Some involvement of a dopaminergic system in the pathophysiology of RLS is undisputed. The strongest argument is based on the rapid and dramatic improvement of RLS with dopaminergic agents (151,152). As reviewed above, brain-imaging studies of the dopaminergic system in the basal ganglia have not revealed consistent abnormalities (see Section ''Basal Ganglia''). Another way to explore the integrity of the dopamine system is by measuring neuroendocrine responses to challenges with dopaminergic agonists or dopamine-blocking substances. For example, metoclopramide (a dopamine blocker) normally causes an increase in both prolactin and human growth hormone (hGH). Basic 24-hour time courses of prolactin and growth hormone do not differ between RLS subjects and controls (153). Furthermore, challenges with a dopamine antagonist in the early afternoon revealed a normal response in RLS subjects (154). Neuroendocrine response to a levodopa challenge was more pronounced during the night vs. the morning in both RLS subjects and controls, but both the decrease in prolactin and the increase in hGH were especially pronounced in RLS subjects at night. This might suggest a hypersensitivity of postsynaptic dopamine receptors at night in the RLS population (155).
The measurement of metabolites of the dopamine synthesis and degradation in CSF is another way to explore this system. High levels of free dopamine, homovanillic acid (HVA), free norepinephrine, and 3-methoxy-4-hydroxypheny-lethyleneglycol have been found in the morning CSF of a single patient with severe, familial, early-onset RLS (156). A subsequent systematic study in RLS subjects in the evening found normal dopaminergic metabolites in the CSF and blood (157). In an earlier study (158) with morning CSF samples, HVA and neopterin did not differ between RLS subjects and age-matched controls, but bio-pterin was increased in RLS subjects. Serendipitously, one study found lower dopamine, 3, 4-dihydroxyphenylacetic acid and HVA nocturnal urinary excretion levels in four subjects with a PLMS index of >5 in a placebo night (159). Earley et al. also looked for circadian changes in CSF dopamine metabolites (159a). Compared to controls, they found larger changes (a.m. vs. p.m.) in tetrahydrobiopterin (BH4), HVA:5HIAA ratio, and 3-OMD for RLS patients. All three metabolites were higher at 10 a.m. compared to 10 p.m. sample. Therefore RLS patients seem to have a greater diurnal variation than controls. In summary, the response to dopaminergic agents is probably one of the most closely associated features of RLS. Finding a marker for an altered dopamine system in RLS has proven to be more difficult, and it seems likely that the dopamine system is predominantly involved in the cir-cadian expression of restless legs symptoms.
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