Skip to main content
NCBI home page
British Journal of Pharmacology logoLink to British Journal of Pharmacology
. 1994 May;112(1):97–106. doi: 10.1111/j.1476-5381.1994.tb13036.x

Anticonvulsant effects of the glycine/NMDA receptor ligands D-cycloserine and D-serine but not R-(+)-HA-966 in amygdala-kindled rats.

W Löscher 1, P Wlaź 1, C Rundfeldt 1, H Baran 1, D Hönack 1
PMCID: PMC1910310  PMID: 8032669

Abstract

1. The effects of the glycine/NMDA receptor partial agonists, D-cycloserine and (+)-HA-966 and the full agonist, D-serine, on focal seizure threshold and behaviour have been determined in amygdala-kindled rats, i.e. a model of focal (partial) epilepsy. The uncompetitive NMDA receptor antagonist, MK-801, was used for comparison. 2. The high efficacy glycine partial agonist, D-cycloserine, did not alter the threshold for induction of amygdaloid afterdischarges (ADT) at doses of 20-80 mg kg-1 i.p., but significant ADT increases were determined after application of higher doses (160 and 320 mg kg-1). The ADT increases after these high doses were long-lasting; significant elevations were still observed 2 days after drug injection. Determination of D-cycloserine in plasma and brain tissue showed that it was rapidly eliminated from plasma. Compared to peak levels in plasma, only relatively low concentrations of D-cycloserine were measured in brain tissue. 3. The low efficacy glycine partial agonist, (+)-HA-966, 10-40 mg kg-1 i.p., did not alter the ADT or seizure recordings (seizure severity, seizure duration, afterdischarge duration) at ADT currents. However, the drug dose-dependently increased the duration of postictal behavioural and electroencephalographic depression in kindled rats. At the higher dose tested, postictal immobilization was dramatically increased from 3 min to about 120 min. This might indicate that glutamatergic activity is decreased postictally, which is potentiated or prolonged by (+)-HA-966. 4. Like D-cycloserine, the glycine receptor full agonist, D-serine, injected bilaterally into the lateral ventricles at a dose of 5 mumol, significantly increased the ADT, while no effect was seen at a lower dose (2.5 mumol). 5. The anticonvulsant effects observed with D-cycloserine were completely antagonized by combined treatment with (+)-HA-966, indicating that the effects of D-cycloserine were mediated by the glycine/NMDA receptor complex. 6. MK-801, 0.1 mg kg-1, did not alter the focal seizure threshold or seizure recordings at ADT current, but induced marked phencyclidine(PCP)-like behavioural alterations, such as hyperlocomotion, stereotypies and motor impairment. No PCP-like behaviours were observed after D-cycloserine, D-serine or (+)-HA-966. High doses of (+)-HA-966 induced moderate motor impairment in kindled rats.(ABSTRACT TRUNCATED AT 400 WORDS)

