Skip to main content
SpringerLink
Log in

Evidence that punctate intracerebral administration of 6-hydroxydopamine fails to produce selective neuronal degeneration

Comparison with copper sulfate and factors governing the deportment of fluids injected into brain

  • Published:
Naunyn-Schmiedeberg's Archives of Pharmacology Aims and scope Submit manuscript

Summary

Various doses of 6-hydroxydopamine (6-OHDA) and copper sulfate were injected into brain regions having a different composition of monoamine-containing neurons: The red nucleus, substantia nigra-ventral tegmental area, caudate-putamen nucleus, and thalamus. Brains were subsequently histochemically processed for acetylcholinesterase and NADH-diaphorase activities and for cupric ion; traditional histology was also performed. A maximum of four regions of neuropathology was observed occurring successively in relation to the cannula: (1) A zone of complete absence of neural, glial, and vascular elements due to tissue displacement by the cannula, (2) an area consisting of a dense layer of glia cells 0.05–0.2 mm thick immediately surrounding the cannula tract, (3) a region exhibiting virtually complete loss of neural elements accompanied over time by extensive gliosis, and (4) a zone of neuronal loss probably occurring as a function of retrograde degeneration and/or reaction to other injury processes. Intracerebral insertion of the cannula without fluid infusion or injections of the respective vehicles of CuSO4 and 6-OHDA produced Zone 1 and 2 degeneration at all sites tested; Zone 4 damage was also seen but reliably only in the red nucleus and substantia nigra. Injection of solutions of 6-OHDA and CuSO4 produced Zone 1, 2, and 3 degeneration at all target areas tested. Zone 3 damage was the most prominent neuropathology, and Zone 4 cell loss was observed only in relation to the special anatomical characteristics of the neurons in the brain region infused. It was found that the degree of myelination of a particular brain region markedly influenced the nature and extent of Zone 3 damage.

Extensive neuronal degeneration was seen after intrarubral administration of 6-OHDA even though the cell bodies of the red nucleus contain neither dopamine nor noradrenaline. The rigidity and hypokinesia produced by bilateral 6-OHDA injection into the substantia nigra-ventral tegmental area were very similar to the motor manifestations produced by CuSO4. No dose of 6-OHDA was found which both (1) produced neuronal degeneration attributable unequivocally to the action of the drug and (2) affected only those neurons having a particular type of neurotransmitter. We conclude that specificity of neuron destruction can be achieved with 6-OHDA only to the extent that the drug is injected into brain regions which are neurochemically homogeneous. The discrepancies between the interpretation of other investigators and our own results concerning the neurotoxic specificity of 6-OHDA can be resolved by considering the basic morphological characteristics of the neurons affected (e.g., Golgi Type I or II), the topography of the neural region injected (e.g., heavily myelinated or not), and more traditional processes such as retrograde and anterograde degeneration and classical injury reactions.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Agid, Y., Javoy, F., Glowinski, J., Bovet, D., Sotelo, C.: Injection of 6-hydroxydopamine into the substantia nigra of the rat. II. Diffusion and specificity. Brain Res. 58, 291–301 (1973)

    Google Scholar 

  • 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 

  • Andén, N.-E., Fuxe, K., Hamberger, B., Hökfelt, T.: A quantitative study on the nigro-neostriatal dopamine neuron system in the rat. Acta physiol. scand. 67, 306–312 (1966)

    Google Scholar 

  • Andén, N.-E., Fuxe, K., Ungerstedt, U.: Monoamine pathways to the cerebellum and cerebral cortex. Experientia (Basel) 23, 838 (1967)

    Google Scholar 

  • Bartholini, G., Richards, J. G., Pletscher, A.: Dissociation between biochemical and ultrastructural effects of 6-hydroxydopamine in rat brain. Experientia (Basel) 26, 142–144 (1970)

