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

Abstract

Male Sprague-Dawley rats were given 0.407 mmoles/kg of D,L-alpha-methyl-p-tyrosine methylester HCl (H44/68; alpha-MT) at eleven time-points between 0--24 h, or 8 doses between 0.013--1.628 mmoles/kg of the drug at 1 h before i.v. injection of 160 micronCi tyrosine-2,6-3H. The rats were killed 15 min after tyrosine-3H and brain alpha-MT, tyrosine and catecholamines (endogenous and labelled), and plasma alpha-MT and tyrosine (--3H) were chromatographically isolated before being assayed spectrophotofluorimetrically (endogenous) or by liquid scintillation methods (labelled compounds). A delayed penetration of alpha-MT from plasma into brain, different elimination rates of alpha-MT in plasma and brain, and decreasing brain/plasma drug concentration on increasing alpha-MT dosages, indicated, that alpha-MT in brain and plasma belong to different pharmacokinetic compartments. The endogenous levels of catecholamines in the time-response experiments, declined to a minimum 4 h after alpha-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 dose-related up to 0.407 mmoles/kg of alpha-MT, with no further decline on higher doses. The maximal inhibition of brain catecholamine synthesis occurred within 30 min after alpha-MT administration and the inhibition correlated better with the brain than with plasma alpha-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 alpha-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 alpha-MT or different availabilities of alpha-MT in the two neuron populations. At the three highest doses of alpha-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).