The use of neurotoxic dihydroxytryptamines as tools for morphological studies and localized lesioning of central indolamine neurons

  • A. Björklund
  • A. Nobin
  • U. Stenevi


The usefulness of three neurotoxic dihydroxytryptamines — 5,6-dihydroxytryptamine, 5,7-dihydroxytryptamine and 4,5-dihydroxytryptamine — for fluorescence microscopical tracing and localized lesioning of central indolamine-containing axon bundles has been studied in the rat brain. The lesions produced by intraventricularly or intracerebrally administered dihydroxytryptamines were found to be much superior to mechanical or electrolytic lesions in producing extensive accumulations of fluorescence in the indolamine axon pathways. This greatly improves the possibilities for tracing of the normally non-fluorescent or weakly fluorescent indolamine axons from their cells of origin for long distances through the main fibre bundles and their branches. Much new information concerning the anatomy of the indolamine neuron systems is obtained with this technique, and some preliminary observations are presented.

The efficiency of local, intracerebral injections of small amounts of dihydroxytryptamines for regional denervations in the CNS was also tested. It was found that local injections of 4 μg of either of the three compounds into the ventromedial tegmentum and into the grey matter of the spinal cord produced extensive and probably rather selective damage to the ascending and descending indolamine fibre tracts and — although to a lesser and variable extent — the noradrenaline and dopamine systems. The denervating effects of the tegmental and the spinal cord injections were with respect to the serotonin-containing neurons comparable to those obtained by others after large lesions that destroy almost the entire midbrain raphe region, and after total transections of the spinal cord, respectively. The characteristics and the specificity of the dihydroxytryptamine-induced lesions are discussed.

