COMPARISON OF THE EFFECTS OF 2 1-METHYL-4-PHENYL-1,2,3,6-TETRAHYDROPYRIDINE ANALOGS, 1-METHYL-4-(2-THIENYL)-1,2,3,6-TETRAHYDROPYRIDINE AND 1-METHYL-4-(3-THIENYL)-1,2,3,6-TETRAHYDROPYRIDINE, ON MONOAMINE-OXIDASE INVITRO AND ON DOPAMINE IN MOUSE-BRAIN

  • 1 February 1987
    • journal article
    • research article
    • Vol. 240  (2) , 415-420
Abstract
1-Methyl-4-(2-thienyl)-1,2,3,6-tetrahydropyridine (2-MTTP) and 1-methyl-4-(3-thienyl)-1,2,3,6-tetrahydropyridine were compared with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) with respect to their interactions with MOA (monoamine oxidase) in vitro and their ability to produce persistent depletion of striatal dopamine and its metabolites, 3,4-dihydroxyphenylacetic acid and homovanillic acid, in mice. Both 2-MTTP and 1-methyl-4-(3-thienyl)-1,2,3,6-tetrahydropyridine were like MPTP in being potent, competitive inhibitors of MAO-A (MAO type A) and weak, noncompetitive inhibitors of MAO-B (MAO type B) in vitro. 2-MTTP resulted in persistent depletion of striatal dopamine, 3,4-dihydroxyphenylacetic acid and homovanillic acid 1 week after the last of four daily injections to mice although 2-MTTP was less than one-fourth as potent as MPTP. The other isomer, 1-methyl-4-(3-thienyl)-1,2,3,6-tetrahydropyridine, failed to deplete dopamine or its metabolites in mouse striatum. Dopamine and its metabolites were also depleted in mouse nucleus accumbens by 2-MTTP and by MPTP; however, norepinephrine in frontal cortex was depleted by MPTP but not by 2-MTTP. The depletion of dopamine, 3,4-dihydroxyphenylacetic acid and homovanillic acid by 2-MTTP was prevented by pretreatment with deprenyl, a selective inhibitor of MAO-B, or with EXP 561, a dopamine uptake inhibitor, just as the depletion by MPTP was prevented. Mouse brain MAO oxidized 2-MTTP in vitro less rapidly than it oxidized MPTP; deprenyl was a potent inhibitor of the oxidation of both substrates, suggesting that MAO-B oxidizes both 2-MTTP and MPTP. The oxidation of 1-methyl-4-(3-thienyl)-1,2,3,6-tetrahydropyridine was slower and relatively insensitive to deprenyl, suggesting that MAO-B was not involved. These findings, revealed that 2-MTTP mimics MPTP in producing persistent depletion of striatal dopamine and its metabolites in mice, appear to be the first demonstration that replacement of the phenyl group of MPTP with a heterocycle can result in retention of neurotoxic effects on striatal dopamine neurons.