Naunyn-Schmiedeberg's Archives of Pharmacology

, Volume 304, Issue 2, pp 111–123 | Cite as

Inhibition of the in vivo biosynthesis and changes of catecholamine levels in rat brain after α-methyl-p-tyrosine; time- and dose-response relationships

  • E. Widerlöv
  • T. Lewander


Male Sprague-Dawley rats were given 0.407 mmoles/kg of D,l-α-methyl-p-tyrosine methylester HCl (H44/68; α-MT) at eleven time-points between 0–24h, or 8 doses between 0.013–1.628 mmoles/kg of the drug at 1 h before i. v. injection of 160 μCi tyrosine-2,6-3H. The rats were killed 15 min after tyrosine-3H and brain α-MT, tyrosine and catecholamines (endogenous and labelled), and plasma α-MT and tyrosine (-3H) were chromatographically isolated before being assayed spectrophotofluorimetrically (endogenous) or by liquid scintillation methods (labelled compounds).

A delayed penetration of α-MT from plasma into brain, different elimination rates of α-MT in plasma and brain, and decreasing brain/plasma drug concentration on increasing α-MT dosages indicated, that α-MT in brain and plasma belong to different pharmacokinetic compartments.

The endogenous levels of catecholamines in the time-response experiment, declined to a minimum 4 h after α-MT administration, where the dopamine level was 38% and the noradrenaline level 51% of the saline controls. Kinetic data of the catecholamine elimination is given. In the dose-response experiment the decrease in the endogenous catecholamine levels was doserelated up to 0.407 mmoles/kg of α-MT, with no further decline on higher doses.

The maximal inhibition of brain catecholamine synthesis occurred within 30 min after α-MT administration and the inhibition correlated better with the brain than with plasma α-MT content. The inhibition was dose-related with a maximal synthesis inhibition of 95% for dopamine and 80% for noradrenaline at the highest dose of α-MT. The duration of synthesis inhibition and storage depletion were shorter for noradrenaline (12 h) than for dopamine (16 h). Further, the ED50 for synthesis inhibition of dopamine (0.057 mmoles/kg) was half of the ED50 for synthesis inhibition of noradrenaline (0.117 mmoles/kg). This might suggest different sensitivities towards α-MT or different availabilities of α-MT in the two neuron populations.

At the three highest doses of α-MT there were signs of interference with the uptake process for tyrosine from plasma into the brain. This was indicated by increased plasma levels and decreased brain levels of tyrosine (-3H).

Key words

α-Methyltyrosine Brain Catecholamines Dose-response Time-response 


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Copyright information

© Springer-Verlag 1978

Authors and Affiliations

  • E. Widerlöv
    • 1
  • T. Lewander
    • 1
  1. 1.Psychiatric Research CenterUniversity of Uppsala, Ulleråker HospitalUppsalaSweden

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