Key words

Neurotoxic dihydroxytryptamines Central indolamine neurons Localized lesions Fluorescence microscopy 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Andén, N.-E., Dahlström, A., Fuxe, K., Larsson, K., Olson, L., Ungerstedt, U.: Ascending monoamine neurons to the telencephalon and diencephalon. Acta physiol. scand. 67, 313–326 (1966)Google Scholar
  2. Anderson, E.: Bulbospinal serotonin-containing neurons and motor control. Fed. Proc. 31, 107–112 (1972)Google Scholar
  3. Baumgarten, H. G., Björklund, A., Holstein, A., Nobin, A.: Chemical degeneration of indolamine axons in rat brain by 5,6-dihydroxytryptamine, an ultrastructural study. Z. Zellforsch. 129, 256–271 (1972a)Google Scholar
  4. Baumgarten, H. G., Björklund, A., Lachenmayer, L., Nobin, A.: Evaluation of the effects of 5,7-dihydroxytryptamine on serotonin and catecholamine neurons in the rat CNS. Acta physiol. scand., Suppl. 391, 1–20 (1973a)Google Scholar
  5. Baumgarten, H. G., Björklund, A., Lachenmayer, L., Nobin, A., Stenevi, U.: Long-lasting selective depletion of brain serotonin by 5,6-dihydroxytryptamine. Acta physiol. scand., Suppl. 373, 1–16 (1971)Google Scholar
  6. Baumgarten, H. G., Björklund, A., Nobin, A., Schlossberger, H. G.: Effects of several hydroxylated tryptamines on central monoamine neurons. In preparation (1973b)Google Scholar
  7. Baumgarten, H. G., Evetts, K. D., Holman, R. B., Iversen, L. L., Vogt, M., Wilson, G.: Effects of 5,6-dihydroxytryptamine on monoaminergic neurones in the central nervous system of the rat. J. Neurochem. 19, 1587–1597 (1972b)Google Scholar
  8. Baumgarten, H. G., Lachenmayer, L.: 5,7-Dihydroxytryptamine: Improvement in chemical lesioning of indoleamine neurons in the mammalian brain. Z. Zellforsch. 135, 399–414 (1972)Google Scholar
  9. Baumgarten, H. G., Lachenmayer, L., Björklund, A.: Nobin, A., Rosengren, E.: Long-term recovery of serotonin concentrations in the rat CNS following 5,6-dihydroxytryptamine. Life Sci. 12, 357–364 (1973c)Google Scholar
  10. Bertler, Å.: Effect of reserpine on the storage of catecholamines in brain and other tissues. Acta physiol. scand. 51, 75–83 (1961)Google Scholar
  11. Bertler, Å., Carlsson, A., Rosengren, E., Waldeck, B.: A method for the fluorimetric determinations of adrenaline, noradrenaline, and dopamine in tissues. Kungl. Fysiogr. Sällsk. Lund Förh. 28, 121–123 (1958)Google Scholar
  12. Björklund, A., Falck, B., Owman, Ch.: Fluorescence microscopic and microspectro-fluorometric techniques for the cellular localization and characterization of biogenic amines. In: Methods of investigative and diagnostic endocrinology (ed. S. A. Berson) vol. 1: The thyroid and biogenic amines (eds. J. E. Rall and I. J. Kopin), p. 318–368. Amsterdam. North-Holland Publ. Co. 1972aGoogle Scholar
  13. Björklund, A., Falck, B., Stenevi, U.: Microspectrofluorimetric characterization of monoamines in the central nervous system: Evidence for a new neuronal monoamine-like compound. In: Progress in brain research (ed. O. Eränkö), vol. 34: Histochemistry of nervous transmission, p. 63–73, Amsterdam: Elsevier 1971 aGoogle Scholar
  14. Björklund, A., Falck, B., Stenevi, U.: Classification of monoamine neurones in the rat mesencephalon: Distribution of a new monoamine neurone system. Brain Res. 32, 269–285 (1971b)Google Scholar
  15. Björklund, A., Nobin, A.: Fluorescence histochemical and microspectrofluorometric mapping of dopamine and noradrenaline cell groups in the rat diencephalon. Brain Res. 51, 193–205 (1973)Google Scholar
  16. Björklund, A., Nobin, A., Stenevi, U.: Effects of 5,6-hydroxytryptamine on nerve terminal serotonin and serotonin uptake in the rat brain. Brain Res. 53, 117–127 (1973a)Google Scholar
  17. Björklund, A., Nobin, A., Stenevi, U.: Regeneration of central serotonin neurons after axonal degeneration induced by 5,6-dihydroxytryptamine. Brain Res. 50, 214–220 (1973b)Google Scholar
  18. Björklund, A., Owman, Ch., West, K. A.: Peripheral sympathetic innervation and serotonin cells in the habenular region of the rat brain. Z. Zellforsch. 127, 570–579 (1972b)Google Scholar
  19. Carlsson, A., Magnusson, T., Rosengren, E.: 5-Hydroxytryptamine of the spinal cord normally and after transection. Experientia (Basel) 19, 359–360 (1963)Google Scholar
  20. Dahlström, A., Fuxe, K.: Evidence for the existence of monoamine-containing neurons in the central nervous system: I. Demonstration of monoamines in the cell bodies of brain stem neurones. Acta physiol. scand. 62, Suppl. 232, 1–55 (1964)Google Scholar