    Google Scholar 

  • Breese, G. R., Cooper, B. R., Smith, R. D.: Biochemical and behavioural alterations following 6-hydroxydopamine administration into brain. In: E. Usdin and S. H. Snyder (Eds.): Frontiers in catecholamine research, pp. 701–706 New York: Pergamon Press, Inc. 1973

    Google Scholar 

  • Breese, G. R., Kopin, I. J., Weise, V. K.: Effects of amphetamine derivatives on brain dopamine and norepinephrine. Brit. J. Pharmacol. 38, 537–545 (1970)

    Google Scholar 

  • Breese, G. R., Traylor, T. D.: Depletion of brain noradrenaline and dopamine by 6-hydroxydopamine. Brit. J. Pharmacol. 42, 88–99 (1971)

    Google Scholar 

  • Butcher, L. L., Fox, S. S.: Motor effects of copper in the caudate nucleus: Reversible lesions with ion-exchange resin beads. Science, 160, 1237–1238 (1968)

    Google Scholar 

  • Butcher, S. G., Butcher, L. L.: Origin and modulation of acetylcholine activity in the neostriatum. Brain Res. 71, 167–171 (1974)

    Google Scholar 

  • Cajal, S. Ramon y: Histologie du système nerveux de l'homme et des vertébres. Paris: Maloine 1909

    Google Scholar 

  • Cammermeyer, J.: Nonspecific changes of the central nervous system in normal and experimental material In: G. H. Bourne (Ed.) The structure and function of nervous tissue, Volume VI, Structure IV and Physiology II, pp. 131–251. New York: Academic Press 1972

    Google Scholar 

  • Cohen, E. B., Pappas, G. D.: Dark profiles in the apparently-normal central nervous system: A problem in the electron microscopic identification of early anterograde axonal degeneration. J. comp. Neurol. 136, 375–396 (1969)

    Google Scholar 

  • 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 neurons. Acta physiol. scand., Suppl. 232 62, 1–55 (1964)

    Google Scholar 

  • Evetts, K. D., Iversen, L. L.: Effects of protriptyline on depletion of catecholamines induced by 6-hydroxydopamine. J. Pharm. Pharmacol. 22, 540–543 (1970)

    Google Scholar 

  • Friede, R. L.: A histochemical atlas of tissue oxidation in the brain stem of the cat. Basel-New York: S. Karger 1961

    Google Scholar 

  • Friede, R. L.: Topographic brain chemistry. New York: Academic Press 1966.

    Google Scholar 

  • Gulley, R. L., Wood, R. L.: The fine structure of the neurons in the rat substantia nigra. Tissue and Cell 3, 675–690 (1971)

    Google Scholar 

  • Hedreen, J. C., Chalmers, J. P.: Neuronal degeneration in rat brain induced by 6-hydroxydopamine: A histological and biochemical study. Brain Res. 47, 1–36 (1972)

    Google Scholar 

  • Heikkila, R., Cohen, G.: Inhibition of biogenic amine uptake by hydrogen peroxide: A mechanism for toxic effects of 6-hydroxydopamine. Science 172, 1257–1258 (1971)

    Google Scholar 

  • Hökfelt, T., Ungerstedt, U.: Specificity of 6-hydroxydopamine induced degeneration of central monoamine neurons: An electron and fluorescence microscopic study with special reference to intracerebral injection on the nigro-striatal dopamine system. Brain Res. 60, 269–297 (1973)

    Google Scholar 

  • Jonsson G.: Comment in discussion on effect of 6-hydroxydopamine on the peripheral adrenergic nerves. In: T. Malmfors and H. Thoenen (Eds.): 6-Hydroxydopamine and catecholamine neurons, p. 349. Amsterdam: North Holland Publ. Co. 1971

    Google Scholar 

  • Jonsson, G., Sachs, C.: Degenerative and nondegenerative effects of 6-hydroxydopamine on adrenergic nerves. J. Pharmacol. exp. Ther. 180, 625–635 (1972)