Full text

PDF
97

Selected References

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

  1. Baron B. M., Harrison B. L., McDonald I. A., Meldrum B. S., Palfreyman M. G., Salituro F. G., Siegel B. W., Slone A. L., Turner J. P., White H. S. Potent indole- and quinoline-containing N-methyl-D-aspartate antagonists acting at the strychnine-insensitive glycine binding site. J Pharmacol Exp Ther. 1992 Sep;262(3):947–956. [PubMed] [Google Scholar]
  2. Bristow L. J., Hutson P. H., Thorn L., Tricklebank M. D. The glycine/NMDA receptor antagonist, R-(+)-HA-966, blocks activation of the mesolimbic dopaminergic system induced by phencyclidine and dizocilpine (MK-801) in rodents. Br J Pharmacol. 1993 Apr;108(4):1156–1163. doi: 10.1111/j.1476-5381.1993.tb13520.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Croucher M. J., Bradford H. F. 7-Chlorokynurenic acid, a strychnine-insensitive glycine receptor antagonist, inhibits limbic seizure kindling. Neurosci Lett. 1990 Oct 2;118(1):29–32. doi: 10.1016/0304-3940(90)90241-z. [DOI] [PubMed] [Google Scholar]
  4. Croucher M. J., Bradford H. F. The influence of strychnine-insensitive glycine receptor agonists and antagonists on generalized seizure thresholds. Brain Res. 1991 Mar 8;543(1):91–96. doi: 10.1016/0006-8993(91)91051-2. [DOI] [PubMed] [Google Scholar]
  5. DUNHAM N. W., MIYA T. S. A note on a simple apparatus for detecting neurological deficit in rats and mice. J Am Pharm Assoc Am Pharm Assoc. 1957 Mar;46(3):208–209. doi: 10.1002/jps.3030460322. [DOI] [PubMed] [Google Scholar]
  6. Dingledine R., McBain C. J., McNamara J. O. Excitatory amino acid receptors in epilepsy. Trends Pharmacol Sci. 1990 Aug;11(8):334–338. doi: 10.1016/0165-6147(90)90238-4. [DOI] [PubMed] [Google Scholar]
  7. Dunn R. W., Flanagan D. M., Martin L. L., Kerman L. L., Woods A. T., Camacho F., Wilmot C. A., Cornfeldt M. L., Effland R. C., Wood P. L. Stereoselective R-(+) enantiomer of HA-966 displays anxiolytic effects in rodents. Eur J Pharmacol. 1992 Apr 22;214(2-3):207–214. doi: 10.1016/0014-2999(92)90120-s. [DOI] [PubMed] [Google Scholar]
  8. FUST B., BOHNI E., PELLMONT B., ZBINDEN G., STUDER A. Experimentelle Untersuchungen mit D-Cycloserin. Schweiz Z Tuberc Pneumonol. 1958;15(3):129–157. [PubMed] [Google Scholar]
  9. Flood J. F., Morley J. E., Lanthorn T. H. Effect on memory processing by D-cycloserine, an agonist of the NMDA/glycine receptor. Eur J Pharmacol. 1992 Oct 20;221(2-3):249–254. doi: 10.1016/0014-2999(92)90709-d. [DOI] [PubMed] [Google Scholar]
  10. Foster A. C., Kemp J. A. Neurobiology. Glycine maintains excitement. Nature. 1989 Mar 30;338(6214):377–378. doi: 10.1038/338377a0. [DOI] [PubMed] [Google Scholar]
  11. Freeman F. G., Jarvis M. F. The effect of interstimulation interval on the assessment and stability of kindled seizure thresholds. Brain Res Bull. 1981 Dec;7(6):629–633. doi: 10.1016/0361-9230(81)90109-x. [DOI] [PubMed] [Google Scholar]
  12. Frenk H., Engel J., Jr, Ackermann R. F., Shavit Y., Liebeskind J. C. Endogenous opioids may mediate post-ictal behavioral depression in amygdaloid-kindled rats. Brain Res. 1979 May 11;167(2):435–440. doi: 10.1016/0006-8993(79)90842-4. [DOI] [PubMed] [Google Scholar]
  13. Henderson G., Johnson J. W., Ascher P. Competitive antagonists and partial agonists at the glycine modulatory site of the mouse N-methyl-D-aspartate receptor. J Physiol. 1990 Nov;430:189–212. doi: 10.1113/jphysiol.1990.sp018288. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Hutson P. H., Bristow L. J., Thorn L., Tricklebank M. D. R-(+)-HA-966, a glycine/NMDA receptor antagonist, selectively blocks the activation of the mesolimbic dopamine system by amphetamine. Br J Pharmacol. 1991 Aug;103(4):2037–2044. doi: 10.1111/j.1476-5381.1991.tb12372.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Johnson J. W., Ascher P. Glycine potentiates the NMDA response in cultured mouse brain neurons. Nature. 1987 Feb 5;325(6104):529–531. doi: 10.1038/325529a0. [DOI] [PubMed] [Google Scholar]
  16. Kemp J. A., Leeson P. D. The glycine site of the NMDA receptor--five years on. Trends Pharmacol Sci. 1993 Jan;14(1):20–25. doi: 10.1016/0165-6147(93)90108-v. [DOI] [PubMed] [Google Scholar]
