Norepinephrine loss selectively enhances chronic nigrostriatal dopamine depletion in mice and rats

In this study we investigated whether a selective pattern of norepinephrine loss potentiates methamphetamine-induced striatal dopamine depletion in rats. We also evaluated whether chronic norepinephrine depletion reduces the threshold dose of methamphetamine necessary to induce long-lasting striatal dopamine loss in mice and in rats. Pre-treatment with the selective noradrenergic neurotoxin DSP-4 (50 mg/kg, i.p.) in mice and in rats significantly enhanced methamphetamine-induced striatal dopamine depletion. Administration of a low dose of methamphetamine (1 x 5 mg/kg and 3 x 5 mg/kg, respectively, i.p., at 2-h interval) to C57B1/6N mice and Sprague-Dawley rats did not decrease striatal dopamine levels when injected alone but produced a significant decrease in striatal dopamine when given to rodents carrying a long-lasting norepinephrine depletion previously induced by DSP-4. Our results suggest that norepinephrine loss might both enhance neurotoxic damage and decrease the threshold for neurotoxicity to nigrostriatal dopaminergic neurons in different animal species.