GABAB Receptor-Mediated Inhibition of Synaptic Transmission in the Hippocampus: Pharmacology and Intracellular Mechanisms

  • Patrick Dutar
  • Roger A. Nicoll


Gamma-aminobutyric acid (GABA) is a major inhibitory neurotransmitter in the central nervous system that affects cellular excitability by opening or closing a variety of ion channels or by modulating a number of intracellular messengers. Some actions of GABA are associated with an increase in membrane conductance to Cl- ions and are antagonized by the GABA antagonists bicuculline and Picrotoxin. Receptors mediating these effects are referred to as GABAA receptors and have been investigated intensively, especially because of their close association to the benzodiazepine and barbiturate binding sites. More recently, presynaptic bicuculline-insensitive actions of GABA have been discovered by Bowery and his colleagues, who opened up a new field of investigation (see Bowery, 1982). These actions are mediated by GABAB receptors, which are specifically activated by the GABAB agonists baclofen and 3-aminopropylphosphonic acid. We describe in this chapter recent data concerning the presynaptic actions mediated by GABAB receptors in the hippocampus. We first briefly summarize the better known postsynaptic effects of GABAB receptor activation.


Pertussis Toxin GABAB Receptor Stratum Radiatum Presynaptic Action Inhibitory Postsynaptic Potential 
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. Allerton CA, Boden PR, Hill RG (1989): Actions of the GABAB agonist, (-)-baclofen, on neurones in deep dorsal horn of the rat spinal cord in vitro. Br J Pharmacol 96:29–38PubMedGoogle Scholar
  2. Baumann PA, Wicki P, Stierlin C, Waldmeier PC (1990): Investigations on GABAB receptor-mediated autoinhibition of GABA release. Naunyn-Schmied Arch Pharmacol 341:88–93CrossRefGoogle Scholar
  3. Blaxter TJ, Carlen PL (1985): Pre and post-synaptic effects of baclofen in the rat hippocampal slice. Brain Res 341:195–199PubMedCrossRefGoogle Scholar
  4. Blaxter TJ, Carlen PL, Davies MF, Kujtan PW (1986): 7-Aminobutyric acid hyperpolar-izes rat hippocampal pyramidal cells through a calcium-dependent potassium conductance. J Physiol 373:181–195PubMedGoogle Scholar
  5. Blaxter TJ, Cottrell GA (1985): Actions of GABA and ethylenediamine on CA1 pyramidal neurons of the rat hippocampus. Q J Exp Physiol 70:75–93PubMedGoogle Scholar
  6. Bowery NG (1982): Baclofen: 10 years on. TiPS 3:400–403Google Scholar
  7. Burke SP, Nadler JV (1988): Regulation of glutamate and aspartate release from slices of the hippocampal CA1 area: effects of adenosine and baclofen. J Neurochem 51:1541–1551PubMedCrossRefGoogle Scholar
  8. Calabresi P, Mercuri NB, De Murtas M, Bernardi G (1991): Involvement of GABA systems in feedback regulation of glutamate- and GABA-mediated synaptic potentials in rat neostriatum. J Physiol 440:581–599PubMedGoogle Scholar
  9. Colmers WF, Pittman QJ (1989): Presynaptic inhibition by neuropeptide Y and baclofen in hippocampus: insensitivity to pertussis toxin treatment. Brain Res 498:99–104PubMedCrossRefGoogle Scholar
  10. Colmers WF, Williams JT (1988): Pertussis toxin pretreatment discriminates between pre and postsynaptic actions of baclofen in rat dorsal raphe nucleus in vitro. Neurosci Lett 93:300–306PubMedCrossRefGoogle Scholar
  11. Connors BW, Malenka RC, Silva LR (1988): Two inhibitory postsynaptic potentials, and GABAA and GABAB receptor-mediated responses in neocortex of rat and cat. J Physiol 406:443–468PubMedGoogle Scholar
  12. Cruelli V, Haby M, Jassik-Gerschenfeld D, Leresche N, Pirchio M (1988): Cl- and K+-dependent inhibitory postsynaptic potentials evoked by interneurons of the rat lateral geniculate nucleus. J Physiol 399:153–176Google Scholar
  13. Davies CH, Davies SN, Collingridge GL (1990): Paired-pulse depression of monosynaptic GABA-mediated inhibitory postsynaptic responses in rat hippocampus. J Physiol 424:513–531PubMedGoogle Scholar
