Naunyn-Schmiedeberg's Archives of Pharmacology

, Volume 308, Issue 3, pp 239–247 | Cite as

Effect of acute and chronic treatment of tandamine, a new heterocyclic antidepressant, on biogenic amine metabolism and related activities

  • T. A. Pugsley
  • W. Lippmann


The effects of tandamine, a clinically effective heterocyclic antidepressant, administered either acutely (10 mg/kg i.p) or chronically (10 mg/kg i.p. daily for 21 days) on biogenic amine uptake and metabolism in the rat were determined and a comparison with desipramine was made. Tandamine, similarly to desipramine, blocked norepinephrine (NE) uptake in rat brain and heart following both acute and chronic administration. No effect of tandamine on dopamine (DA) or serotonin (5-HT) uptake was observed. Both drugs lowered endogenous brain NE when given chronically but not acutely. In contrast, no such effect on brain DA and 5-HT or heart NE was observed. Tandamine, like desipramine, administered chronically prior to an intraventricular injection of 3H-NE, produced increases in the decline of 3H-NE as indicated by decreased 3H-NE with increased levels of 3H-normetanephrine in brain stem of rats, suggesting an increased turnover of NE. No such effect was observed following acute treatment. Both drugs increased the behavioural effects of L-Dopa following an acute oral administration, with tandamine appearing superior to desipramine at the lower dose examined (10 mg/kg). Tandamine was 57–833 times less effective in binding to rat brain muscarinic receptors than desipramine, imipramine, butriptyline and amitriptyline, respectively. Thus, tandamine affects biogenic amine mechanism following either acute or chronic administration in a fashion similar to desipramine, but unlike desipramine, it exhibits relatively little anticholinergic properties, a further indication of the potential use of tandamine in the treatment of human depression, particularly where an increase in drive is desired.

