Brain Slices pp 87-112 | Cite as


Synaptic Pharmacology
  • Raymond Dingledine


Central nervous system pharmacology is in the midst of a new stage of development. With the advent of sensitive and specific radioreceptor binding assays for studying drug-receptor interactions, rapid advances have been made in the biochemical investigation of drug and transmitter mechanisms. Our knowledge of the physiological actions of neuroactive drugs has also progressed in recent years, due in large part to the extensive use of the iontophoretic technique coupled with extra- and intracellular recording from cells in the intact brain. Although such in vivo studies provide an important and necessary foundation for any serious investigation of the effects of a drug on the nervous system, detailed information about the site and mode of action of drugs is very difficult to obtain. In vivo electrophysiological studies of neurons in the mammalian brain generally suffer from two difficulties that prohibit detailed analysis: (1) insufficient mechanical stability to permit long-lasting intracellular recordings on a routine basis and (2) an inability to know the equilibrium concentration of drugs in the interstitial space. These drawbacks can be overcome with the use of brain slices, which forms the basis of a strong rationale for the utility of these preparations in neuropharmacological investigations.


Pyramidal Cell Hippocampal Slice Vasoactive Intestinal Polypeptide Mossy Fiber Input Resistance 
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. Alger, B. E. and Nicoll, R. A., 1979, GABA-mediated biphasic inhibitory responses in hippocampus, Nature, (London) 281:315–317.CrossRefGoogle Scholar
  2. Alger, B. E. and Nicoll, R. A., 1982, Feed-forward dendritic inhibition in rat hippocampal pyramidal cells studied in vitro, J. Physiol. (London) 328:105–123.Google Scholar
  3. Andersen, P., 1975, Organization of hippocampal neurons and their connections, in: The Hippocampus, Volume 1 (R. L. Isaacson and K. H. Pribram, eds.), Plenum Press, New York, pp. 155–175.Google Scholar
  4. Andersen, P., Bie, B., Ganes, T., and Mosfeldt Laursen, A., 1978a, Two mechanisms for effects of GABA on hippocampal pyramidal cells, in: Iontophoresis and Transmitter Mechanisms in the Mammalian Central Nervous System (R. Ryall and J. S. Kelly, eds.), Elsevier N. Holland Biomedical Press, pp. 178–181.Google Scholar
  5. Andersen, P., Silfvenius, H., Sundberg, S. H., Sveen, O., and Wigström, H., 1978b, Functional characteristics of unmyelinated fibres in the hippocampal cortex, Brain Res. 144:11–18.PubMedCrossRefGoogle Scholar
  6. Andersen, P., Eccles, J. C., and Løyning, Y., 1964, Pathway of postsynaptic inhibition in the hippocampus, J. Neurophysiol. 27:608–619.PubMedGoogle Scholar
  7. Andersen, P., Dingledine, R., Gjerstad, L., Langmoen, I. A., and Mosfeldt-Laursen, A., 1980, Two different responses of hippocampal pyramidal cells to application of gamma-amino butyric acid, J. Physiol. (London) 305:279–296.Google Scholar
  8. Azmitia, E. C. and Segal, M., 1979, An autoradiographic analysis of the differential ascending projections of the dorsal and median raphe nuclei in the rat, J. Comp. Neurol. 179:641–668.CrossRefGoogle Scholar
  9. Benardo, L. S. and Prince, D. A., 1982a, Cholinergic excitation of mammalian hippocampal pyramidal cells, Brain Res. 249:315–331.CrossRefGoogle Scholar
  10. Benardo, L. S. and Prince, D. A., 1982b, Ionic mechanisms of cholinergic excitation in mammalian hippocampal pyramidal cells, Brain Res. 249:333–344.CrossRefGoogle Scholar
  11. Ben-Ari, Y., Krnjevic, K., Reiffenstein, R., and Ropert, N., 1981, Intracellular observations on disinhibitory action of acetylcholine in hippocampus, Neuroscience 6:2475–2484.PubMedCrossRefGoogle Scholar