  14. Davies CH, Starkey SJ, Pozza MF, and Collingridge GL (1991): GABAB autoreceptors regulate the induction of LTP. Nature 349:609–611PubMedCrossRefGoogle Scholar
  15. Deisz RA, Prince DA (1989): Frequency-dependent depression of inhibition in guinea-pig neocortex in vitro by GABAB receptor feed-back on GABA release. J Physiol 412:513–541PubMedGoogle Scholar
  16. Dolphin AC, Scott RH (1987): Calcium channel currents and their inhibition by (-) baclofen in rat sensory neurons: modulation by guanine nucleotides. J Physiol 386:1–17PubMedGoogle Scholar
  17. Drew CA, Johnston GA, Weatherby RP (1984): Bicuculline-insensitive GABA-receptors: studies on the binding of (-)-baclofen to rat cerebellar membranes. Neurosci Lett 52:317–321PubMedCrossRefGoogle Scholar
  18. Dunwiddie TV, Taylor M, Cass WA, Fitzpatrick FA, Zahniser NR (1990): Arachidonic acid metabolites do not mediate modulation of neurotransmitter release by adenosine in rat hippocampus or striatum. Brain Res 527:76–80PubMedCrossRefGoogle Scholar
  19. Dutar P, Nicoli RA (1988a): A physiological role for GABAB receptors in the CNS. Nature 332:156–158PubMedCrossRefGoogle Scholar
  20. Dutar P, Nicoli RA (1988b): Pre- and postsynaptic GABAB receptors in the hippocampus have different pharmacological properties. Neuron 1:585–591PubMedCrossRefGoogle Scholar
  21. Dutar P, Rascol O, Lamour Y (1989): ω-conotoxin GVIA blocks synaptic transmission in the CA1 field of the hippocampus. Eur J Pharmacol 174:261–266Google Scholar
  22. El Manira A, Clarac F (1991): GABA-mediated presynaptic inhibition in Crayfish primary afferents by non-A, non-B GABA receptors. Eur J Neurosci 3:1208–1218PubMedCrossRefGoogle Scholar
  23. Gage PW (1992): Activation and modulation of neuronal K+ channels by GABA. Trends Neurosci 15:46–51PubMedCrossRefGoogle Scholar
  24. Gähwiler BH, Brown DA (1985): GABAB receptor-activated K+ current in voltage-clamped CA3 pyramidal cells in hippocampus. Proc Natl Acad Sci USA 82:1558–1562PubMedCrossRefGoogle Scholar
  25. Harrison NL (1990): On the presynaptic action of baclofen at inhibitory synapses between cultured rat hippocampal neurones. J Physiol 422:433–446PubMedGoogle Scholar
  26. Harrison NL, Lovinger DM, Lambert NA, Teyler TJ, Prager R, Ong J, Kerr DIB (1990): The action of 2-hydroxy-saclofen at presynaptic GABAB receptors in the rat hippocampus. Neurosci Lett 119:272–276PubMedCrossRefGoogle Scholar
  27. Hasuo H, Gallagher JP (1988): Comparison of antagonism by phaclofen of baclofen induced hyperpolarizations and synaptically mediated late hyperpolarizing potentials recorded intracellularly from rat dorsolateral septal neurons. Neurosci Lett 86:77–81PubMedCrossRefGoogle Scholar
  28. Heidelberger R, Matthews G (1991): Inhibition of calcium influx and calcium current by 7-aminobutyric acid in single synaptic terminals. Proc Natl Acad Sci USA 88:7135–7139PubMedCrossRefGoogle Scholar
  29. Holz IV GG, Rane SG, Dunlap K (1986): GTP-binding proteins mediate transmitter inhibition of voltage-dependent calcium channels. Nature 319:670–672PubMedCrossRefGoogle Scholar
  30. Horne AL, Kemp JA (1991): The effect of ω-conotoxin GVIA on synaptic transmission within the nucleus accumbens and hippocampus of the rat in vitro. Br J Pharmacol 103:1733–1739PubMedGoogle Scholar
  31. Howe JR, Sutor B, Zieglgansberger W (1987): Baclofen reduced postsynaptic potential of rat cortical neurones by an action other than its hyperpolarizing action. J Physiol 384:539–569PubMedGoogle Scholar
  32. Huston E, Scott RH, Dolphin AC (1990): A comparison of the effect of calcium channel ligands and GABAB agonists and antagonists on transmitter release and somatic calcium channel currents in cultured neurons. Neuroscience 38:721–729PubMedCrossRefGoogle Scholar
  33. Inoue M, Matsuo T, Ogata N (1985a): Possible involvement of K+ conductance in the action of γ-aminobutyric acid in the guinea-pig hippocampus. Br J Pharmacol 86:515–524PubMedGoogle Scholar
  34. Inoue M, Matsuo T, Ogata N (1985b): Baclofen activates voltage-dependent and 4-ami-nopyridine sensitive K+ conductance in guinea-pig hippocampal pyramidal cells maintained in vitro. Br J Pharmacol 84:833–841PubMedGoogle Scholar
