The A11 Lesion/Iron Deprivation Animal Model of Restless Legs Syndrome

Restless legs syndrome (RLS) is a common clinical condition defined by (1) an urge to move the limbs with or without sensations, (2) worsening at rest, (3) improvement with activity, and (4) worsening in the evening or night. Therefore, it is largely a subjective disease. Based on clinical symptoms, demonstrated reduced CNS iron in humans with RLS, and the robust treatment response to dopaminergics, we proposed that the little studied diencephalicspinal (A11) dopaminergic nucleus is involved in disease pathogenesis. Therefore, we lesioned this area and iron deprived rodents in an attempt to mimic human RLS. These animals consistently move more and appear generally agitated and pugnacious. Treatment with medicines known to improve human RLS also improves this phenotype, and medications known to worsen human RLS also worsen it. We have also uncovered some interesting relationships between the destruction of dopaminergic cells and the way iron is stored in the CNS, and noted some spinal dopamine receptor abnormalities with chronic therapy employing human RLS medications. Modeling a subjective human phenotype is always problematic, but we seem to have created an animal that needs/wants to move more, which is consistent with human RLS.