Studies on the mechanism of depletion of striatal dopamine by alpha-methyl-m-tyrosine.
These experiments were designed to study the mechanism of depletion of dopamine (DA) in the striatum produced by alpha-methyl-m-tyrosine (alpha-MMT). alpha-Methyl-m-tyramine (alpha-MMTA), the metabolite of alpha-MMT, appears to be the active DA-depleting agent, since the administration of a decarboxylase inhibitor before alpha-MMT markedly reduced both the formation of alpha-MMTA and the depletion of DA. After injection of alpha-MMT (100 mg/kg i.p.), the striatal concentration of homovanillic acid (HVA) rose by 41% at 1 hour. This is probably due to an increase in DA metabolism, since alpha-MMT markedly enhanced the decline of DA produced by alpha-methyl-p-tyrosine (alpha-MPT). At 2, 3 and 4 hours after alpha-MMT, the concentration of HVA and dihydroxyphenylacetic acid was below control level. The decrease in dihydroxyphenylacetic acid is due partially to a decreased formation of dihydroxyphenylacetic acid from DA. In striatal slices, both alpha-MMT and alpha-MMTA decreased the formation of 3H-H2O and the accumulation of 3H-DA from 1-3,5-3H-tyrosine. Alpha-MMT did not alter the specific activity of 3H-tyrosine or release 3H-DA from the slices, but it did inhibit the activity of tyrosine hydroxylase in striatal homogenates at low concentrations of tyrosine (10 muM). Alpha-MMTA released both newly synthesized and exogenously accumulated 3H-DA from striatal slices. At low concentrations of alpha-MMTA, the percent reduction in 3H-H2O was much greater than the percentage of 3H-DA released into the medium. However, at higher concentrations, the inhibition of 3H-H2O reached a maximum while 3H-DA release kept increasing. These results suggest that both inhibition of tyrosine hydroxylase activity and DA release from storage sites by alpha-MMTA may account for the depletion of DA produced by the injection of alpha-MMT.
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D001545:Benserazide / Q000494:pharmacology; D001958:Brocresine / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D006719:Homovanillic Acid / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D008781:Methyltyrosines / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D013997:Time Factors; D014443:Tyrosine / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D010136:p-Hydroxyamphetamine / Q000378:metabolism
D008781:Methyltyrosines; D015102:3,4-Dihydroxyphenylacetic Acid; D001958:Brocresine; D014443:Tyrosine; D001545:Benserazide; D014446:Tyrosine 3-Monooxygenase; D010136:p-Hydroxyamphetamine; D004298:Dopamine; D006719:Homovanillic Acid