  35. Inoue M, Matsuo T, Ogata N (1985c): Characterization of pre and postsynaptic actions of (-)-baclofen in the guinea-pig hippocampus in vitro. Br J Pharmacol 84:843–851PubMedGoogle Scholar
  36. Kamatchi GL, Ticku MK (1990): Functional coupling of presynaptic GABAB receptors with voltage-gated Ca2+ channel: regulation by protein kinases A and C in cultured spinal cord neurons. Mol Pharmacol 38:342–347PubMedGoogle Scholar
  37. Karbon EW, Enna SJ (1989): GABAB receptors and the augmentation of neurotransmitter-stimulated cyclic AMP production. In: GABA: Basic Research and Clinical Applications, Bowery NG, Nistico G, eds. Pythagora Press Rome, MilanGoogle Scholar
  38. Kerr DIB, Ong J, Prager RH, Gynther BD, Curtis DR (1987): Phaclofen: a peripheral and central baclofen antagonist. Brain Res 405:150–154PubMedCrossRefGoogle Scholar
  39. Lambert NA, Harrison NL, Kerr DIB, Ong J, Prager RH, Teyler TJ (1989): Blockade of the late IPSP in rat CA1 hippocampal neurons by 2-hydroxy-saclofen. Neurosci Lett 107:125–128PubMedCrossRefGoogle Scholar
  40. Lambert NA, Harrison NL, Teyler TT (1991): Baclofen-induced disinhibition in area CA1 of rat hippocampus is resistant to extracellular Ba2+. Brain Res 547:349–352PubMedCrossRefGoogle Scholar
  41. Lanthorn TH, Cotman CW (1981): Baclofen selectively inhibits excitatory synaptic transmission in the hippocampus. Brain Res 225:171–178PubMedCrossRefGoogle Scholar
  42. Malouf AT, Robbins CA, Schwartzkroin PA (1990): Phaclofen inhibition of the slow inhibitory postsynaptic potential in hippocampal slice cultures: a possible role for the GABAB-mediated inhibitory postsynaptic potential. Neuroscience 35:53–61PubMedCrossRefGoogle Scholar
  43. McCormick DA (1989): GAB A as an inhibitory neurotransmitter in human cerebral cortex. J Neurophysiol 62:1018–1027PubMedGoogle Scholar
  44. Miller RJ (1987): Multiple calcium channels and neuronal function. Science 235:46–52PubMedCrossRefGoogle Scholar
  45. Newberry NR, Nicoli RA (1984a): Direct hyperpolarizing action of baclofen on hippocampal pyramidal cells. Nature 308:450–452PubMedCrossRefGoogle Scholar
  46. Newberry NR, Nicoli RA (1984b): A bicuculline-resistant inhibitory post-synaptic potential in rat hippocampal pyramidal cells in vitro. J Physiol 348:239–254PubMedGoogle Scholar
  47. Newberry NR, Nicoli RA (1985): Comparison of the action of baclofen with gamma-aminobutyric acid on rat hippocampal pyramidal cells in vitro. J Physiol 360:161–185PubMedGoogle Scholar
  48. Nicoli RA, Malenka RC, Kauer JA (1990): Functional comparison of neurotransmitter receptor subtypes in mammalian central nervous system. Physiol Rev 70:513–565Google Scholar
  49. Nicoli RA, Dutar P (1989): Physiological roles of GABAA and GABAB receptors in synaptic transmission in the hippocampus. In: Allosteric Modulation of Amino Acid Receptors: Therapeutic Implications, Barnard EA, Costa E, eds. New York: Raven PressGoogle Scholar
  50. Olpe H-R, Karlsson G, Pozza M, Brugger F, Steinmann M, Van Riezen H, Fagg G, Hall RG, Froestl W, Bittiger H (1990): CGP 35348: a centrally active blocker of GABAB receptors. Eur J Pharmacol 187:27–38PubMedCrossRefGoogle Scholar
  51. Osmanovic SS, Shefner SA (1988): Baclofen increases the potassium conductance of rat locus coeruleus neurons recorded in brain slices. Brain Res 438:124–136PubMedCrossRefGoogle Scholar
  52. Pinnock RD (1984): Hyperpolarizing action of baclofen on neurons in the rat substantia nigra slice. Brain Res 322:337–340PubMedCrossRefGoogle Scholar
  53. Piomelli D, Greengard P (1990): Lipoxygenase metabolites of arachidonic acid on neuronal transmembrane signalling. TiPS 11:367–373PubMedGoogle Scholar
  54. Potier B, Dutar P (1993): Presynaptic inhibitory effect of baclofen on hippocampal inhibitory synaptic transmission involves a pertussis toxin-sensitive G-protein. Eur J Pharmacol 231:427–433PubMedCrossRefGoogle Scholar
