Central nervous system toxicity of manganese: Mechanism of manganese concentration in the ventral mesencephalon

Abstract

In the lateral choroid plexus, Mn was sequestered from the blood against a concentration gradient. Intrathecal administration of Mn²⁺ showed that the choroid plexus does not remove Mn from the cerebrospinal fluid and that intrathecal Mn²⁺ rapidly caused neurological abnormalities. Either 1 or 2 mg Mn²⁺/kg intrathecally resulted one day after dosage in a 91% and 95% decrease in the spontaneous motor activity of rats, respectively. Control activity was unchanged by intrathecal NaCl. Five days after administration, dopamine was decreased 70%; and Mn in the ventral mesencephalon was increased 14-fold as compared to controls. Mn in the central nervous system reached a maximum and dopamine reached a minimum 6 hours after 250 μg Mn²⁺/rat, intrathecally. The ventral mesencephalon contained more Mn than any other brain region (p < 0.001). Neurotransmitter reuptake carriers were inhibited in an effort to reduce the Mn concentration in the CNS. To inhibit neurotransmitter reuptake, rats were given cocaine i.p. and later Mn intrathecally. Mn²⁺ caused the ventral mesencephalon Mn concentration to increase from 0.57 μg/g to 31.8 μg/g. Cocaine prior to Mn decreased the concentration from 31.8 μg/g to 3.3 μg/g. To decrease neurotransmitter concentration, rats were given reserpine i.p. and later Mn intrathecally. Mn2+ caused the ventral mesencephalon Mn concentration increased from 0.77 μg/g to 29.9 μg/g. Reserpine prior to Mn decreased the concentration from 29.9 μg/g to 3.7 μg/g. Cocaine or reserpine decreased the Mn concentration in the occipital pole, frontal lobe and caudate putamen but not in the cerebellum. Manganese, cocaine or reserpine decreased the dopamine concentration in the caudate putamen from 10.5 to 6.3, 4.1 or 0.8 μg/g, respectively. The results suggest that intrathecal Mn²⁺ can rapidly cause dopaminergic specific neurotoxicity resulting in: (1) decreased spontaneous motor activity, (2) increased Mn concentration in the ventral mesencephalon and (3) decreased dopamine concentration in the caudate putamen. Mn concentration in the CNS is related to neurotransmitter uptake carriers since inhibiting reuptake or reducing concentrations of neurotransmitters resulted in decreased Mn concentrations in many brain regions.