Brain Advance Access originally published online on July 1, 2006
Brain 2006 129(8):2017-2028; doi:10.1093/brain/awl163
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Support for dopaminergic hypoactivity in restless legs syndrome: a PET study on D2-receptor binding
ervenka11 Department of Clinical Neuroscience, Psychiatry Section, Karolinska Institutet, Karolinska University Hospital Solna Stockholm, Sweden 2 Department of Neurology, Division of Clinical Pharmacology, Karolinska University Hospital Huddinge Stockholm, Sweden 3 Department of Laboratory Medicine, Division of Clinical Pharmacology, Karolinska University Hospital Huddinge Stockholm, Sweden 4 Translational Medicine and Genetics, GlaxoSmithKline Cambridge, UK 5 The University of Manchester, Wolfson Molecular Imaging Centre Manchester, UK 6 Neurology Discovery Medicine, GlaxoSmithKline Harlow, UK
Correspondence to: Simon ervenka, Department of Clinical Neuroscience, Psychiatry Section, Karolinska Institutet, Karolinska University Hospital Solna, Building R5, SE-171 76 Stockholm, Sweden E-mail: simon.cervenka{at}ki.se
Clinical observations support a central role of the dopamine system in restless legs syndrome (RLS) but previous imaging studies of striatal dopamine D2-receptors have yielded inconclusive results. Extrastriatal dopaminergic function has hitherto not been investigated. Sixteen RLS patients naïve to dopaminergic drugs and sixteen matched control subjects were examined with PET. [11C]Raclopride and [11C]FLB 457 were used to estimate D2-receptor availability in striatum and extrastriatal regions, respectively. Examinations were performed both in the morning (starting between 10:00 and 12:00 h) and evening (starting at 18:00 h). Measures were taken to monitor and control for head movement during data acquisition. In the striatum, patients had significantly higher [11C]raclopride binding potential (BP) values than controls. In extrastriatal regions, [11C]FLB 457 BP was higher in patients than controls, and in the regional analysis the difference was statistically significant in subregions of thalamus and the anterior cingulate cortex. The diurnal variability in BP with [11C]FLB 457 and [11C]raclopride was within the previously reported test–retest reproducibility for both radioligands. The study supports involvement of the dopamine system in both striatal and extrastriatal brain regions in the pathophysiology of RLS. The brain regions where differences in D2-receptor binding were shown are implicated in the regulation of affective and motivational aspects of sensory processing, suggesting a possible pathway for sensory symptoms in RLS. Increased D2-receptor availability in RLS may correspond to higher receptor densities or lower levels of endogenous dopamine. Both interpretations are consistent with the hypothesis of hypoactive dopaminergic neurotransmission in RLS, as increased receptor levels can be owing to receptor upregulation in response to low levels of endogenous dopamine. The results do not support variations in dopamine D2-receptor availability as a correlate to the diurnal rhythm of RLS symptoms.
Key Words: brain; human; positron emission tomography; restless legs syndrome
Abbreviations: ACC, anterior cingulate cortex; AST, associative striatum; BP, binding potential; DVR, distribution volume ratio; LST, limbic striatum; PET, positron emission tomography; RLS, restless legs syndrome; ROI, regions of interest; SPET, single PET; SMST, sensorimotor striatum
Received April 19, 2006. Revised May 10, 2006. Accepted May 22, 2006.
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