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

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Summary

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).

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References

  • Andén, N. E., Corrodi, H., Fuxe, K.: Effect of neuroleptic drugs on central catecholamine turnover assessed using tyrosine- and dopamine-β-hydroxylase inhibitors. J. Pharm. Pharmacol. 24, 177–182 (1972)

    Google Scholar 

  • Atack, C. V.: The determination of dopamine by a modification of the dihydroxyindole fluorimetric assay. Br. J. Pharmacol. 48, 699–714 (1973)

    Google Scholar 

  • Barbeau, A.: Biochemistry of Huntington's chorea. In: Advances in Neurology, vol. 1. New York: Raven Press 1973

    Google Scholar 

  • Besson, M. J., Cherami, A., Glowinski, J.: Effects of some psychotropic drugs on dopamine synthesis in the rat striatum. J. Pharmacol. Exp. Ther. 177, 196–205 (1971)

    Google Scholar 

  • Beuthin, F. C., Miya, T. S., Blake, D. E., Bousquet, W. F.: Enhanced sensitivity to noradrenergic agonists and tolerance development to α-methyltyrosine in the rat. J. Pharmacol. Exp. Ther. 181, 446–456 (1972)

    Google Scholar 

  • Brodie, B. B., Costa, E., Dlabac, A., Neff, N. H., Smookler, H. H.: Application of steady state kinetics to the estimation of synthesis rate and turnover time of tissue catecholamines. J. Pharmacol. Exp. Ther. 154, 493–498 (1966)

    Google Scholar 

  • Brodie, H. K. H., Murphy, D. L., Goodwin, F. K., Bunney, W. E.: Catecholamines and mania: The effect of alpha-methyl-paratyrosine on manic behavior and catecholamine metabolism. Clin. Pharmacol. Ther. 12, 218–224 (1971)

    Google Scholar 

  • Bunney, B. S., Aghajanian, G. K.: Electrophysiological effects of amphetamine on dopaminergic neurons. In: Frontiers in Catecholamine Research, pp. 957–963. New York: Pergamon Press 1973

    Google Scholar 

  • Bunney, B. S., Aghajanian, G. K., Roth, R. H.: Comparison of effects of 1-dopa, amphetamine and apomorphine on firing rate of rat dopaminergic neurons. Nature New Biol. 245, 123–125 (1973a)

    Google Scholar 

  • Bunney, B. S., Walters, J. R., Roth, R. H., Aghajanian, G. K.: Dopaminergic neurons: Effect of antipsychotic drugs and amphetamine on single cell activity. J. Pharmacol. Exp. Ther. 185, 560–571 (1973b)

    Google Scholar 

  • Carlsson, A., Lindqvist, M.: Effect of chlorpromazine or haloperidol on formation of 3-methoxytyramine and normetanephrine in mouse brain. Acta Pharmacol. Toxicol. (Kbh.) 20, 140–144 (1963)

    Google Scholar 

  • Carlsson, A., Persson, T., Roos, B.-E., Wålinder, J.: Potentiation of phenothiazines by α-methyltyrosine in treatment of chronic schizophrenia. J. Neural Transm. 33, 83–90 (1972a)

    Google Scholar 

  • Carlsson, A., Kehr, W., Lindqvist, M., Magnusson, T., Atack, C. V.: Regulation of monoamine metabolism in the central nervous system. Pharmacol. Rev. 24, 371–384 (1972b)

    Google Scholar 

  • Carr, L. A., Moore, K. E.: Effects of reserpine and α-methyltyrosine on brain catecholamines and the pituitary-adrenal response to stress. Neuroendocrinology 3, 285–302 (1968)

    Google Scholar 

  • Chang, C. C.: A sensitive method for spectrophotofluorometric assay of catecholamines. Int. J. Neuropharmacol. 3, 643–649 (1964)

    Google Scholar 

  • Corrodi, H., Hanson, L. C. F.: Central effects of an inhibitor of tyrosine hydroxylation. Psychopharmacologia (Berl.) 10, 116–125 (1966)

    Google Scholar 

  • Costa, E.: Simple neuronal models to estimate turnover rate of noradrenergic transmitters in vivo. In: Biochemistry of simple neuronal models. Advances in Biochemical Psychopharmacology (E. Costa and E. Giacobini, eds.), Vol. 2. New York: Raven Press 1970

