Comparison of 1-methyl-4-(p-chlorophenyl)-1,2,3,6-tetrahydropyridine, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and p-chloroamphetamine as monoamine depletors.

1-Methyl-4-(p-chlorophenyl)-1,2,3,6-tetrahydropyridine (PC-MPTP) failed to mimic the effects of MPTP in producing persistent depletion of striatal dopamine and its metabolites in mice one week after the last of four daily doses. MPTP was given at 20 mg/kg, whereas PC-MPTP was given at doses up to 80 mg/kg. In rats, p-chloroamphetamine (PCA) given in a single dose of 0.1 mmole/kg (20.6 mg/kg) i.p. caused marked depletion of hypothalamic serotonin and 5-hydroxyindoleacetic acid (5HIAA) concentration at 6 hrs, and the depletion persisted at 1 day and at 1 week. In contrast, PC-MPTP given at an equimolar dose failed to affect either serotonin or 5HIAA concentration at these times. Apparently the addition of a p-chloro substituent to MPTP eliminates its neurotoxicity to striatal dopamine neurons, and replacement of the aminoisopropyl side chain of PCA with a 1-methyl-1,2,3,6-tetrahydropyridin-4-yl group eliminates its neurotoxicity to brain serotonin neurons.