  17. Klockgether T., Turski L., Schwarz M., Sontag K. H., Lehmann J. Paradoxical convulsant action of a novel non-competitive N-methyl-D-aspartate (NMDA) antagonist, tiletamine. Brain Res. 1988 Oct 4;461(2):343–348. doi: 10.1016/0006-8993(88)90265-x. [DOI] [PubMed] [Google Scholar]
  18. Koek W., Colpaert F. C. Selective blockade of N-methyl-D-aspartate (NMDA)-induced convulsions by NMDA antagonists and putative glycine antagonists: relationship with phencyclidine-like behavioral effects. J Pharmacol Exp Ther. 1990 Jan;252(1):349–357. [PubMed] [Google Scholar]
  19. Lapin I. P. Antagonism of L-glycine to seizures induced by L-kynurenine, quinolinic acid and strychnine in mice. Eur J Pharmacol. 1981 May 22;71(4):495–498. doi: 10.1016/0014-2999(81)90195-3. [DOI] [PubMed] [Google Scholar]
  20. Löscher W. Basic aspects of epilepsy. Curr Opin Neurol Neurosurg. 1993 Apr;6(2):223–232. [PubMed] [Google Scholar]
  21. Löscher W., Hönack D. Anticonvulsant and behavioral effects of two novel competitive N-methyl-D-aspartic acid receptor antagonists, CGP 37849 and CGP 39551, in the kindling model of epilepsy. Comparison with MK-801 and carbamazepine. J Pharmacol Exp Ther. 1991 Feb;256(2):432–440. [PubMed] [Google Scholar]
  22. Löscher W., Hönack D., Hashem A. Anticonvulsant efficacy of clonazepam and the beta-carboline ZK 93423 during chronic treatment in amygdala-kindled rats. Eur J Pharmacol. 1987 Nov 17;143(3):403–414. doi: 10.1016/0014-2999(87)90464-x. [DOI] [PubMed] [Google Scholar]
  23. Löscher W., Hönack D. High doses of memantine (1-amino-3,5-dimethyladamantane) induce seizures in kindled but not in non-kindled rats. Naunyn Schmiedebergs Arch Pharmacol. 1990 May;341(5):476–481. doi: 10.1007/BF00176343. [DOI] [PubMed] [Google Scholar]
  24. Löscher W., Hönack D. The behavioural effects of MK-801 in rats: involvement of dopaminergic, serotonergic and noradrenergic systems. Eur J Pharmacol. 1992 May 14;215(2-3):199–208. doi: 10.1016/0014-2999(92)90029-4. [DOI] [PubMed] [Google Scholar]
  25. Löscher W., Hönack D. The effect of interstimulation interval on the assessment of anticonvulsant drug potency in fully kindled rats. Epilepsy Res. 1990 Dec;7(3):182–196. doi: 10.1016/0920-1211(90)90014-m. [DOI] [PubMed] [Google Scholar]
  26. Löscher W., Hönack D. The novel competitive N-methyl-D-aspartate (NMDA) antagonist CGP 37849 preferentially induces phencyclidine-like behavioral effects in kindled rats: attenuation by manipulation of dopamine, alpha-1 and serotonin1A receptors. J Pharmacol Exp Ther. 1991 Jun;257(3):1146–1153. [PubMed] [Google Scholar]
  27. Löscher W., Hörstermann D., Hönack D., Rundfeldt C., Wahnschaffe U. Transmitter amino acid levels in rat brain regions after amygdala-kindling or chronic electrode implantation without kindling: evidence for a pro-kindling effect of prolonged electrode implantation. Neurochem Res. 1993 Jul;18(7):775–781. doi: 10.1007/BF00966772. [DOI] [PubMed] [Google Scholar]
  28. McNamara J. O., Russell R. D., Rigsbee L., Bonhaus D. W. Anticonvulsant and antiepileptogenic actions of MK-801 in the kindling and electroshock models. Neuropharmacology. 1988 Jun;27(6):563–568. doi: 10.1016/0028-3908(88)90176-1. [DOI] [PubMed] [Google Scholar]
  29. Morimoto K., Sato M. NMDA receptor complex and kindling mechanisms. Epilepsy Res Suppl. 1992;9:297–305. [PubMed] [Google Scholar]
  30. Myslobodsky M. S., Golovchinsky V., Mintz M. Ketamine: convulsant or anti-convulsant? Pharmacol Biochem Behav. 1981 Jan;14(1):27–33. doi: 10.1016/0091-3057(81)90099-x. [DOI] [PubMed] [Google Scholar]
  31. Norris D. O., Mastropaolo J., O'Connor D. A., Novitzki M. R., Deutsch S. I. Glycinergic interventions potentiate the ability of MK 801 to raise the threshold voltage for tonic hindlimb extension in mice. Pharmacol Biochem Behav. 1992 Oct;43(2):609–612. doi: 10.1016/0091-3057(92)90198-o. [DOI] [PubMed] [Google Scholar]
  32. Peterson S. L. 7-Chlorokynurenic acid antagonizes the anticonvulsant activity of D-cycloserine in maximal electroshock seizures. Epilepsy Res. 1992 Oct;13(1):73–81. doi: 10.1016/0920-1211(92)90009-i. [DOI] [PubMed] [Google Scholar]
  33. Peterson S. L. Anticonvulsant drug potentiation by glycine in maximal electroshock seizures is mimicked by D-serine and antagonized by 7-chlorokynurenic acid. Eur J Pharmacol. 1991 Jul 9;199(3):341–348. doi: 10.1016/0014-2999(91)90498-f. [DOI] [PubMed] [Google Scholar]