    Google Scholar 

  • Costa, E., Neff, N. H.: Isotopic and non-isotopic measurements of the rate of catecholamine biosynthesis. In: Biochemistry and pharmacology of the basal ganglia (E. Costa, L. J. Côté, and M. D. Yahr, eds.). New York: Raven Press 1966

    Google Scholar 

  • Dixon, W. J., Massey, F. J., Jr.: Introduction to statistical analysis. New York: McGraw-Hill Book Company 1969

    Google Scholar 

  • Dominic, J. A., Moore, K. E.: Acute effects of α-methyltyrosine on brain catecholamine levels and on spontaneous and amphetamine-stimulated motor activity in mice. Arch. Int. Pharmacodyn. 178, 166–176 (1969)

    Google Scholar 

  • Dost, F. H.: Grundlagen der Pharmakokinetik. Stuttgart: G. Thieme 1968

    Google Scholar 

  • Doteuchi, M., Wang, C., Costa, E.: Compartmentation of dopamine in rat striatum. Mol. Pharmacol. 10, 225–234 (1974)

    Google Scholar 

  • Engelman, K., Jéquier, E., Udenfriend, S., Sjoerdsma, A.: Metabolism of α-methyltyrosine in man: Relationship to its potency as an inhibitor of catecholamine biosynthesis. J. Clin. Invest. 47, 568–576 (1968)

    Google Scholar 

  • Fernstrom, J. D.: The effect of nutritional factors on brain amino acid levels and monoamine synthesis. Fed. Proc. 35, 1151–1156 (1976)

    Google Scholar 

  • Groves, P. M., Wilson, C. J., Young, S. J., Rebec, G. V.: Selfinhibition by dopaminergic neurons. Science 190, 522–529 (1975)

    Google Scholar 

  • Groves, P. M., Young, S. J., Wilson, C. J.: Self-inhibition by dopaminergic neurones: Disruption by (±)-α-methyl-p-tyrosine pretreatment or anterior diencephalic lesions. Neuropharmacology 15, 755–762 (1976)

    Google Scholar 

  • Hanson, L. C. F.: The disruption of conditioned avoidance response following selective depletion of brain catecholamines. Psychopharmacologia (Berl.) 8, 100–110 (1965)

    Google Scholar 

  • Hanson, L. C. F.: Biochemical and behavioural effects of tyrosine hydroxylase inhibition. Psychopharmacologia (Berl.) 11, 8–17 (1967)

    Google Scholar 

  • Javoy, F., Glowinski, J.: Dynamic characteristics of the “functional compartment” of dopamine in dopaminergic terminals of the rat striatum. J. Neurochem. 18, 1305–1311 (1971)

    Google Scholar 

  • Jönsson, L.-E., Änggård, E., Gunne, L.-M.: Blockade of intravenous amphetamine euphoria in man. Clin. Pharmacol. Ther. 12, 889–896 (1971)

    Google Scholar 

  • Koyuncuoğlu, H., Eroğlu, L., Güngör, M.: The effects of dl-p-chlorophenylalanine and dl-α-methyl-p-tyrosine on the brain catecholamine, serotonin and free amino acid contents in rat. Psychopharmacologia (Berl.) 45, 163–166 (1975)

    Google Scholar 

  • Lewander, T., Jonsson, J.: Isolation and determination of free endogenous and radioactive tyrosine in studies on catecholamine synthesis in rat brain. Life Sci. 7, 386–393 (1968)

    Google Scholar 

  • Levitt, M., Spector, S., Udenfriend, S.: Formation of norepinephrine by the isolated heart. Fed. Proc. 23, 562 (1964)

    Google Scholar 

  • Levitt, M., Gibb, J. W., Daly, J. W., Lipton, M., Udenfriend, S.: A new class of tyrosine hydroxylase inhibitors and a simple assay of inhibition in vivo. Biochem. Pharmacol. 16, 1313–1321 (1967)

    Google Scholar 

  • McGeer, P. L., Bagchi, S. P., McGeer, E. G.: Subcellular localization of tyrosine hydroxylase in beef caudate nucleus. Life Sci. 4, 1859–1867 (1965)

