Effects of N-substituted phenyltetrahydropyridines on cerebral high-affinity synaptosomal uptake of dopamine and other monoamines in several mammalian species

Abstract

Effects of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (N-methyl-PTP) and its N-propyl congener (N-propyl-PTP) on the high-affinity uptake of tritiated dopamine (DA), norepinephrine, and serotonin by striatal or cerebral cortical synaptosomes were evaluated in several species (rat, guinea pig, rabbit, calf, and man). Both compounds inhibited uptake of 0.1 ωM labeled amines at IC 50s of 5–10 ωM. Effects of N-methyl-PTP were competitive, reversible, somewhat more potent, and more selective for serotonin than were actions of N-propyl-PTP. Similar effects were found in all species. Neither agent inhibited binding of 3H-labeled spiperone or ADTN to DA receptor sites. 3H-N-methyl-PTP did not appear to be taken up selectively into DA neurons. N-methyl-PTP was highly toxic to the rat in doses that did not alter the metabolism of DA or serotonin in brain. These results, overall, do not provide strong support for the hypothesis that reported neurotoxic actions of N-methyl-PTP are mediated by neuron-specific local transport and intracellular accumulation, or account for species differences in the actions of this toxin, but do suggest interactions with brain monoamine neurons. The actions of the neurotoxic effects of N-methyl-PTP remain unclear.