Central Noradrenergic Receptors: Localization, Function and Molecular Mechanisms

  • Floyd E. Bloom
  • Barry J. Hoffer
  • George R. Siggins


Fluorescence histochemical data make it eminently clear that the catecholamine-containing neurons of the brain are restricted to a relatively small region of the pons and mesencephalon and yet send very discrete axonal tracts to spinal cord, diencephalon and cortices. In order to determine the effects of norepinephrine (NE) on postsynaptic neurons and the changes in these effects produced by drugs which influence behavior, the location and function of the presumed NE-mediated synapses must be determined for each of the regions receiving these fibers. Such data has now been accumulated in detail for the NE projection to the cerebellum (see below) and has been partially elucidated for several other regions. This paper will describe the methods now being used in our laboratory to determine the localization and function of NE-mediated synapses.


Purkinje Cell Locus Coeruleus Mitral Cell Lateral Olfactory Tract Spontaneous Discharge Rate 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Aghajanian, G. K. 1972. LSD and CNS transmission. Ann. Rev. Pharmacol. 12: 157.PubMedCrossRefGoogle Scholar
  2. Aghajanian, G. R. and Bloom, F. E. 1967. Electron-microscopic localization of tritiated norepinephrine in rat brain effects of drugs. Pharmacol. Exp. Ther. 156: 407.Google Scholar
  3. Barker, J. L., Crayton, J. C., and Nicoll, R. A. 1971. Supraoptic neurosecretory cells: Adrenergic and cholinergic sensitivity. Science 171: 208.PubMedCrossRefGoogle Scholar
  4. Bloom, F. E. 1968. Electrophysiological pharmacology of single nerve cells. In: Psychopharmacology, A 10 Year Progress Report (Ed. Effron, D.H.) Washington, D.C.: U.S. Govt. Printing Office.Google Scholar
  5. Bloom, F. E. 1971. Fine structural changes in rat brain after intracisternal injection of 6-hydroxydopamine. In: 6-Hydroxydopamine (Eds. Malmors, T. and Thoenen, H.) Amsterdam: North Holland Publishing Co., pp. 135.Google Scholar
  6. Bloom, F. E. and Costa, E. 1971. The effects of drugs on serotonergic nerve terminals. In: Advances in Cytopharmacology (Ed. Edelson, E.) New York: Raven Press, Vol. I., pp. 379.Google Scholar
  7. Bloom, F. E., von Baumgarten, R., Oliver, A. P., Costa, E. and Salmioraghi, G.C. 1964 a. Microelectrophoretic studies on adrenergic mechanisms of rabbit olfactory bulb neurons. Life Sci. 3: 131.PubMedCrossRefGoogle Scholar
  8. Bloom, F. E., Costa, E. and Salmoiraghi, G. C. 1964 b. Analysis of individual rabbit olfactory bulb neuron response to microelectrophoresis of acetylcholine, norepinephrine and serotonin synergists and antagonists. Pharmacol. Exp. Ther. 146: 16.Google Scholar
  9. Bloom, F. E., Hoffer, B. J. and Siggins, G. R. 1971 Studies on norepinephrine-containing afferents to Purkinje cells of rat cerebellum: I. Localization of the fibers and their synapses. Brain Res. 25: 501.PubMedCrossRefGoogle Scholar
  10. Bloom, F. E., Battenberg, E., Hoffer, B. J., Siggins, G. R., Steiner, A.L., Parker, C.W. and Wedner, H. J. 1972. Noradrenergic stimulation of cyclic adenosine monophosphate in rat Purkinje neurons. Science (submitted for publication).Google Scholar
  11. Bloom, F. E., Hoffer, B. J. and Siggins, G. R. 1972. Norepinephrine mediated synapses: A model system for neuropsychopharmacology. Biol. Psychiat. 4(2): 157.PubMedGoogle Scholar
  12. Boakes, R. J., Bradley, P. B., Brookes, N., Candy, J. M. and Wolstencroft J. H. 1971. Actions of noradrenaline, other sympathomimetic amines and antagonists on neurones in the brainstem of the cat. Brit. J. Pharmacol. 41: 262.Google Scholar