  12. Biscoe, T. J. and Straughan, D. W., 1966, Micro-electrophoretic studies of neurones in the cat hippocampus, J. Physiol. (London) 183:341–359.Google Scholar
  13. Bostock, E., Dingledine, R., Xu, G., and Chang, K.-J., Epileptiform effect of a mu-opioid receptor agonist, morphiceptin, in the hippocampal slice, submitted.Google Scholar
  14. Chang, K.-J., Cooper, B. R., Hazum, E., and Cuatrecasas, P., 1979, Multiple opiate receptors: Different regional distribution in the brain and differential binding of opiates and opioid peptides, Mol. Pharmacol. 16:91–104.PubMedGoogle Scholar
  15. Collingridge, G. L., Kehl, S. J., and McLennan, H., 1982a, Antagonism of amino acid induced excitation of CA1 hippocampal neurones in vitro, J. Physiol. (London) 322:52P.Google Scholar
  16. Collingridge, G. L., Kehl, S. J., and McLennan, H., 1982b, The effect of excitatory amino acid agonists and antagonists on the Schaffer collateral input to rat CA1 hippocampal neurones, J. Physiol. (London) 322:53P.Google Scholar
  17. Corrigall, W. A. and Linseman, M. A., 1980, A specific effect of morphine on evoked activity in the rat hippocampal slice, Brain Res. 192:227–238.PubMedCrossRefGoogle Scholar
  18. Crutcher, K. A., Madison, R., and Davis, J. N., 1981, A study of the rat septohippocampal pathway using anterograde transport of horseradish peroxidase, Neuroscience 6:1961–1973.PubMedCrossRefGoogle Scholar
  19. Dingledine, R., 1981, Possible mechanisms of enkephalin action on hippocampal CA1 pyramidal neurons, J. Neurosci. 1:1022–1035.PubMedGoogle Scholar
  20. Dingledine, R., 1982, Amino acid activated calcium conductance in hippocampal pyramidal cells, Soc. Neurosci. Abstr. 8:796.Google Scholar
  21. Dingledine, R., 1983a, N-Methyl-aspartate activates voltage dependent calcium conductance in rat hippocampal pyramidal neurones, J. Physiol. (London) in press.Google Scholar
  22. Dingledine, R., 1983b, Excitatory amino acids: Modes of action on hippocampal pyramidal cells, Fed. Proc., 42:2281–2285.Google Scholar
  23. Dingledine, R. and Gjerstad, L., 1979, Penicillin blocks hippocampal IPSPs, unmasking prolonged EPSPs, Brain Res. 168:205–209.PubMedCrossRefGoogle Scholar
  24. Dingledine, R. and Gjerstad, L., 1980, Reduced inhibition during epileptiform activity in the in vitro hippocampal slice, J. Physiol. (London) 305:297–313.Google Scholar
  25. Dingledine, R. and Langmoen, I. A., 1980, Conductance changes and inhibitory actions of hippocampal recurrent IPSPs, Brain Res. 185:277–287.PubMedCrossRefGoogle Scholar
  26. Dodd, J. and Kelly, J. S., 1979, Is somatostatin an excitatory transmitter in the hippocampus? Nature (London) 273:674–675.CrossRefGoogle Scholar
  27. Dodd, J. and Kelly, J. S., 1981, The actions of cholecystokinin and related peptides on pyramidal neurones of the mammalian hippocampus, Brain Res. 205:337–350.PubMedCrossRefGoogle Scholar
  28. Dodd, J., Kelly, J. S., and Said, S. I., 1979, Excitation of CA1 neurones of the rat hippocampus by the octacosapeptide, vasoactive intestinal polypeptide (VIP), Br. J. Pharmacol. 66:125P.Google Scholar
  29. Dodd, J., Dingledine, R., and Kelly, J. S., 1981, The excitatory action of acetylcholine on hippocampal neurones of the guinea pig and rat maintained in vitro, Brain Res. 207:109–127.PubMedCrossRefGoogle Scholar
  30. Dunwiddie, T., Mueller, A., Palmer, M., Steward, J., and Hoffer, B., 1980, Electrophysiological interactions of enkephalins with neuronal circuitry in the rat hippocampus. I. Effects on pyramidal cell activity, Brain Res. 184:311–330.PubMedCrossRefGoogle Scholar
