Summary
Groups of rats were injected i.p. with 0.407 or 1.02 mmoles/kg of D, L-α-methyl-p-tyrosine methylester HCl (α-MT). The time-courses forα-MT in plasma and brain were followed together with the endogenous brain dopamine (DA) and noradrenaline (NA) contents.
The elimination ofα-MT from plasma and brain was markedly delayed after the highα-MT dose compared with the low dose. At 40 hours after the injection of 1.02 mmoles/kg ofα-MT both plasma and brain levels were high, whereas noα-MT could be detected in plasma or brain at 16 hours after the lower dose.
The brain catecholamines were decreased to very low values after the higherα-MT dose (DA 14% and NA 10% of controls at 8 and 24 hours respectively). There was no complete recuperation at 40 hours of any of the amines. After the lowerα-MT dose, the DA concentration was back to control levels at 16 hours and NA at 12 hours. Between 16–40 hours after the highα-MT dose a majority of the rats showed prominent signs of sedation, weight loss and dehydration. No such signs were observed in rats receiving 0.407 mmoles/kg. During the first hour after theα-MT injection the declines of DA and NA respectively were almost identical for bothα-MT doses. When the whole time-course (0–8 hours) after the high dose was considered, biphasic declines were obtained for both DA and NA, suggesting at least two different catecholamine pools. However, due to toxic effects after the highα-MT dose, turnover data have to be interpreted with caution.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Andén, N.-E. Effects of amphetamine and some other drugs on central catecholamine mechanisms. In: Amphetamines and Related Compounds; Proceedings of the Mario Negri Institute for Pharmacological Research, Milan, Italy (Costa, E., Garattini, S., eds.). New York: Raven Press. 1970.
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).
Bunney, B. S., Aghajanian, G. K., Roth, R. H. Comparison of effects of 1-dopa, amphetamine and apomorphine on firing rate of rat dopamin-ergic neurons. Nature New Biology245, 123–125 (1973).
Costa, E. Simple neuronal models to estimate turnover rate of noradrenergic transmittersin vivo. In: Biochemistry of Simple Neuronal Models (Advances in Biochemical Psychopharmacology) (Costa, E., Giacobini, E., eds.), Vol. 2. New York: Raven Press. 1970.
Dixon, W. J., Massey, F. J., jr. Introduction to statistical analysis. New York: McGraw-Hill. 1969.
Dost, F. H. Grundlagen der Pharmakokinetik. Stuttgart: G. Thieme. 1968.
Doteuchi, M., Wang, C., Costa, E. Compartmentation of dopamine in rat striatum. Mol. Pharmacol.10, 225–234 (1974).
Engelman, K., Horwitz, D., Jéquier, E., Sjoerdsma, A. Biochemical and pharmacologic effects ofα-methyltyrosine in man. J. Clin. Invest.47, 577–594 (1968).
Glowinski, J., Iversen, L. L. Regional studies of catecholamines in the rat brain. I. The disposition of3H-norepinephrine,3H-dopamine and3H-DOPA in various regions of the brain. J. Neurochem.13, 655–669 (1966).
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. Neuropharmacol.15, 755–762 (1976).
Gudelsky, G. A., Moore, K. E. Differential drug effects on dopamine concentrations and rates of turnover in median eminence, olfactory tubercle and corpus striatum. J. Neural Transm.38, 95–105 (1976).
Hook, J. B., Moore, K. E. The renal handling ofα-methyltyrosine. J. Pharmacol. Exp. Ther.168, 310–314 (1969).
Iversen, L. L., Glowinski, J. Regional studies of catecholamines in the rat brain. II. Rate of turnover of catecholamines in various brain regions. J. Neurochem.13, 671–682 (1966).
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).
Jönsson, L.-E., Änggård, E., Gunne, L.-M. Blockade of intravenous amphetamine euphoria in man. Clin. Pharmacol. Therap.12, 889–896 (1971).
Kopin, I. J., Breese, G. R., Krauss, K. R. Selective release of newly synthesized norepinephrine from the cat spleen during sympathetic nerve stimulation. J. Pharmacol. Exp. Ther.161, 271–278 (1968).
Levitt, M., Spector, S., Udenfriend, S. Formation of norepinephrine by the isolated heart. Fed. Proc.23, 562 (1964).