    Google Scholar 

  • Karnovsky, M. J., Roots, L.: A direct-coloring thiocholine method for cholinesterase. J. Histochem. Cytochem. 12, 219–221 (1964)

    Google Scholar 

  • Kemp, J. M., Powell, T. P. S.: The structure of the caudate nucleus of the cat: Light and electron microscopy. Phil. Trans. B 262, 383–401 (1971)

    Google Scholar 

  • Kim, J.-S.: Effects of 6-hydroxydopamine on acetylcholine and GABA metabolism in rat striatum. Brain Res. 55, 472–475 (1973)

    Google Scholar 

  • Klüver, H., Barrera, E. J.: A method for the combined staining of cells and fibers in the nervous system. J. Neuropath. exp. Neurol. 12, 400–403 (1953)

    Google Scholar 

  • Kostrzewa, R., Jacobowitz, D.: Acute effects of 6-hydroxydopa on central monoamine neurons. Europ. J. Pharmacol. 21, 70–80 (1973)

    Google Scholar 

  • Longo, V. G.: Central effects of 6-hydroxydopamine. Behav. Biol. 9, 397–420 (1973)

    Google Scholar 

  • Lynch, G. S., Lucas, P. A., Deadwyler, S. A.: The demonstration of acetylcholinesterase containing neurons within the caudate nucleus of the rat. Brain Res. 45, 617–621 (1972)

    Google Scholar 

  • Maler, L., Fibiger, H. C., McGeer, P. L.: Demonstration of the nigro-striatal projection by silver staining after nigral injections of 6-hydroxydopamine. Exp. Neurol. 40, 505–515 (1973)

    Google Scholar 

  • Malmfors, T., Thoenen, H. (Eds.): 6-Hydroxydopamine and catecholamine neurons. Amsterdam: North-Holland Publ. Co. 1971

    Google Scholar 

  • McGeer, P. L., McGeer, E. G., Fibiger, H. C., Wickson, V.: Neostriatal cholineacetylase and cholinesterase following selective brain lesions. Brain Res. 35, 308–314 (1971)

    Google Scholar 

  • Miller, R. A., Strominger, N. L.: Efferent connections of the red nucleus in the brainstem and spinal cord of the rhesus monkey. J. comp. Neurol. 152, 327–346 (1973)

    Google Scholar 

  • Moore, R. Y., Bhatnagar, R. K., Heller, A.: Anatomical and chemical studies of a nigro-striatal projection in the cat. Brain Res. 30, 119–135 (1971)

    Google Scholar 

  • Myers, R. D.: Injection of solutions into cerebral tissues: Relation between volume and diffusion. Physiol. Behav. 1, 171–174 (1966)

    Google Scholar 

  • Nicklas, W. J., Berl, S.: In vivo studies on the effect of 6-hydroxydopamine on amino acid metabolism in brain. Brain. Res. 61, 343–356 (1973)

    Google Scholar 

  • Pearse, A. G. E.: Histochemistry: theoretical and applied, Vol. 2, Third Edition. Baltimore: Williams and Wilkins 1972

    Google Scholar 

  • Pellegrino, L. J., Cushman, A. J.: A stereotaxic atlas of the rat brain. New York: Appleton-Century-Crofts 1967

    Google Scholar 

  • Poirier, L. J., Langelier, P., Roberge, A., Boucher, R., Kitsikis, A.: Non-specific histopathological changes induced by the intracerebral injection of 6-hydroxydopamine (6-OH-DA). J. neurol. Sci. 16, 401–416 (1972)

    Google Scholar 

  • Porter, C. C., Totaro, J. A., Stone, C. A.: Effect of 6-hydroxydopamine and some other compounds on the concentration of norepinephrine in the hearts of mice. J. Pharmacol. exp. Ther. 140, 308–316 (1963)

    Google Scholar 

  • Saner, A., Thoenen, H.: Contributions to the molecular mechanism of action of 6-hydroxydopamine. In: T. Malmfors and H. Thoenen (Eds.): 6-hydroxydopamine and catecholamine neurons, pp. 265–275. Amsterdam: North-Holland Publ. Co. 1971