  55. Raiteri M, Bonanno G, Fedele E (1989a): Release of γ-[3H]aminobutyric acid (GABA) from electrically stimulated rat cortical slices and its modulation by GABAB autore-ceptors. J Pharm Exp Ther 250:648Google Scholar
  56. Raiteri M, Pellegrini G, Cantoni C, Bonanno G (1989b): A novel type of GABA receptor in rat spinal cord. Naunyn-Schmied Arch Pharmac 340:666–670CrossRefGoogle Scholar
  57. Rane SG, Walsh MP, McDonald JR, Dunlap K (1989): Specific inhibitors of protein kinase C block transmitter-induced modulation of sensory neuron calcium current. Neuron 3:239–245PubMedCrossRefGoogle Scholar
  58. Scherer RW, Ferkany JW, Enna SJ (1988): Evidence for pharmacologically distinct subsets of GABAB receptors. Brain Res Bull 21:439–443PubMedCrossRefGoogle Scholar
  59. Scholz KP, Miller RJ (1991): GABAB receptor-mediated inhibition of Ca2+ currents and synaptic transmission in cultured rat hippocampal neurones. J Physiol 444:669–686PubMedGoogle Scholar
  60. Seabrook GR, Howson W, Lacey MG (1990): Electrophysiological characterization of potent agonists and antagonists at pre- and postsynaptic GABAB receptors on neurones in rat brain slices. Br J Pharmacol 101:949–957PubMedGoogle Scholar
  61. Sekiguchi M, Sakuta H, Okamoto K, Sakai Y (1990): GABAB receptors expressed in Xenopus oocytes by guinea pig cerebral mRNA are functionally coupled with Ca2+-dependent Cl- channels and with K+ channels, through GTP-binding proteins. Mol Br Res 8:301–309CrossRefGoogle Scholar
  62. Solis JM, Nicoli RA (1992): Pharmacological characterization of GABAB mediated responses in the CA1 region of the rat hippocampal slice. J Neuro sci 12:3466–3472Google Scholar
  63. Soltesz I, Haby N, Leresche N, Crunelli V (1988): The GABAB antagonist phaclofen inhibits the late K+-dependent IPSP in cat and rat thalamic and hippocampal neurones. Brain Res 448:351–354PubMedCrossRefGoogle Scholar
  64. Stevens DR, Gallagher JP, Shinnick-Gallagher P (1985): Further studies on the action of baclofen on neurones of the dorsolateral septal nucleus of the rat, in vitro. Brain Res 358:360–363PubMedCrossRefGoogle Scholar
  65. Stratton KR, Cole AJ, Pritchett J, Eccles CU, Worley PF, Baraban JM (1989): Intrahip-pocampal injection of pertussis toxin blocks adenosine suppression of synaptic responses. Brain Res 494:359–364PubMedCrossRefGoogle Scholar
  66. Thalmann RH (1988): Evidence that guanosine triphosphate (GTP)-binding proteins control a synaptic response in brain: effect of pertussis toxin and GTP7S on the late inhibitory postsynaptic potential of hippocampal CA3 neurons. J Neurosci 8:4589–4602PubMedGoogle Scholar
  67. Thompson SM, Gähwiler BH (1992): Comparison of the actions of baclofen at pre- and postsynaptic receptors in the rat hippocampus in vitro. J Physiol 451:329–345PubMedGoogle Scholar
  68. Tsien RW, Lipscombe D, Madison DV, Bley KR, Fox AP (1988): Multiples types of neuronal calcium channels and their selective modulation. Trends Neurosci 11:431–437PubMedCrossRefGoogle Scholar
  69. Van der Ploeg I, Cintra A, Altiok N, Askelöf P, Fuxe K, Fredholm BB (1991): Limited distribution of pertussis toxin in rat brain after injection into the lateral cerebral ventricles. Neuroscience 44:205–214PubMedCrossRefGoogle Scholar
  70. Waldmeier PC, Wicki P, Feldtrauer JJ, Baumann PA (1988): Potential involvement of a (—)-baclofen-sensitive autoreceptor in the modulation of the release of endogenous GAB A from rat brain slices in vitro. Naunyn-Schmiedebergs Arch Pharmacol 377:289–295Google Scholar
  71. Wang MY, Dun NJ (1990): Phaclofen-insensitive presynaptic inhibitory action of (+)-(—)- baclofen in neonatal rat motoneurones in vitro. Br J Pharmacol 99:413–421PubMedGoogle Scholar
  72. Wojcik WJ, Paez X, Ulivi M (1989): A transduction mechanism for GABAB receptors. In: Allosteric Modulation of Amino Acid Receptors: Therapeutic Implications, Barnard EA, Costa E, eds. New York: Raven PressGoogle Scholar

Copyright information

© Birkhäuser Boston 1993

Authors and Affiliations

  • Patrick Dutar
  • Roger A. Nicoll

There are no affiliations available

Personalised recommendations