  13. Bradley, P. B. and Wolstencroft, J. H. 1962. Excitation and inhibition of brainstem neurones by noradrenaline and acetylcholine. Nature 196: 840.PubMedCrossRefGoogle Scholar
  14. Breckenridge, B. 1964. The measurement of cyclic adenylate in tissues. Proc. Nat. Acad. Sci. 52: 1580.PubMedCrossRefGoogle Scholar
  15. Butcher, R. W. and Baird, C. E. 1968. Effects of prostaglandins on adenosine 3′,5′-monophosphate levels in fat and other tissues. J. Biol. Chem. 243: 1713.PubMedGoogle Scholar
  16. Chu, N-S. and Bloom, F. E. 1972. Single neuron activity of the norepinephrine-containing locus coeruleus nucleus of the brainstem in the cats. Fed. Proc. 31: 377.Google Scholar
  17. Couch, J.R. 1970. Responses of neurons in the raphe nuclei to serotonin, norepinephrine and acetylcholine and their correlation with an excitatory synaptic input. Brain Res. 19: 137.PubMedCrossRefGoogle Scholar
  18. Crayton, J. C. and Bloom, F. E. 1969. Responsiveness of cat raphe nucleus to microelectrophoresis of norepinephrine and serotonin. Anat. Rec. 163: 173.Google Scholar
  19. Cowan, M. W., Gottlieb, D. I., Hendrickson, A. E., Price, J. L. and Woolsey, T. A. 1972. The autoradiographic demonstration of axonal connections in the central nervous system. Brain Res. 37: 21.PubMedCrossRefGoogle Scholar
  20. Dahlström, A. and Fuxe, K. 1964. Evidence for the existence of monoamine-containing cell bodies. Acta. Physiol. Scand. 62:Suppl. 232.Google Scholar
  21. Dahlström, A., Fuxe, K., Olson, L. and Ungerstedt, U. 1965. On the distribution and possible function of monoamine nerve terminals in the olfactory bulb of the rabbit. Life Sci. 4: 2071PubMedCrossRefGoogle Scholar
  22. Falck, B., Hillarp, N-A., Thieme, G. and Torp, A. 1962. Fluorescence of catecholamines and related compounds condensed with formaldehyde. J. Histochem. Cytochem. 10: 348.CrossRefGoogle Scholar
  23. Frederickson, R.C.A., Jordan, L.M. and Phillis, J.W. 1971. The action of noradrenaline on cortical neurons: effect of. Brain Res. 35: 556.PubMedCrossRefGoogle Scholar
  24. Fuxe, F., Hokfelt, T. and Ungerstedt, U. 1970. Morphological and functional aspects of central monoamine neurons. Int. Rev. Neurobiol. 13: 93.CrossRefGoogle Scholar
  25. Glowinski, J. and Baldessarini, R. J. 1966. Metabolism of norepinephrine in the central nervous system. Pharmacol. Rev. 18: 1201.PubMedGoogle Scholar
  26. Hebb, C. 1970. CNS at the cellular level: identity of transmitter agents. Ann. Rev. Physiol. 32: 165.CrossRefGoogle Scholar
  27. Hoffer, B. J., Siggins, G. R. and Bloom, F. E. 1971 a. Studies on norepinephrine-containing afferents to Purkinje cells of rat cerebellum: II. Sensitivity of Purkinje cells to norepinephrine and related substances administered by microiontophoresis. Brain Res. 25: 523.PubMedCrossRefGoogle Scholar
  28. Hoffer, B. J., Siggins, G. R., Oliver, A. P. and Bloom, F.E. 1971 b. Cyclic AMP mediation of norepinephrine inhibition in rat cerebellar cortex: A unique class of synaptic responses. Ann. N.Y. Acad. Sci. 185: 531.PubMedCrossRefGoogle Scholar
  29. Hoffer, B. J., Chu, N-s., and Oliver, A. P. 1972. Cytochemical and electrophysiological studies on central catecholamine-containing neurons. Proc. Vth Intl. Congress Pharmacol., pp. 103.Google Scholar
  30. Hökfelt, T. 1967. Electron microscopic studies on brain slices from regions rich in catecholamine terminals. Acta. Physiol. Scand. 69: 119.PubMedCrossRefGoogle Scholar
  31. Hökfelt, T. 1968. In vitro studies on central and peripheral monoamine neurons at the ultrastructural level. Z. Zellforsch. 91: 1.PubMedCrossRefGoogle Scholar
  32. Hökfelt, T. 1972. Ultrastructural localization of intra-neuronal monoamines - some aspects on methodology. Prog. Brain Res. 34: 213.CrossRefGoogle Scholar