  31. Eccles, J. C., Nicoll, R. A., Oshima, T., and Rubia, F. J., 1977, The anionic permeability of the postsynaptic membrane of hippocampal pyramidal cells, Proc. R. Soc. Lond. [Biol] 198:345–361.CrossRefGoogle Scholar
  32. Gähwiler, B. H. and Maurer, R., 1981, Involvement of µ-receptors in the opioid-induced generation of bursting discharges in hippocampal pyramidal cells, Regulatory Peptides 2:91–96.PubMedCrossRefGoogle Scholar
  33. Gall, C., Brecha, N., Karten, H. J., and Chang, K.-J., 1981, Localization of enkephalin-like immunoreactivity to identified axonal and neuronal populations of the rat hippocampus, J. Comp. Neurol. 198:335–350.PubMedCrossRefGoogle Scholar
  34. Gold, M. R. and Martin, A. R., 1982, Intracellular Cl- accumulation reduces Cl- conductance in inhibitory synaptic channels, Nature 299:828–830.PubMedCrossRefGoogle Scholar
  35. Greenwood, R. S. and Winstead, K. K., 1981, Immunocytochemical double labeling for cholecystokinin and somatostatin in the rat hippocampus, Soc. Neurosci. Abstr. 7:100.Google Scholar
  36. Greenwood, R. S., Godar, S. E., Reaves, T. A., and Hayward, J. N., 1981, Cholecystokinin in hippocampal pathways, J. Comp. Neurol. 203:335–350.PubMedCrossRefGoogle Scholar
  37. Haas, H. L., 1982, Cholinergic disinhibition in hippocampal slices of rat, Brain Res. 233:200–204.PubMedCrossRefGoogle Scholar
  38. Haas, H. L. and Gähwiler, B. H., 1980, Do enkephalins directly affect calcium-spikes in hippocampal pyramidal cells? Neurosci. Lett., 19:89–92.PubMedCrossRefGoogle Scholar
  39. Haas, H. L. and Ryall, R. W., 1980, Is excitation by enkephalins of hippocampal neurons in the rat due to presynaptic facilitation or to disinhibition? J. Physiol. (London) 308:315–330.Google Scholar
  40. Haas, H. L., Felix, D., Celio, M. R., and Inagami, T., 1980, Angiotensin II in the hippocampus. A histochemical and electrophysiological study, Experientia 36:1394–1395.PubMedCrossRefGoogle Scholar
  41. Haas, H. L., Felix, D., and Davis, M. D., 1982, Angiotensin excites hippocampal pyramidal cells by two mechanisms, Cell. Mol. Neurobiol. 2:21–32.CrossRefGoogle Scholar
  42. Hablitz, J. J. and Langmoen, I. A., 1982, Excitation of hippocampal pyramidal cells by glutamate in the guinea-pig and rat, J. Physiol. (London) 325:317–331.Google Scholar
  43. Halliwell, J. V. and Adams, P. R., 1982, Voltage clamp analysis of muscarinic excitation in hippocampal neurons, Brain Res. 250:71–92.PubMedCrossRefGoogle Scholar
  44. Handelmann G., Meyer, D. K., Beinfeld, M. C., and Oertel, W. H., 1981, CCK-containing terminals in the hippocampus are derived from intrinsic neurons: An immunohisto-chemical and radioimmunological study, Brain Res. 224:180–184.PubMedCrossRefGoogle Scholar
  45. Henricksen S. J., Bloom, F. E., McCoy, F., Ling, N., and Guillemin, R., 1978, ß-endorphin induces non-convulsive limbic seizures, Proc. Nat’l. Acad. Sci. USA 75:5221–5225.CrossRefGoogle Scholar
  46. Hounsgaard, J., 1978, Presynaptic inhibitory action of acetylcholine in area CA1 of the hippocampus, Exp. Neurol. 62:787–797.PubMedCrossRefGoogle Scholar
  47. Kimura, H., McGeer, P. L., Peng, J. H., and McGeer, E. G., 1981, The central cholinergic system studied by choline acetyltransferase immunohistochemistry in the cat, J. Comp. Neurol. 200:151–200.PubMedCrossRefGoogle Scholar
  48. Knowles, W. D. and Schwartzkroin, P. A., 1981, Local circuit synaptic interactions in hippocampal brain slices, J. Neurosci. 1:318–322.PubMedGoogle Scholar
  49. Koerner, J. F. and Cotman, C. W., 1981, Micromolar L-2-amino-4-phosphonobutyric acid selectively inhibits perforant path synapses from lateral entorhinal cortex, Brain Res. 216:192–198.PubMedCrossRefGoogle Scholar
