Skip to main content
The Journal of Physiology logoLink to The Journal of Physiology
. 1990 Mar;422:433–446. doi: 10.1113/jphysiol.1990.sp017993

On the presynaptic action of baclofen at inhibitory synapses between cultured rat hippocampal neurones.

N L Harrison 1
PMCID: PMC1190141  PMID: 2352187

Abstract

1. (-)Baclofen reduces inhibitory postsynaptic potentials (IPSPs) and the associated synaptic currents (IPSCs) at inhibitory GABAergic synapses between cultured rat hippocampal neurones. The reversal potential for the IPSC is unaltered. 2. The effect of (-)baclofen is concentration dependent; the EC50 for (-)baclofen is approximately 5 microM. 3. Statistical analyses of the amplitude fluctuations of the IPSC in the presence of (-)baclofen suggested a presynaptic location for the depression of synaptic transmission by (-)baclofen. In control experiments, lowering extracellular Ca2+ produced similar effects. (-)Baclofen has no detectable postsynaptic actions in these cultured neurones. 4. Phaclofen (0.2-0.5 mM) increases IPSC amplitude but does not significantly block the depressant effect of (-)baclofen on synaptic transmission. 5. The effect of (-)baclofen is not blocked by pertussis toxin pre-treatment. 6. It is concluded that (-)baclofen acts presynaptically to reduce the release of GABA. The mechanism by which release is reduced may involve a phaclofen-insensitive GABAB receptor.