  33. Hökfelt, T. and Fuxe, K. 1969. Cerebellar monoamine nerve terminals, a new type of afferent fiber to the cortex cerebelli. Exp. Brain Res. 9: 63.PubMedCrossRefGoogle Scholar
  34. Iversen, L.L. 1967. The Uptake and Storage of Noradrenaline in Sympathetic Nerves, Cambridge University Press.Google Scholar
  35. Iversen, L. L. and Uretsky, N. J. 1971. Biochemical effects of 6-hydroxydopamine on catecholamine-containing neurons in the rat central nervous system. In: 6-Hydroxydopamine. (Eds. Malmfors, T. and Thoenen, H.) Amsterdam: North Holland Publishing Co., pp. 171.Google Scholar
  36. Johnson, E. S., Roberts, M.H.T., Sobieszek, A. and Straughan, D.W. 1969 a. Noradrenaline sensitive cells in cat cerebral cortex. Int. J. Neuropharmacol. 8: 549.PubMedCrossRefGoogle Scholar
  37. Johnson, E. S., Roberts, M.H.T. and Straughan, D. W. 1969 b. The responses of cortical neurones to monoamines under differing anaesthetic conditions. J. Physiol (Lond) 203: 261.Google Scholar
  38. Jones, B. E., Bobillier, P. and Jouvet, M. 1969. Effects de la destruction des neurones contenant des catecholamines du mesencephale sur le cycle veille sommeils du chat. C. R. Soc. Biol. Paris 163: 176.PubMedGoogle Scholar
  39. Jouvet, M. 1969. Biogenic amines and the state of sleep. Science 163: 32.PubMedCrossRefGoogle Scholar
  40. Kakiuchi, S. and Rall, T. W. 1968. The influence of chemical agents on the accumulation of adenosine 3′,5′-phosphate in slices of rabbit cerebellum. Molec. Pharmacol. 4: 367.Google Scholar
  41. Krishna, G., Weiss, B. W., Davies, J. L. and Hynie, S. 1966. Mechanism of nicotinic acid inhibition of hormone-indueed lipolysis. Fed. Proc. 25: 719.Google Scholar
  42. Krnjevic, K. and Phillis, J. W. 1963 a. Actions of certain amines on cerebral cortical neurones. Brit. J. Pharmacol. 20: 471.PubMedGoogle Scholar
  43. Krnjevic, K. and Phillis, J. W. 1963 b. Iontophoretic studies of cortical neurones in the mammalian cerebral cortex. J. Physiol. (Lond) 165: 274.Google Scholar
  44. Kukovetz, W. R. and Poch, G. 1970. Cardiostimulatory effects of cyclic 3′,5′-adenosine monophosphate and its acylated derivatives. Naunyn-Schmiedeberg Arch. Pharmak. 266: 236.CrossRefGoogle Scholar
  45. Larramendi, L.M.H. 1969. Analysis of synaptogenesis in the cerebellum of the mouse. In: Neurobiology of Cerebellar Evolution and Development. (Ed. Llinas, R.) Chicago: Amer. Med. Ass. Press, pp. 803.Google Scholar
  46. Lenn, N. J. 1967. Localization of uptake of tritiated norepinephrine by rat brain in vivo and in vitro using electron microscopy. Amer. J. Anat. 120: 377.CrossRefGoogle Scholar
  47. Lish, P. M., Weikel, J. H. and Dugan, K. W. 1965. Pharmacological and toxicological properties of two new β-adrenergic receptor antagonists. J. Pharmacol. Exp. Ther. 149: 161.PubMedGoogle Scholar
  48. Loizou, L. A. 1969. Projections of the nucleus locus coeruleus in the albino rat. Brain Res. 15: 563.PubMedCrossRefGoogle Scholar
  49. Malmfors, T. and Thoenen, H. (Eds.) 1971. 6-Hydroxydopamine and Catecholamine Neurons. Amsterdam: North Holland Publishing Co., pp. 368.Google Scholar
  50. Nelson, C. N., Hoffer, B. J., and Bloom, F. E. 1972. Evidence for monoamine inputs to frontal polysensory cortex in the squirrel monkey. Fed. Proc. 31: 270.Google Scholar
  51. Nelson, J., Sheu, Y-s. and Bloom, F. E. 1972. A chronic microelectrode advancer (in preparation).Google Scholar
  52. Nicoli, R. A. and Barker, J. L. 1971. The pharmacology of recurrent inhibition in the supraoptic neurosecretory system. Brain Res. 35: 501.CrossRefGoogle Scholar
  53. O′Leary, J. L., Petty, J., Smith, J. M., O′Leary, M. and Inukai, J. 1968. Cerebellar cortex of rat and other animals. A structural and ultrastructurai study. Comp. Neurol. 134: 401.CrossRefGoogle Scholar
