Restless leg syndrome (RLS) is a sensorimotor disorder. Clinical studies have 
implicated the dopaminergic system in RLS, while others have suggested that it 
is associated with insufficient levels of brain iron. To date, alterations in 
brain iron status have been demonstrated but, despite suggestions from the 
clinical literature, there have been no consistent findings documenting a 
dopaminergic abnormality in RLS brain tissue. In this study, the substantia 
nigra and putamen were obtained at autopsy from individuals with primary RLS and 
a neurologically normal control group. A quantitative profile of the 
dopaminergic system was obtained. Additional assays were performed on a 
catecholaminergic cell line and animal models of iron deficiency. RLS tissue, 
compared with controls, showed a significant decrease in D2R in the putamen that 
correlated with severity of the RLS. RLS also showed significant increases in 
tyrosine hydroxylase (TH) in the substantia nigra, compared with the controls, 
but not in the putamen. Both TH and phosphorylated (active) TH were 
significantly increased in both the substantia nigra and putamen. There were no 
significant differences in either the putamen or nigra for dopamine receptor 1, 
dopamine transporters or for VMAT. Significant increases in TH and 
phosphorylated TH were also seen in both the animal and cell models of iron 
insufficiency similar to that from the RLS autopsy data. For the first time, a 
clear indication of dopamine pathology in RLS is revealed in this autopsy study. 
The results suggest cellular regulation of dopamine production that closely 
matches the data from cellular and animal iron insufficiency models. The results 
are consistent with the hypothesis that a primary iron insufficiency produces a 
dopaminergic abnormality characterized as an overly activated dopaminergic 
system as part of the RLS pathology.