, Volume 40, Issue 1, pp 53–64 | Cite as

Effect of iprindole on norepinephrine turnover and transport

  • Barry N. Rosloff
  • John M. Davis
Animal Studies


Iprindole, an antidepressant drug clinically similar to other tricyclic antidepressants, was administered to rats chronically. Such treatment did not alter the rate of decline of the log of brain norepinephrine levels after norepinephrine synthesis inhibition with α-methyltyrosine methyl ester. In addition, a single dose of iprindole did not significantly alter uptake of intracisternally administered H3-norepinephrine or the amount of H3-normetanephrine formed from such administration. Furthermore, iprindole added in vitro showed very low potency in blocking the uptake of labelled norepinephrine, metaraminol, serotonin, and dopamine into crude synaptosomal preparations. The bearing of these findings on the hypothesized mechanism of action of the tricyclic antidepressants, which affect all of the above parameters, is discussed.

Key words

Antidepressants Iprindole Norepinephrine 


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  1. Alpers, H. S., Himwich, H. E.: The effects of chronic imipramine administration on rat brain levels of serotonin, 5-hydroxyindoleacetic acid, norepinephrine, and dopamine. J. Pharmacol. exp. Ther. 180, 531–538 (1972)Google Scholar
  2. Carlsson, A., Corrodi, H., Fuxe, K., Hokfelt, T.: Effects of some antidepressant drugs on the depletion of intraneuronal brain catecholamine stores caused by 4, α-dimethyl-meta-tyramine. Europ. J. Pharmacol. 5, 367–373 (1969)Google Scholar
  3. Colburn, R. W., Goodwin, F. K., Murphy, D. L., Bunney, W. E., Davis, J. M.: Quantitative studies of norepinephrine uptake by synaptosomes. Biochem. Pharmacol. 17, 957–964 (1968)Google Scholar
  4. Corrodi, H., Fuxe, K., Hokfelt, T.: The effect of immobilization stress on the activity of central monoamine neurons. Life Sci. 1, 107–112 (1968)Google Scholar
  5. Costa, E.: The fundamental role of immediate precursors to estimate turnover rate of catecholamines by isotopic labeling. In: Pharmacology and the Future of Man. Proc. 5th Int. Congr. Pharmacology, San Francisco 1972, vol. 4, pp. 215–226 Basel: Karger 1973Google Scholar
  6. Daneman, E. A.: Treatment of depressed patients with iprindole. Psychosomatics 8, 216–221 (1967)Google Scholar
  7. Davis, J. M.: Theories of biological etiology of affective disorders. Int. Rev. Neurobiol. 12, 145–175 (1970)Google Scholar
  8. El Diery, N. K.: Controlled trial of WY-3263: An evaluation of nondrug factors. In: Proceedings of the Fourth World Congress of Psychiatry. International Congress Series no. 150. Amsterdam: Excerpta Medica Foundation, part 4, 3159 (1967)Google Scholar
  9. Fann, W. E., Davis, J. M., Janowsky, D. S., Kaufmann, J. S., Griffith, J. D., Oates, J. A.: Effect of iprindole on amine uptake in man. Arch. gen. Psychiat. 26, 158–162 (1972)Google Scholar
  10. Freeman, J. J., Sulser, F.: Iprindole-amphetamine interactions in the rat: The role of aromatic hydroxylation of amphetamine in its mode of action. J. Pharmacol. exp. Ther. 183, 307–315 (1972)Google Scholar
  11. Giese, J., Ruther, E., Matussek, H.: Quantitative estimation of H3-norepinephrine and its metabolites by thin-layer chromatography. Life Sci. 6, 1975–1982 (1967)Google Scholar
  12. Glowinski, J.: The “functional pool” in central catecholaminergic neurons. In: Pharmacology and the Future of Man: Proc. 5th Int. Congr. Pharmacology, San Francisco 1972, Vol. 4, pp. 204–214. Basel: Karger 1973Google Scholar
