Overactive dopaminergic neurons in the brain are thought to plan an important role in the etiology of schizophrenia. It has been hypothesized that prolonged exposure of catecholamine neurons to excessive levels of dopamine or the oxidative metabolites of dopamine may produce neuronal damage and cell death and be partially responsible for some of the negative symptoms of schizophrenia. We are evaluation the neurotoxic effects of dopamine by using a clonal catecholaminergic cell line isolated from the CNS of the mouse (CATH.a cells). Dopamine produces a time and dose dependent increase in cell death in CATH.a cells. Cell death also occurred after treatment with other catecholamines, as well as the neurotoxic compounds, 6-hydroxydopamine and nitric oxide. Cell death is not receptor mediated since selective noradrenergic and dopaminergic receptor agonists had no effect on CATH.a cell viability. Dopamine induces apoptotic cell death as indicated by DNA fragmentation measured by gel electrophoresis and by flow cytometric analysis. Apoptosis appears to be produced by dopamine autoxidation, since intracellular perodixes increase after dopamine treatment and this increase in peroxides and cell death can both be inhibited by catalase and n-acetylcysteine. Superoxide dismutase appears to be important in the detoxification of dopamine's oxidative metabolites since an inhibitor of this enzyme, diethycarbamate, potentiates both dopamine induced cell death and cell death produced by the superoxide generator, dihydroxyfumarate. Dopamine also decreased the levels of a number of cellular components that help protect cells from free radicals, including superoxide dismutase, glutathione and the antioxidant protein, bcl-2. In addition, antisense to bcl-2 increased the sensitivity of CATH.a cells to dopamine induced cell death. In an attempt to define the cellular pathway for dopamine-induced cell death in CATH.a cells, we found a selective decrease in the mitochondrial membrane potential in CATH.a cells within four hours after the addition of dopamine to the media. These findings indicate that the oxidative products if dopamine cause neurotoxicity through apoptosis in the CATH.a cell line and this may be through a selective action on mitochondria.