Full text

PDF
433

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Andrade R., Malenka R. C., Nicoll R. A. A G protein couples serotonin and GABAB receptors to the same channels in hippocampus. Science. 1986 Dec 5;234(4781):1261–1265. doi: 10.1126/science.2430334. [DOI] [PubMed] [Google Scholar]
  2. Asano T., Ui M., Ogasawara N. Prevention of the agonist binding to gamma-aminobutyric acid B receptors by guanine nucleotides and islet-activating protein, pertussis toxin, in bovine cerebral cortex. Possible coupling of the toxin-sensitive GTP-binding proteins to receptors. J Biol Chem. 1985 Oct 15;260(23):12653–12658. [PubMed] [Google Scholar]
  3. Ault B., Nadler J. V. Baclofen selectively inhibits transmission at synapses made by axons of CA3 pyramidal cells in the hippocampal slice. J Pharmacol Exp Ther. 1982 Nov;223(2):291–297. [PubMed] [Google Scholar]
  4. Barker J. L., Harrison N. L. Outward rectification of inhibitory postsynaptic currents in cultured rat hippocampal neurones. J Physiol. 1988 Sep;403:41–55. doi: 10.1113/jphysiol.1988.sp017237. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bonanno G., Cavazzani P., Andrioli G. C., Asaro D., Pellegrini G., Raiteri M. Release-regulating autoreceptors of the GABAB-type in human cerebral cortex. Br J Pharmacol. 1989 Feb;96(2):341–346. doi: 10.1111/j.1476-5381.1989.tb11823.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Bowery N. G., Hill D. R., Hudson A. L., Doble A., Middlemiss D. N., Shaw J., Turnbull M. (-)Baclofen decreases neurotransmitter release in the mammalian CNS by an action at a novel GABA receptor. Nature. 1980 Jan 3;283(5742):92–94. doi: 10.1038/283092a0. [DOI] [PubMed] [Google Scholar]
  7. Bowery N. G., Hudson A. L., Price G. W. GABAA and GABAB receptor site distribution in the rat central nervous system. Neuroscience. 1987 Feb;20(2):365–383. doi: 10.1016/0306-4522(87)90098-4. [DOI] [PubMed] [Google Scholar]
  8. Christie M. J., North R. A. Agonists at mu-opioid, M2-muscarinic and GABAB-receptors increase the same potassium conductance in rat lateral parabrachial neurones. Br J Pharmacol. 1988 Nov;95(3):896–902. doi: 10.1111/j.1476-5381.1988.tb11719.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Colmers W. F., Williams J. T. Pertussis toxin pretreatment discriminates between pre- and postsynaptic actions of baclofen in rat dorsal raphe nucleus in vitro. Neurosci Lett. 1988 Nov 11;93(2-3):300–306. doi: 10.1016/0304-3940(88)90099-7. [DOI] [PubMed] [Google Scholar]
  10. Connors B. W., Malenka R. C., Silva L. R. Two inhibitory postsynaptic potentials, and GABAA and GABAB receptor-mediated responses in neocortex of rat and cat. J Physiol. 1988 Dec;406:443–468. doi: 10.1113/jphysiol.1988.sp017390. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Deisz R. A., Lux H. D. gamma-Aminobutyric acid-induced depression of calcium currents of chick sensory neurons. Neurosci Lett. 1985 May 14;56(2):205–210. doi: 10.1016/0304-3940(85)90130-2. [DOI] [PubMed] [Google Scholar]
  12. Dolphin A. C., Scott R. H. Inhibition of calcium currents in cultured rat dorsal root ganglion neurones by (-)-baclofen. Br J Pharmacol. 1986 May;88(1):213–220. doi: 10.1111/j.1476-5381.1986.tb09489.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Dunlap K. Two types of gamma-aminobutyric acid receptor on embryonic sensory neurones. Br J Pharmacol. 1981 Nov;74(3):579–585. doi: 10.1111/j.1476-5381.1981.tb10467.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Dutar P., Nicoll R. A. A physiological role for GABAB receptors in the central nervous system. Nature. 1988 Mar 10;332(6160):156–158. doi: 10.1038/332156a0. [DOI] [PubMed] [Google Scholar]
  15. Dutar P., Nicoll R. A. Pre- and postsynaptic GABAB receptors in the hippocampus have different pharmacological properties. Neuron. 1988 Sep;1(7):585–591. doi: 10.1016/0896-6273(88)90108-0. [DOI] [PubMed] [Google Scholar]
  16. Désarmenien M., Feltz P., Occhipinti G., Santangelo F., Schlichter R. Coexistence of GABAA and GABAB receptors on A delta and C primary afferents. Br J Pharmacol. 1984 Feb;81(2):327–333. doi: 10.1111/j.1476-5381.1984.tb10082.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Forsythe I. D., Westbrook G. L. Slow excitatory postsynaptic currents mediated by N-methyl-D-aspartate receptors on cultured mouse central neurones. J Physiol. 1988 Feb;396:515–533. doi: 10.1113/jphysiol.1988.sp016975. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Gähwiler B. H., Brown D. A. GABAB-receptor-activated K+ current in voltage-clamped CA3 pyramidal cells in hippocampal cultures. Proc Natl Acad Sci U S A. 1985 Mar;82(5):1558–1562. doi: 10.1073/pnas.82.5.1558. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Hamill O. P., Marty A., Neher E., Sakmann B., Sigworth F. J. Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches. Pflugers Arch. 1981 Aug;391(2):85–100. doi: 10.1007/BF00656997. [DOI] [PubMed] [Google Scholar]
  20. Harrison N. L., Lambert N. A. Modification of GABAA receptor function by an analog of cyclic AMP. Neurosci Lett. 1989 Oct 23;105(1-2):137–142. doi: 10.1016/0304-3940(89)90025-6. [DOI] [PubMed] [Google Scholar]
  21. Harrison N. L., Lange G. D., Barker J. L. (-)-Baclofen activates presynaptic GABAB receptors on GABAergic inhibitory neurons from embryonic rat hippocampus. Neurosci Lett. 1988 Feb 15;85(1):105–109. doi: 10.1016/0304-3940(88)90437-5. [DOI] [PubMed] [Google Scholar]
  22. Hasuo H., Gallagher J. P. Comparison of antagonism by phaclofen of baclofen induced hyperpolarizations and synaptically mediated late hyperpolarizing potentials recorded intracellularly from rat dorsolateral septal neurons. Neurosci Lett. 1988 Mar 21;86(1):77–81. doi: 10.1016/0304-3940(88)90186-3. [DOI] [PubMed] [Google Scholar]
  23. Hill D. R., Bowery N. G. 3H-baclofen and 3H-GABA bind to bicuculline-insensitive GABA B sites in rat brain. Nature. 1981 Mar 12;290(5802):149–152. doi: 10.1038/290149a0. [DOI] [PubMed] [Google Scholar]
