Low brain iron effects and reversibility on striatal dopamine dynamics

Abstract

Iron deficiency (ID) in rodents leads to decreased ventral midbrain (VMB) iron concentrations and to changes in the dopamine (DA) system that mimic many of the dopaminergic changes seen in RLS patient where low substantia nigra iron is a known pathology of the disease. The ID-rodent model, therefore, has been used to explore the effects that low VMB iron can have on striatal DA dynamics with the hopes of better understanding the nature of iron-dopamine interaction in Restless Legs Syndrome (RLS). Using a post-weaning, diet-induced, ID condition in rats, the No-Net-Flux microdialysis technique was used to examine the effect of ID on striatal DA dynamics and it reversibility with acute infusion of physiological concentrations of iron into the VMB. This study replicated prior findings by showing that the ID condition is associated with increased extracellular striatal DA, reduced striatal DA uptake, and blunted DA-2-receptor-agonist feedback enhancement of striatal DA uptake. Despite the increase in extracellular striatal DA, intracellular striatal DA, as determined in tissue homogenates, was decrease in the ID rat. The study’s key finding was that an infusion of physiological concentrations of iron into the VMB reversed the ID-induced increase in extracellular striatal DA and the ID-induced decrease in intracellular striatal DA but had no effect on the ID-induced changes in DA uptake or on the blunted DA-uptake response to quinpirole. In summary, the ID-rodent model provides highly reproducible changes in striatal DA dynamics that remarkably parallel dopaminergic changes seen in RLS patients. Some but not all of these ID-induced changes in striatal DA dynamics were reversible with physiological increases in VMB iron. The small changes in VMB iron induced by iron infusion likely represent biologically relevant changes in the non-transferrin-bound labile iron pool and may mimic circadian-dependent changes that have been found in VBM extracellular iron.

Targeting hypersensitive corticostriatal terminals in restless legs syndrome

“…Those include an increase in striatal extracellular concentrations of dopamine, a reduction in the density of striatal D2R and an increased tyrosine hydroxylase activity in the ventral midbrain. 12,37 …”

Brain iron deficiency in idiopathic restless legs syndrome measured by quantitative magnetic susceptibility at 7 tesla

“…PLMS is very responsive to dopamine treatment suggesting a major dopamine pathophysiology driving the PLMS [46–48]. Animal studies have demonstrated that low iron in the SN occurs with the increased striatal dopamine activation [49] as seen in RLS [50] presumably leading to over-activation of compensatory mechanisms producing PLMS. Thus the iron status of the SN is expected to associate with the PLMS motor sign of RLS, as it does in this study.…”

Connectome and molecular pharmacological differences in the dopaminergic system in restless legs syndrome (RLS): plastic changes and neuroadaptations that may contribute to augmentation

“…That may not, however, be true. The iron-deficiency (ID) rodent model, which has demonstrated biological changes that closely mimic the changes seen in RLS [21], does implicate changes in dynamic relation between pre and synaptic function that are more complex than simple attribution of increased TH or decreased D2/3R as the primary insult [23]. Despite the uncertainty of what factors contribute to the dynamic change in the dopaminergic function in RLS, this is also an issue of systems dynamics: brain region, oscillatory state, feedback dynamics and other systems are likely to play primary roles in how dopaminergic system “functions” in RLS.…”