Preweaning manganese exposure causes hyperactivity, disinhibition, and spatial learning and memory deficits associated with altered dopamine receptor and transporter levels

Epidemiological studies in children have reported associations between elevated dietary manganese (Mn) exposure and neurobehavioral and neurocognitive deficits. To better understand the relationship between early Mn exposure and neurobehavioral deficits, we treated neonate rats with oral Mn doses of 0, 25, or 50 mg Mn/kg/day over postnatal day (PND) 1-21, and evaluated behavioral performance using open arena (PND 23), elevated plus maze (PND 23), and 8-arm radial maze (PND 33-46) paradigms. Brain dopamine D1 and D2-like receptors, and dopamine transporter (DAT) densities were determined on PND 24, and blood and brain Mn levels were measured to coincide with behavioral testing (PND 24, PND 36). Preweaning Mn exposure caused hyperactivity and behavioral disinhibition in the open arena, but no altered behavior in the elevated plus maze. Manganese-exposed males committed significantly more reference and marginally more working errors in the radial arm maze compared to controls. Fewer Mn exposed males achieved the radial maze learning criterion, and they required more session days to reach it compared to controls. Manganese-exposed animals also exhibited a greater frequency of stereotypic response strategy in searching for the baited arms in the maze. These behavioral and learning deficits were associated with altered expression of the dopamine D1 and D2 receptors and the DAT in prefrontal cortex, nucleus accumbens, and dorsal striatum. These data corroborate epidemiological studies in children, and suggest that exposure to Mn during neurodevelopment significantly alters dopaminergic synaptic environments in brain nuclei that mediate control of executive function behaviors, such as reactivity and cognitive flexibility.