  50. Koerner, J. F. and Cotman, C. W., 1982, Response of Schaffer collateral-CA1 pyramidal cell synapses of the hippocampus to analogues of acidic amino acids, Brain Res. 251:105–115.PubMedCrossRefGoogle Scholar
  51. Krnjevic, K., Pumain, R., and Renaud, L., 1971,The mechanism of excitation by acetylcholine in the cerebral cortex, J. Physiol. (London) 215:247–268.Google Scholar
  52. Lanthorn, T. H. and Cotman, C. W., 1981, Baclofen selectively inhibits excitatory synaptic transmission in the hippocampus, Brain Res. 225:171–178.PubMedCrossRefGoogle Scholar
  53. Lee, H. K., Dunwiddie, T., and Hoffer, B., 1980, Electrophysiological interactions of enkephalins with neuronal circuitry in the rat hippocampus. II. Effects on interneuron excitability, Brain Res. 184:331–342.PubMedCrossRefGoogle Scholar
  54. Lindvall, O. and Bjorkland, A., 1974, The organization of the ascending catecholamine neurone systems in the rat brain, as revealed by the glyoxylic acid fluorescence method, Acta Physiol. Scand. 73(suppl 412): l-48.Google Scholar
  55. Loren, I., Emson, P. C., Fahrenkrug, J., Bjorklund, A., Alumets, J., Hakänson, R., and Sundler, F., 1979, Distribution of vasoactive intestinal polypeptide in the rat and mouse brain, Neuroscience 4:1953–1976.PubMedCrossRefGoogle Scholar
  56. Lorente de Nó, R., 1934, Studies on the structure of the cerebral cortex. II. Continuation of the study of the amnionic system, J. Psychol. Neurol. (Leipzig) 46:113–177.Google Scholar
  57. Lynch, G., Rose, G., and Gall, C., 1978, Anatomical and functional aspects of the septo-hippocampal projections, in: Functions of the Septo-Hippocampal System, Ciba Foundation Symposium no. 58, Elsevier-North Holland, Amsterdam, pp 5–20.Google Scholar
  58. Lynch, G. S., Jensen, R. A., McGaugh, J. L., Davila, K., and Oliver, M. W., 1981, Effects of enkephalin, morphine and naloxone on the electrical activity of the in vitro hip-pocampal slice preparation, Exp. Neurol. 71:527–540.PubMedCrossRefGoogle Scholar
  59. MacDonald, J. F. and Wojtowicz, J. M., 1982, The effects of L-glutamate and its analogues upon the membrane conductance of central murine neurones in culture, Canad. J. Physiol. Pharmacol. 60:282–296.CrossRefGoogle Scholar
  60. Masukawa, L. M. and Prince, D. A., 1982, Enkephalin inhibition of inhibitory input to CA1 and CA3 pyramidal neurons in the hippocampus, Brain Res. 249:271–280.PubMedCrossRefGoogle Scholar
  61. McGinty, J. F., Henricksen, S. J., Goldstein, A., Terenius, L., and Bloom, F. E., 1983, Dynorphin is contained within hippocampal mossy fibers: Immunochemical alterations after kainic acid administration and colchicine-induced neurotoxicity, Proc. Natl. Acad. Sci. USA 80:589–593.PubMedCrossRefGoogle Scholar
  62. Moore, R. Y. and Halaris, A. E., 1975, Hippocampal innervation by serotonin neurons of the midbrain raphe in the rat, J. Comp. Neurol. 152:163–174.Google Scholar
  63. Nadler, J. V., Vaca, K. W., White, W. F., Lynch, G. S., and Cotman, C. W., 1976, Aspartate and glutamate as possible transmitters of excitatory hippocampal afférents, Nature (London) 260:538–540.CrossRefGoogle Scholar
  64. Nadler, J. V., White, W. F., Vaca, K. W., Perry, B. W., and Cotman, C. W., 1978, Biochemical correlates of transmission mediated by glutamate and aspartate, J. Neurochem. 31:147–155.PubMedCrossRefGoogle Scholar
  65. Nicoll, R. A., Alger, B. E., and Jahr, C. E., 1980, Enkephalin blocks inhibitory pathways in the vertebrate CNS, Nature (London) 287:22–25.CrossRefGoogle Scholar
  66. Ribak, C. E., Vaughn, J. E., and Saito, K., 1978, Immunocytochemical localization of glutamic acid decarboxylase in neuronal sonata following colchicine inhibition of axonal transport, Brain Res. 140:315–332.PubMedCrossRefGoogle Scholar