Magnusson, G., Corrodi, H., Hansson, E. Renal lesions induced byα-methyltyrosine methylester andα-methyltyrosine. Acta Pharmacol. Toxicol.28, 435–444 (1970).
Moore, K. E., Wright, P. F., Bert, J. K. Toxicologic studies withα-methyltyrosine, an inhibitor of tyrosine hydroxylase. J. Pharmacol. Exp. Ther.155, 506–515 (1967).
Moore, K. E., Dominic, J. A. Tyrosine hydroxylase inhibitors. Fed. Proc.30, 859–870 (1971).
Nybäck, H. Regional disappearance of catecholamines formed from14C-tyrosine in rat brain: Effect of synthesis inhibitors and chlorpromazine. Acta Pharmacol. Toxicol.30, 372–384 (1971).
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).
Persson, T. Central and peripheral catecholamine turnover studied by means of3H-DOPA and3H-tyrosine. Acta Pharmacol. Toxicol.27, 397–409 (1969).
Persson, T., Waldeck, B. Some problems encountered in attempting to estimate catecholamine turnover using labelled tyrosine. J. Pharm. Pharmac.22, 473–478 (1970).
Rech, R. H., Borys, H. K., Moore, K. E. Alterations in behaviour and brain catecholamine levels in rats treated withα-methyl-tyrosine. J. Pharmacol. Exp. Ther.153, 412–419 (1966).
Riggs, D. S. The mathematical approach to physiological problems. Baltimore: Williams & Wilkins. 1963.
Sedvall, G. Receptor feedback and dopamine turnover in CNS. In: Handbook of Psychopharmacology, Section I, Vol. 6: Biogenic Amine Receptors (Iversen, L. L., Iversen, S. D., Snyder, S. H., eds.). New York: Plenum Press. 1975.
Sedvall, G. C., Weise, V. K., Kopin, I. J. The rate of norepinephrine synthesis measuredin vivo during short intervals; influence of adrenergic nerve impulse activity. J. Pharmacol. Exp. Ther.159, 274–282 (1968).
Spector, S. Inhibitors of endogenous catecholamine biosynthesis. Pharmacol. Rev.18, 599–609 (1966).
Udenfriend, S., Zaltzman-Nirenberg, P., Nagatsu, T. Inhibitors of purified beef adrenal tyrosine hydroxylase. Biochem. Pharmacol.14, 837–845 (1965).
Weiner, N. A critical assessment of methods for the determination of monoamine synthesis turnover ratesin vivo. In: Neuropsychopharmacology of Monoamines and Their Regulatory Enzymes (Usdin, E., ed.). New York: Raven Press. 1974.
Widerlöv, E., Lewander, T. Inhibition of thein vivo biosynthesis and changes of catecholamine levels in rat brain afterα-methyl-p-tyrosine; time- and dose-response relationships. Naunyn-Schmiedeberg's Arch. Pharmacol.304, 111–124 (1978 a).
Widerlöv, E., Lewander, T. The relationship between amphetamine antagonism and depletion of brain catecholamines by alpha-methyl-p-tyrosine in rats. Naunyn-Schmiedeberg's Arch. Pharmacol.304, 125–134 (1978 b).
Widerlöv, E., Lewander, T.: Tolerance toα-methyl-p-tyrosine in rats; studies on the antagonism of amphetamine induced motor activity and excitatory behaviour. Psychopharmacol. (in press, 1978 c).
Widerlöv, E., Lewander, T. Regional rat brain synthesis and levels of catecholamines afterα-methyl-p-tyrosine. In: Catecholamines: Basic and Clinical Frontiers. Fourth Catecholamine Symposium (Usdin, E., ed.). New York: Pergamon Press. 1979. (In press, 1978 d.)
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. Psychiatry33, 501–505 (1976).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Widerlöv, E. Dose-dependent pharmacokinetics of α-methyl-p-tyrosine (α-MT) and comparison of catecholamine turnover rates after two doses of α-MT. J. Neural Transmission 44, 145–158 (1979). https://doi.org/10.1007/BF01253059
Received:
Issue Date:
DOI: https://doi.org/10.1007/BF01253059