The divalent metal transporter 1 (DMT1) is a major iron transporter required for 
iron absorption and erythropoiesis. Loss of DMT1 function results in microcytic 
anemia. While iron plays an important role in neural function, the behavioral 
consequences of DMT1 deficiency are largely unexplored. The goal of this study 
was to define the neurobehavioral and neurochemical phenotypes of homozygous 
Belgrade (b/b) rats that carry DMT1 mutation and explore potential mechanisms of 
these phenotypes. The b/b rats (11-12 weeks old) and their healthy littermate 
heterozygous (+/b) Belgrade rats were subject to elevated plus maze tasks. The 
b/b rats spent more time in open arms, entered open arms more frequently and 
traveled more distance in the maze than +/b controls, suggesting increased 
impulsivity. Impaired emotional behavior was associated with down-regulation of 
GABA in the hippocampus in b/b rats. Also, b/b rats showed increased GABAA 
receptor α1 and GABA transporter, indicating altered GABAergic function. 
Furthermore, metal analysis revealed that b/b rats have decreased total iron, 
but normal non-heme iron, in the brain. Interestingly, b/b rats exhibited 
unusually high copper levels in most brain regions, including striatum and 
hippocampus. Quantitative PCR analysis showed that both copper importer copper 
transporter 1 and exporter copper-transporting ATPase 1 were up-regulated in the 
hippocampus from b/b rats. Finally, b/b rats exhibited increased 8-isoprostane 
levels and decreased glutathione/glutathione disulfide ratio in the hippocampus, 
reflecting elevated oxidative stress. Combined, our results suggest that copper 
loading in DMT1 deficiency could induce oxidative stress and impair GABA 
metabolism, which promote impulsivity-like behavior. Iron-copper model: 
Mutations in the divalent metal transporter 1 (DMT1) decrease body iron status 
and up-regulate copper absorption, which leads to copper loading in the brain 
and consequently increases metal-induced oxidative stress. This event disrupts 
GABAergic neurotransmission and promotes impulsivity-like behavior. Our model 
provides better understanding of physiological risks associated with imbalanced 
metal metabolism in mental function and, more specifically, the interactions 
with GABA and redox control in the treatment of emotional disorders.