    Google Scholar 

  • Schubert, P., Kreutzberg, G. W., Reinhold, K., Herz, A.: Selective uptake of 3H-6-hydroxydopamine by neurons of the central nervous system. Exp. Brain Res. 17, 539–548 (1973)

    Google Scholar 

  • Skinner, J. E.: Neuroscience: a laboratory manual, p. 137. Philadelphia: W. B. Saunders 1971

    Google Scholar 

  • Sotelo, C., Javoy, F., Agid, Y., Glowinski, J.: Injection of 6-hydroxydopamine in the substantia nigra of the rat. I. Morphological study. Brain Res. 58, 269–290 (1973)

    Google Scholar 

  • Thoenen, H., Tranzer, J. P.: Chemical sympathectomy by selective destruction of adrenergic nerve endings with 6-hydroxydopamine. Naunyn-Schmiedebergs Arch. Pharmak. exp. Path. 261, 271–288 (1968)

    Google Scholar 

  • Thoenen, H., Tranzer, J. P.: The pharmacology of 6-hydroxydopamine. Ann. Rev. Pharmacol. 13, 169–180 (1973)

    Google Scholar 

  • Tranzer, J. P., Thoenen, H.: An electron microscopic study of selective, acute degeneration of sympathetic nerve terminals after administration of 6-hydroxydopamine. Experientia (Basel) 24, 155–156 (1968)

    Google Scholar 

  • Ungerstedt, U.: Histochemical studies on the effect of intracerebral and intraventricular injections of 6-hydroxydopamine on monoamine neurons in the rat brain. In: T. Malmfors and H. Thoenen (Eds.): 6-Hydroxydopamine and catecholamine neurons, pp. 101–127. Amsterdam: North-Holland Publ. Co. 1971a

    Google Scholar 

  • Ungerstedt, U.: Stereotaxic mapping of the monoamine pathways in the rat brain. Acta physiol. scand., Suppl. 367, 1–48 (1971b)

    Google Scholar 

  • Ungerstedt, U.: Use of intracerebral injections of 6-hydroxydopamine as a tool for morphological and functional studies on central catecholamine neurons. In: T. Malmfors and H. Thoenen (Eds.): 6-Hydroxydopamine and catecholamine Neurons, pp. 315–332. Amsterdam: North-Holland Publ. Co. 1971c

    Google Scholar 

  • Ungerstedt, U., Butcher, L. L., Butcher, S. G., Andén, N.-E., Fuxe, K.: Direct chemical stimulation of dopaminergic mechanisms in the neostriatum of the rat. Brain Res. 14, 461–471 (1969)

    Google Scholar 

  • Uzman, L. L.: The nature of copper-binding in normal and Wilson's disease brains. In: J. Folch-Pi (Ed.): Chemical pathology of the nervous system, pp. 151–159. London: Pergamon-Press 1961

    Google Scholar 

  • Walshe, J. M.: The biochemistry of copper in man and its role in the pathogenesis of Wilson's disease (hepatolenticular degeneration). In: J. N. Cumings (Ed.): Biochemical aspects of nervous disease, pp. 111–150. New York: Plenum Press 1972

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Psychology, University of California, 90024, Los Angeles, California, 90024, USA

    Larry L. Butcher, Sheila M. Eastgate & Gordon K. Hodge

Authors
  1. Larry L. Butcher
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sheila M. Eastgate
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gordon K. Hodge
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Butcher, L.L., Eastgate, S.M. & Hodge, G.K. Evidence that punctate intracerebral administration of 6-hydroxydopamine fails to produce selective neuronal degeneration. Naunyn-Schmiedeberg's Arch. Pharmacol. 285, 31–70 (1974). https://doi.org/10.1007/BF00499527

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00499527

Key words

Search

Navigation