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 Mn(2+)-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 mumol) 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 mumol of Mn2+ revealed maximal depletion of all substances investigated (except 5-hydroxyindoleacetic 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 mumol) 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 mumol) produced extensive 45Ca2+ accumulation throughout basal ganglia, accumbens, and cerebral cortex. In hippocampus, high Mn2+ (0.4 mumol) produced limited 45Ca2+ accumulation in subiculum and dentate gyrus, whereas low Fe2+ (0.1 mumol) 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+.