  34. Peterson S. L., Boehnke L. E. Anticonvulsant effects of MK-801 and glycine on hippocampal afterdischarge. Exp Neurol. 1989 May;104(2):113–117. doi: 10.1016/s0014-4886(89)80003-2. [DOI] [PubMed] [Google Scholar]
  35. Peterson S. L., Schwade N. D. The anticonvulsant activity of D-cycloserine is specific for tonic convulsions. Epilepsy Res. 1993 Jun;15(2):141–148. doi: 10.1016/0920-1211(93)90094-n. [DOI] [PubMed] [Google Scholar]
  36. Racine R., Okujava V., Chipashvili S. Modification of seizure activity by electrical stimulation. 3. Mechanisms. Electroencephalogr Clin Neurophysiol. 1972 Mar;32(3):295–299. doi: 10.1016/0013-4694(72)90178-2. [DOI] [PubMed] [Google Scholar]
  37. Rao T. S., Cler J. A., Compton R. P., Emmett M. R., Mick S., Sun E. T., Iyengar S., Wood P. L. Neuropharmacological characterization of 1-aminocyclopropane-1-carboxylate and 1-aminocyclobutane-1-carboxylate, ligands of the N-methyl-D-aspartate-associated glycine receptor. Neuropharmacology. 1990 Mar;29(3):305–309. doi: 10.1016/0028-3908(90)90018-m. [DOI] [PubMed] [Google Scholar]
  38. Rundfeldt C., Löscher W. Development of tolerance to the anticonvulsant effect of vigabatrin in amygdala-kindled rats. Eur J Pharmacol. 1992 Mar 31;213(3):351–366. doi: 10.1016/0014-2999(92)90624-d. [DOI] [PubMed] [Google Scholar]
  39. STOREY P. B., MCLEAN R. L. A current appraisal of cycloserine. Antibiotic Med Clin Ther (New York) 1957 Apr;4(4):223–232. [PubMed] [Google Scholar]
  40. Schuster G. M., Schmidt W. J. D-cycloserine reverses the working memory impairment of hippocampal-lesioned rats in a spatial learning task. Eur J Pharmacol. 1992 Nov 24;224(1):97–98. doi: 10.1016/0014-2999(92)94825-g. [DOI] [PubMed] [Google Scholar]
  41. Singh L., Donald A. E., Foster A. C., Hutson P. H., Iversen L. L., Iversen S. D., Kemp J. A., Leeson P. D., Marshall G. R., Oles R. J. Enantiomers of HA-966 (3-amino-1-hydroxypyrrolid-2-one) exhibit distinct central nervous system effects: (+)-HA-966 is a selective glycine/N-methyl-D-aspartate receptor antagonist, but (-)-HA-966 is a potent gamma-butyrolactone-like sedative. Proc Natl Acad Sci U S A. 1990 Jan;87(1):347–351. doi: 10.1073/pnas.87.1.347. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Singh L., Oles R. J., Tricklebank M. D. Modulation of seizure susceptibility in the mouse by the strychnine-insensitive glycine recognition site of the NMDA receptor/ion channel complex. Br J Pharmacol. 1990 Feb;99(2):285–288. doi: 10.1111/j.1476-5381.1990.tb14695.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Sirviö J., Ekonsalo T., Riekkinen P., Jr, Lahtinen H., Riekkinen P., Sr D-cycloserine, a modulator of the N-methyl-D-aspartate receptor, improves spatial learning in rats treated with muscarinic antagonist. Neurosci Lett. 1992 Nov 9;146(2):215–218. doi: 10.1016/0304-3940(92)90081-h. [DOI] [PubMed] [Google Scholar]
  44. Skolnick P., Marvizón J. C., Jackson B. W., Monn J. A., Rice K. C., Lewin A. H. Blockade of N-methyl-D-aspartate induced convulsions by 1-aminocyclopropanecarboxylates. Life Sci. 1989;45(18):1647–1655. doi: 10.1016/0024-3205(89)90274-9. [DOI] [PubMed] [Google Scholar]
  45. Skolnick P., Miller R., Young A., Boje K., Trullas R. Chronic treatment with 1-aminocyclopropanecarboxylic acid desensitizes behavioral responses to compounds acting at the N-methyl-D-aspartate receptor complex. Psychopharmacology (Berl) 1992;107(4):489–496. doi: 10.1007/BF02245261. [DOI] [PubMed] [Google Scholar]
  46. Toth E., Lajtha A., Sarhan S., Seiler N. Anticonvulsant effects of some inhibitory neurotransmitter amino acids. Neurochem Res. 1983 Mar;8(3):291–302. doi: 10.1007/BF00965719. [DOI] [PubMed] [Google Scholar]
  47. Von Lubitz D. K., Lin R. C., McKenzie R. J., Devlin T. M., McCabe R. T., Skolnick P. A novel treatment of global cerebral ischaemia with a glycine partial agonist. Eur J Pharmacol. 1992 Aug 14;219(1):153–158. doi: 10.1016/0014-2999(92)90594-t. [DOI] [PubMed] [Google Scholar]
  48. Whitcomb K., Lupica C. R., Rosen J. B., Berman R. F. Adenosine involvement in postictal events in amygdala-kindled rats. Epilepsy Res. 1990 Aug;6(3):171–179. doi: 10.1016/0920-1211(90)90070-c. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Pharmacology are provided here courtesy of The British Pharmacological Society

RESOURCES