The Effect of Iron Deficiency on In Vivo Catecholamine Signaling

Open Access
Author:
Bianco, Laura Elizabeth
Graduate Program:
Nutrition
Degree:
Doctor of Philosophy
Document Type:
Dissertation
Date of Defense:
October 02, 2007
Committee Members:
  • John Elliot Beard, Committee Chair
  • Byron C Jones, Committee Member
  • Rebecca L Corwin, Committee Member
  • James Robert Connor, Committee Member
Keywords:
  • iron deficiency
  • norepinephrine
  • dopamine
  • microdialysis
  • brain
Abstract:
Iron is vital for proper neuronal functioning and development. Deficiencies in this nutrient can result in decreased DA clearance, transporter density, and in dopamine (D1 and D2) receptor densities. These studies were designed to examine the relationship between iron deficiency and diurnal cycle on catecholaminergic systems. Through the use of in vivo microdialysis we have demonstrated several novel findings regarding iron deficiency and catecholamines in vivo as well as extended our knowledge regarding the impact of iron deficiency. The first aim was designed to probe the interaction between iron deficiency and the functionality on the link between the D2 receptor and the dopamine transporter. Using the D2R agonist quinpirole coupled with the no net flux protocol we found that the synthetic pathway through protein kinase A was not altered by iron deficiency, however, the protein kinase C (PKC) pathway which upregulates transport was compromised. These findings indict the PKC signal transduction pathway as a potential target for the influence of iron deficiency on catecholaminergic systems and a site for future work. The second aim focused on the interaction of L-DOPA and iron deficiency on monoamine metabolism. We observed that L-DOPA administration to ID rats favored the synthesis of norepinephrine (NE) while also resulting in a blunted dopamine (DA) response. Additionally, tissue concentrations of NE along with increased dopamine-beta-hydroxylase activity were also observed indicating that iron deficiency also alters the noradrenergic system. This has potential ramifications in iron deficient patients who are prescribed L-DOPA as the efficacy of the drug may be compromised. The third aim was designed to examine the effects of iron deficiency on diurnal extracellular catecholamines and behavior. We found that iron deficiency resulted in increased DA concentration but decreased NE concentration at the onset of the dark cycle. This indicates that diurnal regulation of synthesis or release is altered by iron deficiency. Although the exact mechanism for these findings is unknown most likely iron deficiency results in a dysregulation of DƒÒH activity. Additionally, we also found that in the forty five minutes prior to onset of the light cycle (transition to inactive phase) stereotypy is also increased in ID rats. This is interesting as it corresponds to the complaints of increased symptoms before bed in restless legs syndrome (RLS) patients. The fourth aim focused on the effects of iron infusion into the ventral midbrain vs the striatum. In this experiment, we attempted to remediate DA functioning in the striatum by rescuing iron status in the VMB (cell bodies) or the ST (terminal fields) by iron infusion. We found that VMB but not striatal infusion ameliorated defects in extracellular DA and intracellular DA. Additionally, infusion into the VMB also corrected the deficits in the D2R ¡V DAT linkage reported in aim 1. Finally, we examined how iron deficiency altered diurnal and sex effects in the dopaminergic system of a genetically inbred strain of mice. First, we found a sex by diet effect in the striatal concentrations of NE and HVA. We also measured DA efflux by infusion of amphetamine and again found an effect of time of day, diet, and sex with increased DA overflow in ID female mice in the morning. These results confirm the hints in the literature regarding a differential effect of ID in males vs females. Thus, this is clear evidence that female subjects must also be considered in future work. These findings are very important given the relationship between iron deficiency, dopamine, and restless legs syndrome. They serve to further our understanding of the impact of iron deficiency in catecholaminergic systems in the brain.