Central and peripheral catecholamine depletion by 1-methyl-4-phenyl-tetrahydropyridine (MPTP) in rodents.
1-Methyl-4-phenyl-tetrahydropyridine (MPTP) given in single doses to rats depleted norepinephrine concentration in heart and mesenteric artery but had little effect on catecholamine concentration in brain. MPTP did not share with amphetamine the ability to cause persistent depletion of striatal dopamine in iprindole-treated rats. Administration of MPTP via osmotic minipumps implanted s.c. for 24 hrs after a loading dose of MPTP in rats resulted in depletion of striatal dopamine and its metabolites one week later. MPTP in vitro was a reasonably potent, competitive and reversible inhibitor of MAO-A (monoamine oxidase type A). MPTP appeared to inhibit MAO-A in rat brain in vivo as determined by its antagonism of the inactivation of MAO-A by pargyline and by its antagonism of the increase in dopamine metabolites resulting from the administration of Ro 4-1284, a dopamine releaser. The inhibition of MAO-B by MPTP in vitro was noncompetitive, time-dependent, and not fully reversed by dialysis, consistent with the findings of others that MPTP is acted upon by MAO-B. In mice, four successive daily doses of MPTP is acted upon by MAO-B. In mice, four successive daily doses of MPTP given s.c. resulted in marked depletion of dopamine and its metabolites one week later, and the depletion of dopamine was completely prevented by pretreatment with deprenyl, which inhibited MAO-B but not MAO-A. These and other studies in rodents may help in elucidating the mechanisms involved in the destructive effects of MPTP on striatal dopamine neurons that lead to symptoms of Parkinson's disease in humans and in monkeys.
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D007488:Iprindole / Q000494:pharmacology; D051379:Mice; D008995:Monoamine Oxidase / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism*; D011725:Pyridines / Q000633:toxicity*; D051381:Rats
D011725:Pyridines; D007488:Iprindole; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000661:Amphetamine; D008995:Monoamine Oxidase; D004298:Dopamine; D009638:Norepinephrine