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Calcium Currents and Potassium Conductance Changes Explain Low-Dose Sedative Drug Actions in Mammalian Hippocampal Neurons

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Calcium, Neuronal Function and Transmitter Release

Part of the book series: Topics in the Neurosciences ((TNSC,volume 1))

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Summary

It is often assumed that sedative drugs cause neuronal depression by activating GABAergic mechanisms. Using intracellular recordings from in-vitro rat and guinea pig CA1 and CA3 neurons, this lab is studying the ionic mechanisms of lower, non-anesthetic doses of ethanol (≤20mM), pentobarbital (< 100 uM) and 2 benzodiazepines (midazolam and clonazepam (≤10−8M). All drugs caused a hyperpolarization, usually with moderately increased conductance and decreased spontaneous spiking. Intracellular chloride injection had no effect on these responses. Post-spike long-lasting afterhyperpolarizatons (AHPs), thought to be due to Ca++ -mediated K+ conductance (Ca-gK), were consistently enhanced by these drugs. In the presence of TTX, Ca++ spikes were examined. Ethanol and pentobarbital had no effect or tended to diminish whereas midazolam enhanced these Ca++ spikes. Zero Ca++ perfusate did not prevent ethanol or pentobarbital actions, but blocked midazolam actions. Intracellularly injected cesium, which blocks gK, blocked ethanol effects. Low drug doses had no effect or slightly diminished GABA actions, whereas higher (anesthetic) doses tended to enhance GABA actions.

We conclude that: 1) All these sedative drugs cause neuronal inhibtion at non-anesthetic doses by augmenting Ca-gK and not GABA actions or gCl. 2) Ethanol and pentobarbital, which tend to diminish Ca++ spikes, augment Ca-gK possibly by increasing intracellular [Ca++] from intracellular stores. 3) Hawever, benzodiazepine neuronal inhibiton can be explained by increasing inward Ca++ flux which then activates gK.

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References

  1. Carlen, P.L. and Blaxter, T.J.: Cerebellar Rirkinje cells In vitro; membrane properties and the effects of ethanol. Soc. Neurosci. 10, 1984.

    Google Scholar 

  2. Carlen, P.L., Qirevich, N. and Durand, D.: Low dose ethanol augments calcium-mediated mechanisms measured intracellularly in hippocampal neurons. Science 215: 306–309, 1982.

    Article  PubMed  CAS  Google Scholar 

  3. Carlen, P.L., Gurevich, N. and Polc, P.: The excitatory effects of the specific benzodiapezine antagonist Ro-14-7437, measured intracellularly in hippocampal CA1 cells. Brain Res. 271: 115–119, 1983.

    Article  PubMed  CAS  Google Scholar 

  4. Carlen, P.L., Qirevich, N. and Polc, P.: Low-dose benzodiazepine neuronal inhibition: Enhanced Ca++-mediated K+ conductance. Brain. Res. 271: 358–364, 1983.

    Article  PubMed  CAS  Google Scholar 

  5. Carlen, P.L., Qirevich, N. and O’Beime, M.: Electrophysiological evidence for increased calcium-mediated potassium conductance by low-dose sedative hypnotic drugs. In: Calcium in Biologicial Systems: Ca2+ as a Regulator of Membrane Permeability. Eds. Rubin, R.P., Weiss, G. and Putney, J.W., 1984, In Press.

    Google Scholar 

  6. Gurevich, N., Davies, M.F. and Carlen, P.L.: Low dose clonazeam inhibition and CGS-8216 excitation of hippocampal CA1 neurons in vitro; a potassium mechanism. Soc. Neurosci. 10: and in preparation, 1984.

    Google Scholar 

  7. O’Beime, M., Gurevich, N. and Carlen, P.L.: Pentobarbital inhibiton measured intracellularly in hippocampal CA3 neurons. Soc. Neurosci. 8: 879, 1982, and in preparation.

    Google Scholar 

  8. O’Beime, M.: The effects of low dosages of sodium pentobarbital on the membrane properties of hippocampal pyramidal cells of the guinea pig: An in-vitro study. M.Sc. Thesis, Department of Physiology, University of Toronto, 1984.

    Google Scholar 

  9. Krnjevic, K. and Lisiewicz, A.: Injections of calcium ions into spinal motoneurones. J. Physiol. 225: 363–390, 1972.

    PubMed  CAS  Google Scholar 

  10. Meech, R.W.: Intracellular calcium injection causes increased potassium conductance in Aplysia nerve cells. Comp. Biochem. Physiol. 42A:493–499, 1972.