    Google Scholar 

  • Moore, K. E.: Effects of α-methyltyrosine on brain catecholamines and conditioned behavior in guinea pigs. Life Sci. 5, 55–65 (1966)

    Google Scholar 

  • Moore, K. E., Dominic, J. A.: Tyrosine hydroxylase inhibitors. Fed. Proc. 30, 859–870 (1971)

    Google Scholar 

  • Nagatsu, T., Levitt, M., Udenfriend, S.: Tyrosine hydroxylase. The initial step in norepinephrine biosynthesis. J. Biol. Chem. 239, 2910–2917 (1964)

    Google Scholar 

  • Nybäck, H.: Effects of neuroleptic drugs on brain catecholamine neurons. An experimental study using 14C-labelled tyrosine. Stockholm: Kihlström & Söner Boktryckeri AB 1971a

    Google Scholar 

  • Nybäck, H.: Regional disappearance of catecholamines formed from 14C-tyrosine in rat brain: Effect of synthesis inhibitors and of chlorpromazine. Acta Pharmacol. Toxicol. 30, 372–384 (1971b)

    Google Scholar 

  • Nybäck, H., Sedvall, G.: Effect of chlorpromazine on accumulation and disappearance of catecholamines formed from tyrosine-C14 in brain. J. Pharmacol. Exp. Ther. 162, 294–301 (1968)

    Google Scholar 

  • Paden, C.: A revised method for studying the kinetic compartmentation of dopamine in rat striatum. Neuroscience Abstr. 2, 793 (1976)

    Google Scholar 

  • Papeschi, R., Randrup, A.: Catalepsy, sedation and hypothermia induced by alpha-methyl-p-tyrosine in the rat. An ideal tool for screening of drugs active on central catecholaminergic receptors. Pharmacopsychiat. 6, 137–157 (1973)

    Google Scholar 

  • Persson, T., Waldeck, B.: Some problems encountered in attempting to estimate catecholamine turnover using labelled tyrosine. J. Pharm. Pharmacol. 22, 473–478 (1970)

    Google Scholar 

  • Rech, R. H., Borys, H. K., Moore, K. E.: Alteractions in behavior and brain catecholamine levels in rats treated with α-methyltyrosine. J. Pharmacol. Exp. Ther. 153, 412–419 (1966)

    Google Scholar 

  • Reis, D. J., Ross, R. A., Pickel, V. M., Lewander, T., Joh, T. H.: Some differences in tyrosine hydroxylase in central noradrenergic and dopaminergic neurons. In: Chemical tools in catecholamine research, vol. II, (O. Almgren, A. Carlsson and J. Engel, eds.). Amsterdam: North-Holland Publishing Company 1975

    Google Scholar 

  • Scheel-Krüger, J.: Comparative studies of various amphetamine analogues demonstrating different interactions with the metabolism of the catecholamines in the brain. Eur. J. Pharmacol. 14, 47–59 (1971)

    Google Scholar 

  • Schoenfeld, R. I., Seiden, L. S.: Effect of α-methyltyrosine on operant behavior and brain catecholamine levels. J. Pharmacol. Exp. Ther. 167, 319–327 (1969)

    Google Scholar 

  • Spector, S., Inhibitors of endogenous catecholamine biosynthesis. Pharmacol. Rev. 18, 599–609 (1966)

    Google Scholar 

  • Spector, S., Sjoerdsma, A., Udenfriend, S.: Blockade of endogenous norepinephrine synthesis by α-methyl-tyrosine, an inhibitor of tyrosine hydroxylase. J. Pharmacol. Exp. Ther. 147, 86–95 (1965)

    Google Scholar 

  • Stein, D., Jouvet, M., Pujol, J.-F.: Effects of α-methyl-p-tyrosine upon amine metabolism and sleep states in the cat. Brain Res. 72, 360–365 (1974)

    Google Scholar 

  • Stern, W. C., Morgane, P. J.: Effects of α-methyltyrosine on REM sleep and brain amine levels in the cat. Biol. Psychiatry 6, 301–305 (1973)

