Summary
A method is described for measuring the inhibition of transmitter uptake into noradrenaline (NA) and 5-hydroxytryptamine (5-HT) neurons incubated in plasma from patients receiving tricyclic antidepressants. The potency was determined of the tricyclic antidepressants nortriptyline and chlorimipramine in inhibiting NA and 5-HT uptake by rat brain slices incubated in buffer or human plasma. As expected, nortriptyline produced greater inhibition of NA than of 5-HT uptake, and chlorimipramine had more effect on 5-HT uptake. These drugs caused 10 to 100 times more inhibition of monoamine uptake from buffer than from plasma, probably because they were bound to plasma proteins. Plasma from patients taking nortriptyline inhibited NA uptake by brain slices 35—55% of the value found in each subject in a pretreatment sample. During long term therapy the concentration of a drug in plasma should be in equilibrium with its concentration at central receptor sites. Thus, it seems likely that the present results reflect the inhibition of uptake by the central monoaminergic neurons of patients taking tricyclic antidepressants. The method also permits evaluation of inter-individual differences in the effects of various antidepressants on NA and 5-HT nerve terminals. It can also be used to evaluate the relative effects of various antidepressants on these two monoaminergic systems.
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Åsberg, M., Bertilsson, L., Tuck, D., Cronholm, B., Sjöqvist, F.: 5-Hydroxyindole-3-acetic acid and indole-3-acetic acid concentrations in the cerebrospinal fluid of depressed patients before and during treatment with nortriptyline. Clin. Pharmacol. Ther. In Press.
Baldessarini, R. J., Kopin, I. J.: The effect of drugs on the release of norepinephrine-H3 from central nervous system tissues by electrical stimulationin vitro. J. Pharmacol. Ther.156, 31–38 (1967).
Borgå, O., Hamberger, B., Malmfors, T., Sjöqvist, F.: The role of plasma protein binding in the inhibitory effect of nortriptyline on the neuronal uptake of norepinephrine. Clin. Pharmacol. Ther.11, 581–588 (1970).
Borgå, O., Azarnoff, D., Forshell, G. P., Sjöqvist, F.: Plasma protein binding of trcyclic antidepressants in man. Biochem. Pharmacol.18, 2135–2143 (1969).
Campbell, I. C., Todrick, A.: Plasma protein binding of tricyclic antidepressive drugs. J. Pharm. Pharmacol.22, 226–227 (1970).
Carlsson, A., Corrodi, H., Fuxe, K., Hökfelt, T.: Effect of some antidepressant drugs on the depletion of intraneuronal brain 5-hydroxytryptamine stores caused by 4-methyl-α-ethylmeta-tyramine. Europ. J. Pharmacol.5, 357–366 (1969).
Carlsson, A.: Structural specificity for inhibition of C-14-5-hydroxytryptamine uptake by cerebral slices. J. Pharm. Pharmacol.22, 729–732 (1970).
Dengler, H. J., Michaelsson, I. A., Speigel, H. E., Titus, E.: The uptake of labeled norepinephrine by isolated brain and other tissues of the cat. Int. J. Neuropharmacol.1, 23–38 (1962).
Farnebo, L.-O.: Histochemical demonstration of transmitter release from noradrenaline, dopamine and 5-hydroxytryptamine nerve terminals in field stimulated rat brain slices. Z. Zellforsch.122, 503–519 (1971).
Fuxe, K.: Evidence for the existence of monoamine neurons in the central nervous system. III. The monoamine nerve terminal. Z. Zellforsch.65, 573–596 (1965).
Hamberger, B.: Reserpine-resistant uptake of catecholamines in isolated tissues of the rat. A histochemical study. Acta physiol. scand., Suppl. 295, 1–56 (1967).
Hammer, W., Brodie, B. B.: Application of isotope derivative technique to assay of secondary amines: Estimation of desipramine by acetylation with3H-acetic anhydride. J. Pharmacol exp. Ther.157, 503–507 (1967).
Jonsson, G., Hamberger, B., Malmfors, T., Sachs, C.: Uptake and accumulation of3H-noradrenaline in adrenergic nerves of rat iris. Effect of reserpine, monoamine oxidase and tyrosine hydroxylase inhibition. Europ. J. Pharmacol.8, 58–72 (1969).
Lapin, I. P., Oxenkrug, G. F.: Intensification of the central serotoninergic processes as a possible determinant of the thymoleptic effect. Lancet1969 I, 132–136.
Lidbrink, P., Jonsson, G., Fuxe, K.: The effect of imipramine-like drugs and antihistamine drugs on uptake mechanisms in central noradrenaline and 5-hydroxytryptamine neurons. Neuropharmacol.10, 521–536 (1971).
Lingjaerde, O.: Inhibitory effect of two newer antidepressants, LU 5-003 and LU 3-010 on serotonin uptake in human blood platelets. Psychopharmacol. (Berl.)17, 94–99 (1970).
McIlwain, H., Rodnight, R.: Practical Neurochemistry. London: J. and A. Churchill 1962.
McIlwain, H.: Biochemistry and the central nervous system. Boston: Little, Brown 1966.
Nyström, B., Olsson, L., Ungerstedt, U.: Noradrenaline nerve terminals in human cerebral cortex: first histochemical evidence. Science176, 924 (1972).
Pletscher, A.: Metabolism, transfer and storage of 5-hydroxytryptamine in blood platelets. Brit. J. Pharmacol.32, 1–16 (1968).
Ross, S. B., Renyi, A. L.: Inhibition of the uptake of tritiated 5-hydroxytryptamine in brain tissue. Europ. J. Pharmacol.7, 270–277 (1969).
Ross, S. B., Renyi, A. L., Ögren, S.-O.: Inhibition of the uptake of noradrenaline and 5-hydroxytryptamine by chlorphentermine and chlorimipramine. Europ. J. Pharmacol.17, 107–112 (1972).
Rutledge, C. O., Jonsson, J.: Metabolic pathways of dopamine and norepinephrine in rabbit brainin vitro. J. Pharmacol. exp. Ther.157, 493–502 (1967).
Sachs, C., Jonsson, G.: Degeneration of central and peripheral noradrenaline neurons produced by 6-hydroxy-Dopa. J. Neurochem.19, 1561–1575 (1972).
Schildkraut, J. J., Kety, S. S.: Biogenic amines and emotion. Science156, 21–30 (1967).
Shaskan, E. G., Snyder, S. H.: Kinetics of serotonin accumulation into slices from rat brain. J. Pharmacol. exp. Ther.175, 404–418 (1970).
Sjöqvist, F.: A pharmacokinetic approach to the treatment of depression. Int. Pharmacopsychiat.6, 147–169 (1972).
Ungerstedt, U.: Stereotaxic mapping of the monoamine pathways in the rat brain. Acta physiol. scand., Suppl.367, 1–48 (1971).
Van Praag, H. M., Korf, J.: Endogenous depressions with and without disturbances in the 5-hydroxytryptamine metabolism: A biochemical classification? Psychopharmacol. (Berl.)19, 148–152 (1971).
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Hamberger, B., Tuck, J.R. Effect of tricyclic antidepressants on the uptake of noradrenaline and 5-hydroxytryptamine by rat brain slices incubated in buffer or human plasma. Eur J Clin Pharmacol 5, 229–235 (1973). https://doi.org/10.1007/BF00567009
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DOI: https://doi.org/10.1007/BF00567009