Pre- and postsynaptic neurotoxic effects of dopamine demonstrated by intrastriatal injection

Considerable evidence indicates that dopamine (DA) may play a neurotoxic role in brain in certain pathologic circumstances. To investigate this issue, dopamine (1000 nmol/1 microliter) was directly injected into the striatum of anesthetized Sprague-Dawley rats. Control animals received equal-volume injections of gamma-aminobutyric acid (GABA) or NaCl at identical concentrations (diluted in distilled H2O, pH 7.0-7.7). Brains were removed 7 to 9 days later and frozen or fixed and sectioned for histologic and autoradiographic analysis. Dopamine injection resulted in a small-volume (3.3-mm3) lesion in comparison to control GABA and NaCl injections which produced only a needle track < 0.6 mm3 in volume (P < 0.01). Dose dependency of DA toxicity was demonstrated, with substantial parenchymal damage requiring an injection of 500 nmol/1 microliter. Within the lesion, marked neuronal loss, macrophage invasion, and capillary and glial proliferation were present. Acetylcholinesterase staining and D1 receptor binding were markedly reduced as well. [3H]RO5-4864 binding to peripheral benzodiazepine receptors (on astrocytes) was increased in the periphery of the lesion. The binding of 1-[3H]benzo[b]cyclohexylthiophenylpiperidine to dopamine uptake sites was also reduced, but over a wider striatal area in comparison to local parenchymal damage. Prior interruption of the dopaminergic nigrostriatal pathway (by injection of 6-hydroxydopamine) appeared to potentiate the toxicity of intrastriatal dopamine injection. The findings indicate that local injection of dopamine produces both post- and presynaptic damage to nigrostriatal structures, and support the contention that dopamine may act as a low-potency neurotoxin.