SELECTIVE LESIONS BY MANGANESE AND EXTENSIVE DAMAGE BY IRON AFTER INJECTION INTO RAT STRIATUM OR HIPPOCAMPUS

Regional Ca-45(2+) accumulation and analysis of monoamines and metabol ites in dissected tissues were used to localize, quantify, and charact erize brain damage after intracerebral injections of Mn2+ into striatu m and hippocampus. The specificity of Mn2+-induced lesions is describe d in relation to brain damage produced by local Fe2+ or 6-hydroxydopam ine (6-OHDA) injections. In striatum, Fe2+ and Mn2+ produced dose-depe ndent (0.05-0.8 mu mol) dopamine (DA) depletion, with Fe2+ being 3.4 t imes more potent than Mn2+. Studies examining the time course of chang es in monoamine levels in striatum following local application of 0.4 mu mol of Mn2+ revealed maximal depletion of all substances investigat ed (except 5-hydroxyin-doleacetic acid) after 3 days. The effects on D A (87% depletion at day 3) and its major metabolites were most pronoun ced and lasted until at least 90 days (40% depletion), whereas seroton in and noradrenaline levels recovered within 21 and 42 days, respectiv ely. In addition, levels of 3-methoxytyramine, which is used as an ind ex of DA release, also recovered within 42 days, indicating a function al restoration of DA neurotransmission despite substantial loss of DA content. Intrastriatal Mn2+ (0.4 mu mol) produced time-dependent Ca-45 (2+) accumulation in striatum, globus pallidus, entopeduncular nucleus , several thalamic nuclei, and substantia nigra pars reticulata ipsila teral to the injection site. In contrast, 6-OHDA injected at a dose eq uipotent in depleting DA produced significantly less Ca-45(2+) accumul ation in striatum and globus pallidus and no labeling of other brain a reas, whereas Fe2+ (0.4 mu mol) produced extensive Ca-45(2+) accumulat ion throughout basal ganglia, accumbens, and cerebral cortex. In hippo campus, high Mn2+ (0.4 mu mol) produced limited Ca-45(2+) accumulation in subiculum and dentate gyrus, whereas low Fe2+ (0.1 mu mol) produce d widespread Ca-45(2+) accumulation throughout hippocampus, thalamus, and cerebral cortex. It is concluded that (a) Mn2+ is selectively neur otoxic to pathways intrinsic to the basal ganglia, (b) intrastriatal i njections can be used as a model for systemic Mn2+ intoxications, and (c) high endogenous Fe3+ and/or catecholamine levels potentiate the ne urotoxicity of Mn2+.