Bimodal induction of dopamine-mediated striatal neurotoxicity is mediated through both activation of D1 dopamine receptors and autoxidation

Striatal neurodegeneration occurs through unknown mechanisms in certain neurodegenerative disorders characterized by increased and sustained synaptic levels of dopamine (DA). Treatment of rat primary striatal neurons with DA causes profound neurotoxicity, with increased production of free radicals and accelerated neuronal death. DA effects were partly reduced by the antioxidant sodium metabisulfite (SMBS), and the D1 DA receptor antagonist, SCH 23390, and were completely blocked upon co-treatment with SMBS and SCH 23390. Part of DA effects were mimicked by either H2O2, or by the D1 agonist, SKF R-38393, indicating the existence of two distinct signaling pathways through which the neurotoxicity of DA is manifest. DA effects did not proceed through D2-like DA or beta-adrenergic receptor signaling pathways. The D1 receptor-mediated and the autoxidative pathways of DA neurotoxicity converge to cause activation and/or increased synthesis of neuronal and inducible, but not endothelial, nitric oxide synthase (NOS). The reduction of DA striatal neurotoxicity through blockade of D1 DA receptors, suggests novel therapeutic approaches in the management of striatal neurodegeneration. (C) 2003 Elsevier Inc. All rights reserved.