Neurotoxicity of MPTP and Uptake of MPPT into Dopamine and Norepinephrine Neurons in Mice

Abstract

We have earlier demonstrated that 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) produces a direct toxicity on DA neurons in the substantia nigra (SN) and norepinephrine (NE) neurons in the locus coeruleus (LC) other than in the terminals. These results suggest that DA neurons in the SN and NE neurons in the LC are possibly able to uptake MPP+ through the DA and NE uptake systems, respectively, presumably via DA and NE dendrites. The present study examined this hypothesis. Adult male BALB/c mice were used. In the first part, animals received various combinations of nomifensine (NOM, a specific DA uptake blocker) and MPTP treatment. NOM was infused to the SN or striatum at 1.5 μg and 3.0 μg per day for a total of seven days. The infusion volume was 0.25 and 0.5 μl, respectively. MPTP was given systemically (IP) at 30 mg/kg per day for a total of seven days. On each day, NOM was given 30 min prior to MPTP injection. In the second part, animals received the same combinations of desimipramine (DMI, a specific NE uptake blocker) and MPTP treatments. DMI was infused to the LC and hippocampus at 1.25 μg and 2.5 μg per day 30 min before MPTP injection for a total of 7 days. The volumes of infusion were 0.25 μl in the LC and 0.5 μl in the hippocampus. Animals were subject to locomotor activity test 7 days after the last MPTP, MPP+ (saline) injections. They were then sacrificed and brain tissues of the striatum and hippocampus were subject to DA and NE analyses with HPLC fluorescence detection. Results indicated that MPTP consistently and markedly decreased DA level in the striatum and NE level in the hippocampus. It also impaired locomotor activity and produced long-lasting tremor in mice. NOM pretreatment in the striatum completely prevented MPTP’s toxicity, while NOM pretreatment in the SN only partially, but significantly, prevented MPTP’s toxicity on both DA and motor activity.