving totally or partially with movement of the legs (or both the legs and the arms) and occurring only at, or worsening towards, evening and night. 1 Together with these major diagnostic criteria, three other criteria are classically considered supportive (but not diagnostically necessary) diagnostic criteria for RLS, including positive family history for RLS, response to dopaminergic drugs and presence of periodic limb movements (PLMs), assessed by leg activity devices or polysomnography while awake or during sleep. 1 The 2014 Revised International Restless Legs Syndrome Study Group (IRLSSG) Diagnostic Criteria for RLS introduced as the fifth essential criterion the requirement that the above clinical features not be related to other medical or behavioural conditions, often referred to as “RLS mimics”—such as myalgia, venous stasis, leg oedema, arthritis, leg cramps, positional discomfort or habitual foot tapping (symptoms commonly confused with RLS)—and added course specifiers to classify RLS as chronic-persistent versus intermittent symptoms, and for clinical significance of RLS. 2 Although the exact pathophysiology of idiopathic RLS (iRLS) is not well established, dopaminergic dysfunction and brain iron insufficiency are the most accepted theories. In this review, we summarise the main findings related to neurochemistry and biochemical findings of iRLS. Tou ch MEd ica l MEdia Search Strategy References for this review were identified through a PubMed search that included the period from 1966 until 5 March 2015. The term “restless legs syndrome” was crossed with “neurochemistry”, “biochemistry”, “neurotransmitters”, “dopamine”, “noradrenaline”, “norepinephrine”, “adrenaline”, “epinephrine”, “serotonin”, “GABA”, “glycine”, “glutamate”, “neuropeptides”, “iron”, “ferritin”, “transferrin”, “white matter”, “grey matter” and “transcranial magnetic stimulation”. This search retrieved 1,480 references that were examined one-for-one, with those strictly related to neurochemical findings in iRLS (n=109) selected. This review aims to provide an extensive descriptive review of studies published on this topic, to summarise the main conclusions and to propose suggestions for future studies. Dopaminergic Dysfunction The excellent therapeutic response of RLS to dopaminergic drugs, together with some neuropathological, neuroimaging, biochemical and experimental data, supports the possible role of the dopaminergic system in the pathophysiology of RLS. Neuropathological Data To date, only a few post-mortem studies have focused on the dopaminergic system in iRLS. Connor et al. 3 described similar tyrosine– hydroxylase (TH) staining in the substantia nigra of seven RLS patients compared with five controls in one study, a finding confirmed by Walters et al. 4 However, in a further study analysing the substantia nigra and putamen of eight iRLS female patients, the substantia nigra of eight female controls and the putamen of seven female controls, these authors reported 5 35