    Google Scholar 

  • Stolk, J. M., Rech, R. H.: Antagonism of D-amphetamine by alphamethyl-L-tyrosine: Behavioral evidence for the participation of catecholamine stores and synthesis in the amphetamine stimulant response. Neuropharmacology 9, 249–263 (1970)

    Google Scholar 

  • Sulser, F., Owens, M. L., Norvich, M. R., Dingell, J. V.: The relative role of storage and synthesis of brain norepinephrine in the psychomotor stimulation evoked by amphetamine or by desipramine and tetrabenazine. Psychopharmacologia (Berl.) 12, 322–332 (1968)

    Google Scholar 

  • Svensson, T. H., Waldeck, B.: On the role of brain catecholamines in motor activity: Experiments with inhibitors of synthesis and of monoamine oxidase. Psychopharmacologia (Berl.) 18, 357–365 (1970)

    Google Scholar 

  • Svensson, T. H., Waldeck, B.: On the relation between motor activity and the degree of enzyme inhibition following inhibition of tyrosine hydroxylase. Acta Pharmacol. Toxicol. (Kbh.) 29, 60–64 (1971)

    Google Scholar 

  • Takahashi, S., Gjessing, L. R.: A fluorometric method combined with thin layer chromatography for determination of norepinephrine, epinephrine and dopamine in human urine. Clin. Chim. Acta 36, 369–378 (1972)

    Google Scholar 

  • Udenfriend, S., Zaltzman-Nirenberg, P., Nagatsu, T.: Inhibitors of purified beef adrenal tyrosine hydroxylase. Biochem. Pharmacol. 14, 837–845 (1965)

    Google Scholar 

  • Waalkes, T. P., Udenfriend, S.: A fluorometric method for the estimation of tyrosine in plasma and tissues. J. Lab. Clin. Med. 50, 733–736 (1957)

    Google Scholar 

  • Weiner, N.: A critical assessment of methods for the determination of monoamine synthesis turnover rates in vivo. In: Neuropsychopharmacology of monoamines and their regulatory enzymes (E. Usdin, ed.). New York: Raven Press 1974

    Google Scholar 

  • Weissman, A., Koe, B. K.: Behavioral effects of L-α-methyltyrosine, an inhibitor of tyrosine hydroxylase. Life Sci. 4, 1037–1048 (1965)

    Google Scholar 

  • Widerlöv, E., Lewander, T.: The relationship between amphetamine antagonism and depletion of brain catecholamines by alphamethyl-p-tyrosine in rats. Naunyn-Schmiedeberg's Arch. Pharmacol. 304, 125–134 (1978)

    Google Scholar 

  • Wurtman, R. J., Larin, F., Mostafapour, S., Fernstrom, J. D.: Brain catechol synthesis: Control by brain tyrosine concentration. Science 185, 183–184 (1974)

    Google Scholar 

  • Wurtman, R. J., Fernstrom, J. D.: Control of brain neurotransmitter synthesis by precursor availability and nutritional state. Biochem. Pharmacol. 25, 1691–1696 (1976)

    Google Scholar 

  • Wålinder, J., Skott, A., Carlsson, A., Roos, B.-E.: Potentiation by metyrosine of thioridazine effects in chronic schizophrenics. A long-term trial using double-blind cross-over technique. Arch. Gen. Psychiatry 33, 501–505 (1976)

    Google Scholar 

  • Änggård, E., Gunne, L.-M.: Clinical and pharmacological studies of amphetamine-dependent subjects. Neuropsychopharmacology. Proceedings of the IX Congress of the Collegium Internationale Neuropsychopharmacologicum, Paris 7–12 July (1974), pp. 253–261. Excerpta Medica International Congress Series No. 359, Amsterdam 1975

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  1. Psychiatric Research Center, University of Uppsala, Ulleråker Hospital, S-750 17, Uppsala, Sweden

    E. Widerlöv & T. Lewander

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  1. E. Widerlöv
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Widerlöv, E., Lewander, T. Inhibition of the in vivo biosynthesis and changes of catecholamine levels in rat brain after α-methyl-p-tyrosine; time- and dose-response relationships. Naunyn-Schmiedeberg's Arch. Pharmacol. 304, 111–123 (1978). https://doi.org/10.1007/BF00495547

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