  13. Glowiniski, J., Axelrod, A.: Inhibition of uptake of tritiated noradrenaline in the intact rat brain by imipramine and structurally related compounds. Nature (Lond.) 204, 1318–1319 (1964)Google Scholar
  14. Glowinski, J., Axelrod, A.: Effects of drug on the disposition of H3-norepinephrine in the rat brain. Pharmacol. Rev. 18, 775–787 (1966)Google Scholar
  15. Glowinski, J., Axelrod, A., Iversen, L. L.: Regional studies of catecholamines in the rat brain. IV. Effects of drug on the disposition and metabolism of 3H-norepinephrine and H3-dopamine. J. Pharmacol. exp. Ther. 153, 30–41 (1966)Google Scholar
  16. Gluckman, M. I., Baum, T.: The pharmacology of iprindole, a new antidepressant. Psychopharmacologia (Berl.) 15, 169–185 (1969)Google Scholar
  17. Hertting, G., Axelrod, A., Kopin, I., Whitby, L.: Lack of uptake of catecholamines after chronic denervation of sympathetic nerves. Nature (Lond.) 189, 66 (1961)Google Scholar
  18. Hicks, J. T.: Iprindole, a new antidepressant for use in general office practice. Illinois med. J. 128, 622–626 (1965)Google Scholar
  19. Imlah, N. W., Murphy, K. P., Mellor, C. S.: The treatment of depression: A controlled comparison between iprindole (Prondol) and imipramine. Clin. Trials J. 5, 927–931 (1968)Google Scholar
  20. Johnson, J., Maden, J. G.: The treatment of depressions: Further evaluation of iprindole. Clin. Trials J. 7, 341–344 (1970)Google Scholar
  21. Kopin, I., Axelrod, J., Gordon, E.: The metabolic fate of 3H-epinephrine and 14C-metanephrine in the rat. J. biol. Chem. 236, 2109–2113 (1961)Google Scholar
  22. Kopin, I. J., Hertting, G., Gordon, E. K.: Fate of norepinephrine-H3 in the isolated perfused rat heart. J. Pharmacol. exp. Ther. 138, 34–40 (1962)Google Scholar
  23. Lahti, R. A., Maickel, R. P.: The tricyclic antidepressants — inhibition of norepinephrine uptake as related to potentiation of norepinephrine and clinical efficacy. Biochem. Pharmacol. 20, 482–486 (1971)Google Scholar
  24. Lemberger, L., Sernatinger, E., Kuntzman, R.: Effect of desmethylimipramine, iprindole, and Dolor-erythro-α-(3,4,-dichIorophenyl)-B-(t-butyl amino) propanol HCI on the metabolism of amphetamine. Biochem. Pharmacol. 19, 3021–3028 (1970)Google Scholar
  25. Lidbrink, P., Jonsson, G., Fuxe, K.: The effect of imipramine-like drugs and antihistamine drugs on uptake mechanism in the central noradrenaline and 5-hydroxy-tryptamine neurons. Neuropharmacology 10, 521–536 (1971)Google Scholar
  26. Maas, J. W., Faweett, J. A., Dekirmenjian, H.: Catecholamine metabolism, depressive illness, and drug response. Arch. gen. Psychiat. 26, 252–262 (1972)Google Scholar
  27. McClatchey, W. T., Moffat, J., Irvin, G. M.: A double-blind study of WY-3263, imipramine, and placebo. J. Ther. clin. Res. 1, 13–15 (1967)Google Scholar
  28. Neff, N. H., Costa, E.: Effect of tricyclic antidepressants and chlorpromazine on brain catecholamine synthesis. In: Antidepressant Drugs. A. Garrattini and M. N. G. Dukes, eds. Amsterdam: Excerpta Medica Foundation, pp. 28–34 (1967)Google Scholar
  29. Rickels, K., Chung, H., Csanalosi, I., Sablosky, W., Simon, J.: Iprindole and imipramine in non-psychotic depressed outpatients. Brit. J. Psychiat. 123, 329–339 (1973)Google Scholar
  30. Rickels, K., Gordon, P. E., Mecklenberg, R.: Iprindole in neurotic depressed general practice patients: A controlled study. Psychosomatics 9, 208–214 (1968)Google Scholar
  31. Roffler-Tarlov, S., Schildkraut, J. J., Draskoczy, P. R.: Effects of acute and chronic administration of desmethylimipramine on the content of norepinephrine and other monoamines in the rat brain. Biochem. Pharmacol. 22, 2923–2925 (1973)Google Scholar