  21. Daly, J., Fuxe, K., Jonsson, G.: Effects of intracerebral injections of 5,6-dihydroxytryptamine on central monoamine neurons. Evidence for selective degeneration of central 5-hydroxytryptamine neurons. Brain Res. 49, 476–482 (1973)Google Scholar
  22. Fuxe, K., Hökfelt, T., Ungerstedt, U.: Localization of indolealkylamines in CNS. Advanc. Pharmacol. 6, 235–251 (1968)Google Scholar
  23. Fuxe, K., Jonsson, G.: A modification of the histochemical fluorescence method for the improved localization of 5-hydroxytryptamine. Histochemie 11, 161–166 (1967)Google Scholar
  24. Green, A. R., Koslow, S. H., Costa, E.: Identification and quantitation of a new indolealkylamine in rat hypothalamus. Brain Res. 51, 371–374 (1973)Google Scholar
  25. Häggendal, J.: An improved method for fluorometric determination of small amounts of adrenaline and noradrenaline in plasma and tissues. Acta physiol. scand. 59, 242–254 (1963)Google Scholar
  26. Hamberger, B.: Reserpine-resistant uptake of catecholamines in isolated tissues of the rat. Acta physiol. scand., Suppl. 295, 1–47 (1967)Google Scholar
  27. Heller, A., Harvey, J. A., Moore, R. Y.: A demonstration of a fall in brain serotonin following central nervous system lesions in the rat. Biochem. Pharmacol. 11, 859–866 (1962)Google Scholar
  28. Horn, A. S., Baumgarten, H. G., Schlossberger, H. G.: Inhibition of the uptake of 5-hydroxytryptamine, noradrenaline and dopamine into rat brain homogenates by various hydroxylated tryptamines. J. Neurochem. 21, 233–236 (1973)Google Scholar
  29. Jonsson, G.: Studies on the uptake and accumulation of 3H-6-hydroxydopamine in adrenergic nerves. In: 6-Hydroxydopamine and catecholamine neurons (eds. T. Malmfors and H. Thoenen), p. 243–256. Amsterdam: North-Holland Pubsl. Co. 1971Google Scholar
  30. Kuhar, M. J., Aghajanian, G. K., Roth, R. H.: Tryptophan hydroxylase activity and synaptosomal uptake of serotonin in discrete brain regions after midbrain raphe lesions: Correlations with serotonin levels and histochemical fluorescence. Brain Res. 44, 165–176 (1972)Google Scholar
  31. Kuhar, M. J., Roth, R. H., Aghajanian, G. K.: Selective reduction of tryptophan hydroxylase activity in rat forebrain after midbrain raphe lesions. Brain Res. 35, 167–176 (1971)Google Scholar
  32. Moore, R. Y.: Brain lesions and amine metabolism. Int. Rev. Neurobiol. 13, 67–91 (1970)Google Scholar
  33. Moore, R. Y., Bhatnagar, R. K., Heller, A.: Anatomical and chemical studies of a nigroneostriatal projection in the cat. Brain Res. 30, 119–135 (1971)Google Scholar
  34. Moore, R. Y., Heller, A.: Monoamine levels and neuronal degeneration in rat brain following lateral hypothalamic lesions. J. Pharmacol. exp. Ther. 156, 12–22 (1967)Google Scholar
  35. Nobin, A., Baumgarten, H. G., Björklund, A., Lachenmayer, L., Stenevi, U.: Axonal degeneration and regeneration of the bulbo-spinal indolamine neurons after 5,6-dihydroxytryptamine treatment. Brain Res. 56, 1–24 (1973)Google Scholar
  36. Poirier, L. J., Langelier, P., Roberge, A., Boucher, R., Kitsikis, A.: Non-specific histopathological changes induced by the intracerebral injection of 6-hydroxydopamine. J. neurol. Sci. 16, 401–416 (1972)Google Scholar
  37. Sachs, Ch., Jonsson, G.: Degeneration of central and peripheral noradrenaline neurons produced by 6-hydroxy-DOPA, J. Neurochem. 19, 1561–1575 (1972)Google Scholar
  38. Saner, A., Thoenen, H.: Contributions to the molecular mechanism of action of 6-hydroxydopamine. In: 6-Hydroxydopamine and catecholamine neurons (eds. T. Malmfors and H. Thoenen), p. 265–276. Amsterdam: North-Holland Publ. Co. 1971Google Scholar
  39. Ungerstedt, U.: 6-Hydroxydopamine induced degeneration of central monoamine neurons. Europ. J. Pharmacol. 5, 107–110 (1968)Google Scholar
  40. Ungerstedt, U.: Histochemical studies on the effects of intracerebral and intraventricular injections of 6-hydroxydopamine on monoamine neurons in the rat brain. In: 6-Hydroxydopamine and catecholamine neurons (eds. T. Malmfors and H. Thoenen), p. 101–127. Amsterdam: North-Holland Publ. Co. 1971aGoogle Scholar
  41. Ungerstedt, U.: Stereotaxic mapping of the monoamine pathways in the rat brain. Acta physiol. scand., Suppl. 367, 1–48 (1971b)Google Scholar

Copyright information

© Springer-Verlag 1973

Authors and Affiliations

  • A. Björklund
    • 1
  • A. Nobin
    • 1
  • U. Stenevi
    • 1
  1. 1.Department of HistologyUniversity of LundSweden

Personalised recommendations