  54. Olson, L. and Fuxe, K. 1971. On the projections from the locus coeruleus noradrenaline neurons. Brain Res. 28: 165.PubMedCrossRefGoogle Scholar
  55. Richardson, K. C. 1966. Electron microscopic identification of autonomic nerve fibers. Nature 210: 756.PubMedCrossRefGoogle Scholar
  56. Salmoiraghi, G. C. and Bloom, F. E. 1964. The pharmacology of individual neurons. Science 144: 493.PubMedCrossRefGoogle Scholar
  57. Salmoiraghi, G. C. and Stefanis, C. 1967. A critique of iontophoretic studies of central nervous system neurons. Int. Rev. Neurobiol. 10: 1.PubMedCrossRefGoogle Scholar
  58. Salmoiraghi, G. C. and Weight, F. F. 1967. Micromethods in neuropharmacology: An approach to the study of anesthetics. Anesthesiology 28: 54.PubMedCrossRefGoogle Scholar
  59. Salmoiraghi, G. C., Bloom, F. E. and Costa, E. 1964. Adrenergic mechanisms in rabbit olfactory bulb. Am. J. Physiol. 207: 1417.PubMedGoogle Scholar
  60. Siggins, G. R., Hoffer, B. J. and Bloom, F. E. 1969. Cyclic adenosine monophosphate: Possible mediator for norepinephrine effects on cerebellar Purkinje cells. Science 165: 1018.PubMedCrossRefGoogle Scholar
  61. Siggins, G. R., Hoffer, B. J. and Bloom, F. E. 1971 a. Studies on norepinephrine-containing afferents to Purkinje cells of rat cerebellum. III. Evidence for mediation of norepinephrine effects by cyclic 3′ 5′-adenosine monophosphate. Brain Res. 25: 535.PubMedCrossRefGoogle Scholar
  62. Siggins, G. R., Hoffer, B. J. and Bloom, F. E. 1971 b. Prostaglandin norepinephrine interactions in brain: Microelectrophoretic and histochemical correlates. Ann. N.Y. Acad. Sci. 180: 302.PubMedCrossRefGoogle Scholar
  63. Siggins, G. R., Oliver, A. P., Hoffer, B. J. and Bloom, F. E. 1971 c. Cyclic adenosine monophosphate and norepinephrine: Effects on transmembrane properties of Purkinje cells. Science 171: 192.PubMedCrossRefGoogle Scholar
  64. Siggins, G. R., Hoffer, B. J., Oliver, A. P. and Bloom, F. E. 1971 d. Activation of a central noradrenergic projection to cerebellum. Nature 233: 481.PubMedCrossRefGoogle Scholar
  65. Snyder, S. H., Taylor, K. M., Coyle, J. T. and Meyerhoff, J. L. 1970. The role of brain dopamine in behavioral regulation and the actions of psychotropic drugs. Amer. J. Psychiat. 127: 117.Google Scholar
  66. Stone, T.W. 1971. Are noradrenaline excitations artifacts? Nature 234: 145.PubMedCrossRefGoogle Scholar
  67. Sutherland, E. W., Rall, T. W. and Menon, T. 1962. Adenyl cyclase. I. Distribution, preparation and properties. Biol. Chem.237: 1220.Google Scholar
  68. Sutherland, E. W., Robinson, G. A. and Butcher, R. 1968. Some aspects of the biological role of adenosine 3′,5′-monophosphate. Circulation 3: 279.Google Scholar
  69. Ungerstedt, U. 1971. Stereotaxic mapping of the monoamine pathways in the rat brain. Acta. Physiol. Scand. Suppl. 367.Google Scholar
  70. Wedner, H. J., Hoffer, B. J., Battenberg, E., Steiner, A. L., Parker, C. W. and Bloom, F.E. 1972. A method for detecting intracellular cyclic adenosine monophosphate by immunofluorescence. J. Histochem. Cytochem. (in press).Google Scholar
  71. Weight, F. F. 1971. Mechanisms of synaptic transmission. Neurosciences Res. 4:1.Google Scholar
  72. Weiss, B. and Kidman, A.D. 1969. Neurobiological significance of cyclic 3′5′-adeonsine monophosphate. In: Advances in Biochemical Psychopharmacology (Eds. Costa, E. and Greengard, P.) New York: Raven Press, Vol. 1, pp. 131.Google Scholar

Copyright information

© Plenum Press, New York 1973

Authors and Affiliations

  • Floyd E. Bloom
    • 1
  • Barry J. Hoffer
    • 1
  • George R. Siggins
    • 1
  1. 1.Laboratory of Neuropharmacology, Division of Special Mental Health Research, National Institute of Mental HealthSt. Elizabeths HospitalUSA

Personalised recommendations