  67. Robinson, J. H. and Deadwyler, S. A., 1981, Intracellular correlates of morphine excitation in the hippocampal slice preparation, Brain Res. 224:375–387.PubMedCrossRefGoogle Scholar
  68. Schwartzkroin, P. A. and Mathers, L. H., 1978, Physiological and morphological identification of a non-pyramidal hippocampal cell type, Brain Res. 157:1–10.PubMedCrossRefGoogle Scholar
  69. Segal, M., 1982, Multiple actions of acetylcholine at a muscarinic receptor studied in the rat hippocampal slice, Brain Res. 246:77–87.PubMedCrossRefGoogle Scholar
  70. Silfvenis, H., Olofsson, S., and Ridderheim, P.-A., 1980, Induced epileptiform activity evoked from dendrites of hippocampal neurones, Acta Physiol. Scand. 108:109–111.CrossRefGoogle Scholar
  71. Storm-Mathisen, J., 1977, Localization of transmitter candidates in the brain: The hippo- campal formation as a model, Prog. Neurobiol. 8:119–181.PubMedCrossRefGoogle Scholar
  72. Thalmann, R. H., Peck, E. J., and Ayala, G. F., 1981, Biphasic response of hippocampal pyramidal neurons to GABA, Neurosci. Lett. 21:319–324.PubMedCrossRefGoogle Scholar
  73. Urea, G., Frenk, H., Liebeskind, J. C., and Taylor, A. N., 1977, Morphine and enkephalin: Analgesic and epileptic properties, Science 197:83–86.CrossRefGoogle Scholar
  74. Valentino, R. J. and Dingledine, R., 1981, Presynaptic inhibitory effect of acetylcholine in the hippocampus, J. Neurosci. 1:787–792.Google Scholar
  75. Valentino, R. J. and Dingledine, R., 1982, Pharmacological characterization of opioid effects in the rat hippocampal slice, J. Pharmacol. Exp. Ther. 223:502–509.PubMedGoogle Scholar
  76. Vincent, S. R., Kimura, H., and McGeer, E. G., 1981, Organization of substance P fibers within the hippocampal formation demonstrated with a biotin-avidin immunoperoxidase technique, J. Comp. Neurol. 199:113–123.PubMedCrossRefGoogle Scholar
  77. Watkins, J. C. and Evans, R. H., 1981, Excitatory amino acid transmitters, Annu. Rev. Pharmacol. Toxicol. 21:165–204.PubMedCrossRefGoogle Scholar
  78. White, W. F., Nadler, J. V., Hamberger, A., Cotman, C. W., and Cummins, J. T., 1977, Glutamate as a transmitter of hippocampal perforant path, Nature (London) 270:356–357.CrossRefGoogle Scholar
  79. White, W. F., Nadler, J. V., and Cotman, C. W., 1979, The effect of acidic amino acid antagonists on synaptic transmission in the hippocampal formation in vitro, Brain Res. 164:177–194.PubMedCrossRefGoogle Scholar
  80. Wieraszko, A. and Lynch, G., 1979, Stimulation-dependent release of possible transmitter substances from hippocampal slices studied with localized perfusion, Brain Res. 160:372–376.PubMedCrossRefGoogle Scholar
  81. Wong, R. K. S. and Prince, D. A., 1979, Dendritic mechanisms underlying penicillin-induced epileptiform activity, Science 204:1228–1231.PubMedCrossRefGoogle Scholar
  82. Wong, R. K. S. and Watkins, D. J., 1982, Cellular factors influencing GABA response in hippocampal pyramidal cells, J. Neurophysiol. 48:938–951.PubMedGoogle Scholar
  83. Yamamoto, C. and Kawai, N., 1967, Presynaptic action of acetylcholine in thin sections from the guinea pig dentate gyrus in vitro, Exp. Neurol. 19:176–187.PubMedCrossRefGoogle Scholar
  84. Zieglgänsberger, W., French, E., Siggins, G., and Bloom, F., 1979, Opioid peptides may excite hippocampal pyramidal neurons by inhibiting adjacent inhibitory interneurons, Science 205:415–417.PubMedCrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1984

Authors and Affiliations

  • Raymond Dingledine
    • 1
  1. 1.Department of PharmacologyUniversity of North CarolinaChapel HillUSA

Personalised recommendations