Iron deficiency (ID) in early life is known to alter neurological development and functioning, but data regarding specific effects on dopamine biology are lacking. The objective of this study was to determine the extent of functional alterations in dopamine receptors in two dopaminergic tracts in young, growing, iron-deficient rats. Forty male and 40 female weanling Sprague-Dawley rats were fed either an iron-deficient (ID) diet or control (CN) diet for 6 weeks. ID decreased densities of D(1) and D(2) receptors in the caudate-putamen and decreased D(2) receptor densities in the nucleus accumbens. There were no apparent effects of ID on the affinities for the ligands in either receptor in several brain regions. In situ hybridization studies for both dopamine receptors revealed no significant effect of ID on mRNA expression for either receptor. Iron-deficient rats had a significantly higher ED(50) for raclopride-induced hypolocomotion in male and female rats compared to control rats of each sex. The loss of iron in the striatum due to dietary ID was significantly correlated with the decrease in D(2) receptor density; however, this relationship was not apparent in other brain regions. These experiments thus demonstrate abnormal dopamine receptor density and functioning in several brain regions that are related to brain regional iron loss. Importantly, the impact of ID on dopamine was more pronounced in males than females, demonstrating sex-related different sensitivities to nutrient deprivation.

Iron deficiency anemia in early life produces profound changes in both in vivo and in vitro evaluations of dopamine (DA) functioning. This study employed both behavioral and biochemical approaches to examine the biological bases of alterations in striatal DA metabolism seen in iron-deficient rats. The purpose was to determine whether the DA transporter (DAT) was functionally altered in postweaning iron deficiency. Male and female 21-d-old Sprague-Dawley rats (n = 40) were fed either an iron-deficient (ID) diet (3 mg Fe/kg diet) or a control (CN) diet (35 mg Fe/kg diet) for 4 wk before behavioral testing. Motor activity responses to graded doses (3.75-30 mg/kg body) of the DA uptake inhibitor, cocaine, were significantly blunted in iron-deficient rats with a 50% higher half-maximal effective dose (ED(50)) in both males and females (CN-female, 7.1 +/- 0.9 mg/kg; ID-female, 11.2 +/-1.3 mg/kg; CN-male, 12.0 +/- 0.7 mg/kg; and ID-male, 17.0 +/- 1.8 mg/kg). Radioligand binding assays with (3)H-1-(2-(diphenylmethoxy)-ethyl)-4-(3-phenylpropyl) piperazine ((3)H-GBR12935) demonstrated that iron deficiency did not alter the affinity of the ligand for the DAT but did significantly decrease the density of the transporter by 30% in caudate putamen and 20% in nucleus accumbens. Iron deficiency also significantly decreased (3)H-DA uptake into striatal synaptosomes, but did not affect release of DA with potassium chloride stimulation. These experiments provide supporting evidence that elevated levels of extracellular DA in the striatum of iron-deficient rats is likely to be the result of decreased DAT functioning and not increased rates of release.

The location and function of iron in the central nervous system are reviewed with particular emphasis on human biology. Iron is distributed to different cell types in the brain in a heterogeneous fashion through the action of transferrin, transferrin receptors, and the metabolic needs of those cells. The function of this iron and its storage is documented in states of growth and development as well as during pathological states associated with aging. The information relating this biology to current observations of attention deficits in iron‐deficient humans is also reviewed.

CPA is a reliable and sensitive index of the aversive motivational state accompanying withdrawal from acute opioid dependence.

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