  24. Hill D. R., Bowery N. G., Hudson A. L. Inhibition of GABAB receptor binding by guanyl nucleotides. J Neurochem. 1984 Mar;42(3):652–657. doi: 10.1111/j.1471-4159.1984.tb02732.x. [DOI] [PubMed] [Google Scholar]
  25. Holz G. G., 4th, Rane S. G., Dunlap K. GTP-binding proteins mediate transmitter inhibition of voltage-dependent calcium channels. Nature. 1986 Feb 20;319(6055):670–672. doi: 10.1038/319670a0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Howe J. R., Sutor B., Zieglgänsberger W. Baclofen reduces post-synaptic potentials of rat cortical neurones by an action other than its hyperpolarizing action. J Physiol. 1987 Mar;384:539–569. doi: 10.1113/jphysiol.1987.sp016469. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Huettner J. E., Baughman R. W. Primary culture of identified neurons from the visual cortex of postnatal rats. J Neurosci. 1986 Oct;6(10):3044–3060. doi: 10.1523/JNEUROSCI.06-10-03044.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Karbon E. W., Enna S. J. Characterization of the relationship between gamma-aminobutyric acid B agonists and transmitter-coupled cyclic nucleotide-generating systems in rat brain. Mol Pharmacol. 1985 Jan;27(1):53–59. [PubMed] [Google Scholar]
  29. Kerr D. I., Ong J., Prager R. H., Gynther B. D., Curtis D. R. Phaclofen: a peripheral and central baclofen antagonist. Brain Res. 1987 Mar 3;405(1):150–154. doi: 10.1016/0006-8993(87)90999-1. [DOI] [PubMed] [Google Scholar]
  30. Lacey M. G., Mercuri N. B., North R. A. On the potassium conductance increase activated by GABAB and dopamine D2 receptors in rat substantia nigra neurones. J Physiol. 1988 Jul;401:437–453. doi: 10.1113/jphysiol.1988.sp017171. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Lewis D. L., Weight F. F., Luini A. A guanine nucleotide-binding protein mediates the inhibition of voltage-dependent calcium current by somatostatin in a pituitary cell line. Proc Natl Acad Sci U S A. 1986 Dec;83(23):9035–9039. doi: 10.1073/pnas.83.23.9035. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Nakajima Y., Nakajima S., Inoue M. Pertussis toxin-insensitive G protein mediates substance P-induced inhibition of potassium channels in brain neurons. Proc Natl Acad Sci U S A. 1988 May;85(10):3643–3647. doi: 10.1073/pnas.85.10.3643. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Nelson P. G., Marshall K. C., Pun R. Y., Christian C. N., Sheriff W. H., Jr, Macdonald R. L., Neale E. A. Synaptic interactions between mammalian central neurons in cell culture. II. Quantal Analysis of EPSPs. J Neurophysiol. 1983 Jun;49(6):1442–1458. doi: 10.1152/jn.1983.49.6.1442. [DOI] [PubMed] [Google Scholar]
  34. Newberry N. R., Nicoll R. A. A bicuculline-resistant inhibitory post-synaptic potential in rat hippocampal pyramidal cells in vitro. J Physiol. 1984 Mar;348:239–254. doi: 10.1113/jphysiol.1984.sp015107. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Newberry N. R., Nicoll R. A. Direct hyperpolarizing action of baclofen on hippocampal pyramidal cells. 1984 Mar 29-Apr 4Nature. 308(5958):450–452. doi: 10.1038/308450a0. [DOI] [PubMed] [Google Scholar]
  36. Peet M. J., McLennan H. Pre-and postsynaptic actions of baclofen: blockade of the late synaptically-evoked hyperpolarization of CA1 hippocampal neurones. Exp Brain Res. 1986;61(3):567–574. doi: 10.1007/BF00237582. [DOI] [PubMed] [Google Scholar]
  37. Pfaffinger P. Muscarine and t-LHRH suppress M-current by activating an IAP-insensitive G-protein. J Neurosci. 1988 Sep;8(9):3343–3353. doi: 10.1523/JNEUROSCI.08-09-03343.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Pittaluga A., Asaro D., Pellegrini G., Raiteri M. Studies on [3H]GABA and endogenous GABA release in rat cerebral cortex suggest the presence of autoreceptors of the GABAB type. Eur J Pharmacol. 1987 Nov 24;144(1):45–52. doi: 10.1016/0014-2999(87)90007-0. [DOI] [PubMed] [Google Scholar]
  39. Segal M., Barker J. L. Rat hippocampal neurons in culture: voltage-clamp analysis of inhibitory synaptic connections. J Neurophysiol. 1984 Sep;52(3):469–487. doi: 10.1152/jn.1984.52.3.469. [DOI] [PubMed] [Google Scholar]
  40. Soltesz I., Haby M., Leresche N., Crunelli V. The GABAB antagonist phaclofen inhibits the late K+-dependent IPSP in cat and rat thalamic and hippocampal neurones. Brain Res. 1988 May 17;448(2):351–354. doi: 10.1016/0006-8993(88)91275-9. [DOI] [PubMed] [Google Scholar]
  41. Stevens D. R., Gallagher J. P., Shinnick-Gallagher P. Further studies on the action of baclofen on neurons of the dorsolateral septal nucleus of the rat, in vitro. Brain Res. 1985 Dec 9;358(1-2):360–363. doi: 10.1016/0006-8993(85)90984-9. [DOI] [PubMed] [Google Scholar]
  42. Stirling J. M., Cross A. J., Robinson T. N., Green A. R. The effects of GABAB receptor agonists and antagonists on potassium-stimulated [Ca2+]i in rat brain synaptosomes. Neuropharmacology. 1989 Jul;28(7):699–704. doi: 10.1016/0028-3908(89)90153-6. [DOI] [PubMed] [Google Scholar]
  43. Thalmann R. H. Evidence that guanosine triphosphate (GTP)-binding proteins control a synaptic response in brain: effect of pertussis toxin and GTP gamma S on the late inhibitory postsynaptic potential of hippocampal CA3 neurons. J Neurosci. 1988 Dec;8(12):4589–4602. doi: 10.1523/JNEUROSCI.08-12-04589.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Waldmeier P. C., Wicki P., Feldtrauer J. J., Baumann P. A. Potential involvement of a baclofen-sensitive autoreceptor in the modulation of the release of endogenous GABA from rat brain slices in vitro. Naunyn Schmiedebergs Arch Pharmacol. 1988 Mar;337(3):289–295. doi: 10.1007/BF00168841. [DOI] [PubMed] [Google Scholar]
  45. Wojcik W. J., Neff N. H. gamma-aminobutyric acid B receptors are negatively coupled to adenylate cyclase in brain, and in the cerebellum these receptors may be associated with granule cells. Mol Pharmacol. 1984 Jan;25(1):24–28. [PubMed] [Google Scholar]

Articles from The Journal of Physiology are provided here courtesy of The Physiological Society

RESOURCES