Selective Lesions by Manganese and Extensive Damage by Iron After Injection into Rat Striatum or Hippocampus

Abstract: Regional ⁴⁵Ca²⁺ accumulation and analysis of monoamines and metabolites in dissected tissues were used to localize, quantify, and characterize brain damage after intracerebral injections of Mn²⁺ into striatum and hippocampus. The specificity of Mn²⁺-induced lesions is described in relation to brain damage produced by local Fe²⁺or 6-hydroxydopamine (6-OHDA) injections. In striatum, Fe²⁺ and Mn²⁺ produced dose-dependent (0.05-0.8 μmol) dopamine (DA) depletion, with Fe²⁺ being 3.4 times more potent than Mn²⁺. Studies examining the time course of changes in monoamine levels in striatum following local application of 0.4 μmol of Mn²⁺ revealed maximal depletion of all substances investigated (except 5-hydroxyin-doleacetic acid) after 3 days. The effects on DA (87% depletion at day 3) and its major metabolites were most pronounced and lasted until at least 90 days (40% depletion), whereas serotonin and noradrenaline levels recovered within 21 and 42 days, respectively. In addition, levels of 3-methoxytyramine, which is used as an index of DA release, also recovered within 42 days, indicating a functional restoration of DA neurotransmission despite substantial loss of DA content. Intrastriatal Mn²⁺ (0.4 μmol) produced time-dependent ⁴⁵Ca²⁺ accumulation in striatum, globus pallidus, entopeduncular nucleus, several thalamic nuclei, and substantia nigra pars reticulata ipsilateral to the injection site. In contrast, 6-OHDA injected at a dose equipotent in depleting DA produced significantly less ⁴⁵Ca²⁺ accumulation in striatum and globus pallidus and no labeling of other brain areas, whereas Fe²⁺ (0.4 μmol) produced extensive ⁴⁵Ca²⁺ accumulation throughout basal ganglia, accumbens, and cerebral cortex. In hippocampus, high Mn²⁺ (0.4 μmol) produced limited ⁴⁵Ca²⁺ accumulation in subiculum and dentate gyrus, whereas low Fe²⁺ (0.1 μmol) produced widespread ⁴⁵Ca²⁺ accumulation throughout hippocampus, thalamus, and cerebral cortex. It is concluded that (a) Mn²⁺ is selectively neurotoxic to pathways intrinsic to the basal ganglia, (b) intrastriatal injections can be used as a model for systemic Mn²⁺ intoxications, and (c) high endogenous Fe³⁺ and/or catecholamine levels potentiate the neurotoxicity of Mn²⁺.