    Article  Google Scholar 

  11. Meech, R.W.: The sensitivity of Helix Aspersa neurones to injected calcium ions. J. Physiol (Lond) 237: 259–277, 1974.

    CAS  Google Scholar 

  12. Eckert, R., Tillotson, D.: Potassium activation associated with intraneuronal free calcium. Science 200: 437–439, 1978.

    Article  PubMed  CAS  Google Scholar 

  13. Eckert, R. and Ewald, D.: Residual calcium ions depress activation of calcium dependent current. Science 216: 730–733, 1982.

    Article  PubMed  CAS  Google Scholar 

  14. Eckert, R. and Tilltson, D.L.: Calcium-mediated tnactivation of the calcium conductance in caesium-loaded giant neurones of Aplysia California. J. Physiol 314: 265–280, 1981.

    PubMed  CAS  Google Scholar 

  15. Hagiwara, S. and Byerly, L.: Calcium channel. Annual Rev. of Neurosci 4: 69–125, 1981.

    Article  CAS  Google Scholar 

  16. Hofmeier, G. and Lux, H.D.: The time courses of intracellular free calcium and related electrical effects after injection of CaCl2 into neurons of the snail, Helix pomatia. Pflugers Arch. 391: 242–251, 1981.

    Article  PubMed  CAS  Google Scholar 

  17. Plant, T.D. and Standen, N.B.: Calcium current inacttvation in identified neurones of Helix Aspersa. J. Physiol. 321: 273–285, 1981.

    PubMed  CAS  Google Scholar 

  18. Dingeldine, R.: Brain Slices. Ed. R. Dingledine Plenum Press, New York, 1984, pp.1–442.

    Google Scholar 

  19. Braestrup, C. Squires, R.F. Specific benzodiazepine receptors in rat brain characterized by high-affinity (3H)diazepam-binding: Proc. Natl. Acad. Sci. USA 74: 306–309, 1982.

    Google Scholar 

  20. Kanto, J., Kangas, L., Siirotola, T.: Cerebrospinal-fluid concentrations of diazepam and its metabolites in man. Acta. Pharmacol. et Toxicol. 36: 328–334, 1975.

    Article  CAS  Google Scholar 

  21. Garattini, S. Mussini, E. Marucci, F, Guaitani, A.: Metabolic studies on benzodiazepines in various animal species. Garratini, S., Mussini, E., Randall, L.O. Eds. The Benzodiazepines. New York: Raven Press, 1973, 75–97.

    Google Scholar 

  22. Klotz, U.: Effect of age on levels of diazepam in plasma and brain of rats. Naunyn-Schmiedeberg’s Arch Pharmacol. 307: 167–169, 1979.

    Article  CAS  Google Scholar 

  23. Carlen, P.L., Puil, E. and Qirevich, N,: Ethanol and K+ conductance: Enhancement of the afterhyperpolarizations (AHPs) following action potentials or depolarization evoked with amino acids and effects of K and Na+ channel blockers. Soc. Neurosci. 8: 652, 1982.

    Google Scholar 

  24. Qistafsson, B. Wigstrom, H: Evidence for two types of afterhyperpolarizations in CA1 pyramidal cells in the hippocampus. Brain Res. 206: 462–468, 1981.

    Article  Google Scholar 

  25. Hotson, J.R., Prince, D.A.: A calcium-activated hyperpolarization follows repetitive firing in hippocampal neurons. J. Neurophysiol. 43: 409–419, 1980.

    PubMed  CAS  Google Scholar 

  26. Nicoll, R.A., Alger, B.E.: Synaptic excitation may activate a calcium dependent potassium conductance in hippocampal pyramidal cells. Science 212: 957–959, 1981.

    Article  PubMed  CAS  Google Scholar 

  27. Schwartzkroin, P.A. and Slawsky, M.: Probable calcium spikes in hippocampal neurons. Brain Res. 135: 157–161, 1977.

    Article  PubMed  CAS  Google Scholar 

  28. Nestoros, J.N.: Ethanol specifically potentiates GABA-mediated neurotransmission in feline cerebral cortex. Science 209: 708–710, 1980.

    Article  PubMed  CAS  Google Scholar 

  29. Heyer, E.J., MacDonald, R.L.: Barbiturate reduction of calcium-dependent action potentials: correlation with anesthetic action. Brain Res. 236: 157–171, 1982.