Key words

Tandamine Desipramine Antidepressant Acute and chronic treatment Rat brain Norepinephrine, dopamine and serotonin uptake inhibition Norepinephrine turnover L-Dopa Anticholinergic activity 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  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. Asheroft, G. W., Eccleston, D., Murray, L. G., Green, A. I. M.: Modified amine hypothesis for the aetiology of affective illness. Lancet 1972 II, 573–577Google Scholar
  3. Bogdanski, D. F., Pletscher, A., Brodie, B. B., Udenfriend, S.: Identification and assay of serotonin in brain. J. Pharamcol. Exp. Ther. 117, 82–88 (1956)Google Scholar
  4. Bruinvels, J.: Evidence for inhibition of the re-uptake of 5-hydroxytryptamine and noradrenaline by tetrahydronaphthylamine. Br. J. Pharmacol. 42, 281–286 (1971)Google Scholar
  5. Carlsson, A., Corrodi, H., Fuxe, K., Hökfelt, T.: Effect of antidepressant drugs on the depletion of intraneuronal brain 5-hydroxytryptamine stores caused by 4-methyl-α-ethyl-metatyramine. Eur. J. Pharmacol. 5, 357–366 (1969a)Google Scholar
  6. Carlsson, A., Corrodi, H., Fuxe, K., Hökfelt, T.: Effect of some antidepressant drugs on the depletion of intraneuronal brain catecholamines stores by 4-α-dimethyl-metatyramine. Eur. J. Pharmacol. 5, 367–373 (1969b)Google Scholar
  7. Carlsson, A., Fuxe, K., Hamberger, B., Lindqvist, M.: Biochemical and histochemical studies on the effects of imipramine-like drugs and (+)-amphetamine on central and peripheral catecholamine neurons. Acta Physiol. Scand. 67, 481–497 (1966)Google Scholar
  8. Cordeau, J. P., de Champlain, J., Jacks, B.: Excitation and prolonged waking produced by catecholamines injected into the ventricular system of cats. Can. J. Physiol. Pharmacol. 49, 627–631 (1971)Google Scholar
  9. Corrodi, H., Fuxe, K.: The effect of imipramine on central monoamine neurons. J. Pharm. Pharmacol. 20, 230–231 (1968)Google Scholar
  10. Corrodi, H., Fuxe, K., Hökfelt, T.: The effect of some psychoactive drugs on central monoamine neurons. Eur. J. Pharmacol., 1, 363–368 (1967)Google Scholar
  11. Everett, G. M.: The dopa response potentiation test and its use in screening for antidepressant drugs. In: Antidepressant Drugs (S. Garattini, and M. N. G. Dukes, eds.), pp. 164–167 Amsterdam: Excerpta Medica Foundation (1967)Google Scholar
  12. Euler, U. S., Von, Floding, I.: Fluorometric determinations of noradrenaline and adrenaline in urine. Acta Physiol. Scand. 33, Suppl. 118, 45–47 (1965)Google Scholar
  13. Glowinski, J., Axelrod, J.: Effects of drugs on disposition of 3H-norepinephrine in the rat brain. Pharmacol. Rev. 18, 775–786 (1966)Google Scholar
  14. Glowinski, J., Iversen, L. L.: Regional studies of catecholamines in rat brain. 1. The disposition of 3H-norepinephrine, 3H-dopamine and 3H-dopa, in various regions. J. Neurochem. 15, 655–669 (1966)Google Scholar
  15. Hendley, E. D., Moisset, B., Welch, B. L.: Catecholamine uptake in cerebral cortex: adaptive changes induced by fighting. Science 180, 1050–1952 (1973)Google Scholar
  16. Jaramillo, J.: Pharmacological studies on tandamine hydrochloride, a potential heterocyclic antidepressant. Naunyn-Schmiedeberg's Arch. Pharmacol. 302, 107–113 (1978)Google Scholar
  17. Jirkovsky, I., Humber, L. G., Voith, K., Charest, M.-P.. Syntheses and primary pharmacological screening of tandamine and related tetrahydrothiopyranoindoles with potential antidepressant properties. Arzneim.-Forsch./Drug Res. 27, 1642–1648 (1977)Google Scholar
  18. Kopin, I. J., Axelrod, J., Gordon, E.: The metabolic fate of 3H-epinephrine and C14-metanephrine in the rat. J. Biol. Chem. 236, 2109–2113 (1961)Google Scholar
  19. Lapin, I. P., Oxenkrug, G. F.: Intensification of the central serotoninergic processes as a possible determinant of the thymoleptic effect. Lancet 1, 132–136 (1969)Google Scholar
  20. Laverty, R., Taylor, K. M.: The fluorometric assay of catecholamine and related compounds. Analyt. Biochem. 22, 269–279 (1968)Google Scholar
  21. Lidbrink, P., Jonsson, G, Fuxe, K.: Effect of imipramine-like drugs and antihistamine drugs on uptake mechanisms in the central noradrenaline and 5-hydroxytryptamine neurons. Neuropharmacol. 10, 521–536 (1971)Google Scholar
  22. Lippmann, W., Pugsley, T. A.: The effects of tandamine, a new potential antidepressant agent, on biogenic amine uptake mechanisms and related activities. Biochem. Pharmacol. 25, 1179–1186 (1976)Google Scholar