  32. Rosell, S., Kopin, I. J., Axelrod, J.: Fate of H3-noradrenaline in skeletal muscle-before and following sympathetic stimulation. Amer. J. Physiol. 205, 317–321 (1963)Google Scholar
  33. Ross, S. B., Renyi, A. L., ögren, S. O.: A comparison of the inhibitory activities of iprindole and imipramine on the uptake of 5-hydroxytryptamine and noradrenalin in brain slices. Life Sci. 10, part 1, 1267–1277 (1971)Google Scholar
  34. Schanberg, S. M., Schildkraut, J. J., Kopin, I. J.: The effects of psychoactive drugs on norepinephrine-3H metabolism in brain. Biochem. Pharmaool. 16, 393–399 (1967)Google Scholar
  35. Schildkraut, J. J.: Biogenic amines and affective disorders. Ann. Rev. Med. 25, 333–348 (1974)Google Scholar
  36. Schildkraut, J. J., Dodge, G. A., Logue, M. A.: Effects of tricyclic antidepressants on the uptake and metabolism of intracisternally administered norepinephrine-H3 in rat brain. J. Psychiat. Res. 7, 29–34 (1969)Google Scholar
  37. Schildkraut, J. J., Kety, S. S.: Biogenic amines and emotion. Science 156, 21–30 (1967)Google Scholar
  38. Schildkraut, J. J., Schanberg, S. M., Breese, G. R., Kopin, J. J.: Norepinephrine metabolism and drugs used in the affective disorders: A possible mechanism of action. Amer. J. Psychiat. 124, 600–608 (1967)Google Scholar
  39. Schildkraut, J. J., Winokur, A., Applegate, C. W.: Norepinephrine turnover and metabolism in rat brain after long-term administration of imipramine. Science 168, 867–869 (1970)Google Scholar
  40. Schildkraut, J. J., Winokur, A., Draskoczy, P. R., Hensle, J. H.: Changes in norepinephrine turnover in rat brain during chronic administration of imipramine and protriptyline: A possible explanation for the delay in onset of clinical antidepressant effects. Amer. J. Psychiat. 127, 1032–1039 (1971)Google Scholar
  41. Sterlin, C., Lehmann, H. E., Oliveros, R. F.: A preliminary investigation of WY-3263 versus amitriptyline in depressions. Curr. ther. Res. 10, 576–582 (1968)Google Scholar
  42. Stille, G.: Pharmacological investigation of antidepressant compounds. Pharma-kopsychiat.-Neuropsychopharmak. 1, 92–106 (1968)Google Scholar
  43. Sulser, F., Owens, M. L., Strada, S. J., Dingell, J. V.: Modification by desipramine (DMI) of the availability of norepinephrine released by reserpine in the hypothalamus of the rat in vivo. J. Pharmacol. exp. Ther. 168, 272–282 (1969)Google Scholar
  44. Sutherland, M. S., Sutherland, S. S., Phillip, A. E.: Depressive illness: Comparison of effects of pramindole (WY-3263) and imipramine. Clin. Trials J. 4, 857–860 (1967)Google Scholar
  45. Thierry, A., Javoy, F., Glowinski, J., Kety, S.: Effects of stress on the metabolism of norepinephrine, dopamine, and serotonin in the central nervous system of the rat. I. Modifications of norepinephrine turnover. J. Pharmacol. exp. Ther. 163, 163–171 (1968)Google Scholar
  46. Welch, B., Welch, A.: Differential activation by restraint stress of a mechanism to conserve brain catecholamines and serotonin in mice differing in excitability. Nature (Lond.) 218, 575–577 (1968)Google Scholar
  47. Whitby, L. G., Axelrod, A., Weil-Malherbe, H.: The fate of H3-norepinephrine in animals. J. Pharmacol. exp. Ther. 132, 193–201 (1961)Google Scholar

Copyright information

© Springer-Verlag 1974

Authors and Affiliations

  • Barry N. Rosloff
    • 1
  • John M. Davis
    • 2
  1. 1.Department of PharmacologyVanderbilt University School of Medicine and the Tennessee Neuropsychiatric InstituteNashville
  2. 2.Illinois State Psychiatric Institute and the Department of PsychiatryUniversity of ChicagoChicago

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