    Article  PubMed  CAS  Google Scholar 

  30. Baker, P.F., Schlaepfer, W.W. Uptake and binding of calcium axoplam isolated from giant axons of LOLIG0 and MYXICOLA: J. Physiol. 276: 103–125, 1978.

    PubMed  CAS  Google Scholar 

  31. Blaustein, M.P., Nelson, M.T.: Soldium-calcium exchange: Its role in regulation of cell calcium. Carafoli, E., ed. Calcium transport across biological membranes. New York: Academic Press,217–236, 1982.

    Google Scholar 

  32. Lehninger, A.L.: Mitrochondria and calcium ion in transport. Biochem. J. 119: 129–138, 1970.

    PubMed  CAS  Google Scholar 

  33. Brinley, F.J. Jr.: Regulation of intracellular calcium in squid ions. Fed. Proc. 39: 2778–2782, 1980.

    PubMed  CAS  Google Scholar 

  34. Schatzmann, H.J., Burgin, H.: Calcium in human red blood cells. Ann. N.Y. Acad. Sci. 307: 125–147, 1978.

    Article  PubMed  CAS  Google Scholar 

  35. Michaelis, E.: Effects of depressant drugs on sodium-calcium exchange in researled synaptic membranes. In: Calcium in Biological Systems: Ca2+ as a Regulator of Membrane Permeability. Eds. Rubin, R.P., Weiss, G. and Putney, J. W., 1984, In Press.

    Google Scholar 

  36. Harris, R.A.: Ethanol and pentobarbital inhibiton of intrasynaptasomal sequestration of calcium. Biochem. Pharmacol. 30: 3209–3215, 1981.

    Article  PubMed  CAS  Google Scholar 

  37. Leslie, S.: Sedative-hypnotic drugs and synaptosomal calcium transport. In: Calcium in Biological Systems: Ca2+ as a Regulator of Membrane Permeability. Eds. Rubin, R.P., Weiss, G. and Putney, J. W., 1984, In Press.

    Google Scholar 

  38. Seeman P., Chau, M., Goldberg, M., Sauks, T., Sax., L.: The binding of Ca2+ to the cell membrane by volatile anesthetics (alcohols, acetone, ether) which induce sensitization of nerve or muscle. Biochimica. et Biophysica. Acta 225: 185–193, 1971.

    Article  PubMed  CAS  Google Scholar 

  39. Kmjevic, K.: Exciteable membranes and anesthetics. Fink, B.R. Ed., Cellular Biology and Toxicity of Anesthetics. Baltimore: Williams and Wilkins, 1972, 3–9.

    Google Scholar 

  40. Blaxter, T.J., Davies, M.F., Carlen, P.L. and Gurevich, N.: GABA mediates a calcium-dependent potassium conductance in hippocampal CA1pyramidal cells. Soc. Neurosci. 10., 1984.

    Google Scholar 

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Authors and Affiliations

  1. Departments of Physiology and Medicine (Neurology), Toronto Western Hospital, Playfair Neuroscience Unit, Canada

    P. L. Carlen, N. Gurevich, M. F. Davies, T. J. Blaxter & M. O’Beirne

  2. Addiction Research Foundation Clinical Institute, University of Toronto, Canada

    P. L. Carlen, N. Gurevich, M. F. Davies, T. J. Blaxter & M. O’Beirne

Authors
  1. P. L. Carlen
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  2. N. Gurevich
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  3. M. F. Davies
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  4. T. J. Blaxter
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  5. M. O’Beirne
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Editors and Affiliations

  1. The Hebrew University, Jerusalem, Israel

    Rami Rahamimoff

  2. University College London, London, England

    Bernard Katz

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© 1986 Martinus Nijhoff Publishing, Boston

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Carlen, P.L., Gurevich, N., Davies, M.F., Blaxter, T.J., O’Beirne, M. (1986). Calcium Currents and Potassium Conductance Changes Explain Low-Dose Sedative Drug Actions in Mammalian Hippocampal Neurons. In: Rahamimoff, R., Katz, B. (eds) Calcium, Neuronal Function and Transmitter Release. Topics in the Neurosciences, vol 1. Springer, Boston, MA. https://doi.org/10.1007/978-1-4613-2307-5_32

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  • DOI: https://doi.org/10.1007/978-1-4613-2307-5_32

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-1-4612-9420-7

  • Online ISBN: 978-1-4613-2307-5

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