  23. Maickel, R. P., Cox, R. H. Saillant, J., Miller, F. P.: A method for the determination of serotonin and norepinephrine in discrete areas of rat brain. Int. J. Neuropharmacol. 7, 275–281 (1968)Google Scholar
  24. Neff, N. H., Costa, E.: Effect of tricyclic antidepressant and chlorpromazine on brain catecholamine synthesis. In: Antidepressant drugs (S. Garattini and M. N. G. Dukes, eds.). Int. Congr. Ser. 122, pp. 28–34. Amsterdam: Excerpta Medica Foundation (1967)Google Scholar
  25. Nielsen, M., Braestrup, C.: Chronic treatment with desipramine caused a sustained decrease of 3,4-dihydroxyphenylglycolsulphate and total 3-methoxy-4-hydroxyphenylglycol in rat brain. Naunyn-Schmiedeberg's Arch. Pharmacol. 300, 87–92 (1977)Google Scholar
  26. Nielsen, M., Eplov, L., Scheel-Krüger, J.: The effect of amitriptyline, desimipramine and imipramine on the in vivo brain synthesis of 3H-noradrenaline from 3H-L-Dopa in the rat. Psychopharmacologia (Berl.) 41, 249–254 (1975)Google Scholar
  27. Noble, E. P., Wurtman, R., Axelrod, J.: A simple and rapid method for injecting 3H-norepinephrine into the lateral ventricle of the rat brain. Life Sci. 6, 281–291 (1967)Google Scholar
  28. Plotnikoff, N., Will, F., Evans, A., Meekma, P.: PS-2747: A new antidepressant agent. Arch. Int. Pharmacodyn. 195, 333–342 (1972)Google Scholar
  29. Pugsley, T. A., Lippmann, W.: Effects of tandamine and pirandamine, new potential antidepressants, on the brain uptake of norepinephrine and 5-hydroxytryptamine and related activities. Psychopharmacologia (Berl.) 47, 33–41 (1976)Google Scholar
  30. Randrup, A., Braestrup, C.: Uptake inhibition of biogenic amines by newer antidepressant drugs: relevance to dopamine hypothesis of depression. Psychopharmacologia (Berl.) 53, 309–314 (1977)Google Scholar
  31. Randrup, A., Munkvad, I.: Role of catecholamines in amphetamine excitatory response. Nature 211, 540 (1966)Google Scholar
  32. Roffler-Tarlov, S., Schildkraut, J. J.: Norepinephrine content and turnover in rat brain regions after acute and chronic treatment with desmethylimipramine (DMI). Fed. Proc. 30, 387 (1971)Google Scholar
  33. Roffler-Tarlov, S., Schildkraut, J. J., Draskóczy, P. R.: Effect of acute and chronic administration of desmethylimipramine on the content of norepinephrine and other monoamines in the rat brain. Biochem. Pharmacol. 22, 2923–2926 (1973)Google Scholar
  34. Rosloff, B. N., Davis, J. M.: Effect of iprindole on norepinephrine turnover and transport. Psychopharmacologia (Berl.) 40, 53–64 (1974)Google Scholar
  35. Saletu, B., Kreiger, P., Grünberger, J., Schanda, H., Sletten, I.: Tandamine — a new norepinephrine reuptake inhibitor. Int. Pharmacopsychiat. 12, 137–152 (1977)Google Scholar
  36. 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. Am. J. Psychiat. 127, 72–79 (1971)Google Scholar
  37. Schildkraut, J. J., Roffmann, M., Orsulak, P. J., Schatzberg, A. F., Kling, M. A., Reigle, Th. G.: Effects of short and long-term administration of tricyclic antidepressants and lithium on norepinephrine turnover in brain. Int. Pharmacopsychiat. 9, 193–202 (1976)Google Scholar
  38. Schubert, J., Nybach, H., Sedvall, G.: Effect of antidepressant drugs on the accumulation and disappearance of monoamines formed in vivo from labelled precursors in mouse brain. J. Pharm. Pharmacol. 22, 136–139 (1970)Google Scholar
  39. Todrich, A., Tate, A. C.: The inhibition of human platelet 5-hydroxytryptamine uptake by tricyclic antidepressive drugs. The relation between structure and potency. J. Pharm. Pharmacol. 21, 751–762 (1969)Google Scholar
  40. Welch, B. L., Hendley, E. D., Turek, I.: Norepinephrine uptake into cerebral cortical synaptosomes after one fight or electroconvulsive shock. Science 183, 220–221 (1974)Google Scholar
  41. Whitby, L. G., Axelrod, J., Weil-Malherbe, H.: The fate of 3H-norepinephrine in animals. J. Pharmacol. Exp. Ther. 132, 193–201 (1961)Google Scholar
  42. Yamamura, H. I., Snyder, S. H.: Muscarinic cholinergic binding in rat brain. Proc. Natl. Acad. Sci. USA 71, 1725–1729 (1974)Google Scholar

Copyright information

© Springer-Verlag 1979

Authors and Affiliations

  • T. A. Pugsley
    • 1
  • W. Lippmann
    • 1
  1. 1.Biochemical Pharmacology DepartmentAyerst Research LaboratoriesMontrealCanada

Personalised recommendations