Toxic influence of subchronic paraquat administration on dopaminergic neurons in rats

Abstract

Paraquat is a toxin suggested to contribute to pathogenesis of Parkinson’s disease. The aim of the present study was to examine toxic influence of subchronic treatment with this pesticide (5 days, one injection per day, 2–3 days of withdrawal) on dopaminergic, serotonergic, noradrenergic and GABAergic neurons. Paraquat decreased the number of tyrosine hydroxylase-immunoreactive (TH-ir) neurons in the substantia nigra by 22% (measured 3 days after withdrawal). Two days after withdrawal the levels of the dopamine metabolites and dopamine turnover in the caudate–putamen, substantia nigra and prefrontal cortex were reduced by ca. 20–60%, and the binding of [3H]GBR 12,935 to dopamine transporter dropped by 25–40% in the caudate–putamen. Three days after paraquat withdrawal, the level of dopamine in the caudate–putamen was significantly increased, and earlier decreases in DOPAC and HVA in the substantia nigra, as well as [3H]GBR 12,935 binding in the caudate–putamen were reversed. Moreover, an increase in serotonin turnover in the caudate–putamen and prefrontal cortex, and noradrenaline level in the former structure was observed 2–3 days after paraquat withdrawal. Three days after the last paraquat injection 24–35% decreases in the proenkephalin mRNA levels and 5–7% reduction in glutamic acid decarboxylase (GAD)67 mRNA were found in the caudate–putamen. The present study suggests that subchronic paraquat administration triggers processes characteristic of early stages of dopaminergic neuron degeneration, and activates compensatory mechanisms involving dopaminergic, noradrenergic, serotonergic and GABAergic transmissions.