Amino Acids

, Volume 6, Issue 3, pp 247–260 | Cite as

D-Cycloserine: Agonist turned antagonist

  • T. H. Lanthorn
Review Article


D-Cycloserine can enhance activation of the NMDA receptor complex and could enhance the induction of long-term potentiation (LTP). In animals and humans, D-cycloserine can enhance performance in learning and memory tasks. This enhancing effect can disappear during repeated administration. The enhancing effects are also lost when higher doses are used, and replaced by behavioral and biochemical effects like those produced by NMDA antagonists. It has been reported that NMDA agonists, applied before or after tetanic stimulation, can block the induction of LTP. This may be the result of feedback inhibition of second messenger pathways stimulated by receptor activation. This may explain the antagonist-like effects of glycine partial agonists like D-cycloserine. In clinical trials of D-cycloserine in age-associated memory impairment (AAMI) and Alzheimer's disease, chronic treatment provided few positive effects on learning and memory. This may be due to inhibition of second messenger pathways following chronic stimulation of the receptor complex.


Amino acids D-Cycloserine Glycine site Partial agonist Learning and memory Long-term potentiation Alzheimer's disease 


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  1. Anderson RC, Worth HM, Welles JS, Harris PN, Chen KK (1956) Pharmacology and toxicology of cycloserine. Antibiot Chemother 6: 360–368Google Scholar
  2. Anthony EW, Nevins ME (1993) Anxiolytic effects of NMDA-associated glycine receptor ligands in the rat potentiated startle test. Eur J Pharmacol 250: 317–324Google Scholar
  3. Baxter MG, Lanthorn TH, Frick KM, Golski S, Wan R-Q, Olton DS (1994) D-cycloserine, a novel cognitive enhancer, improves spatial memory in aged rats. Neurobiol Aging 15: 207–213Google Scholar
  4. Berry SD, Thompson RF (1978) Prediction of learning rate from the hippocampal electroencephalogram. Science 200: 1298–1300Google Scholar
  5. Bliss TVP, Gardner-Medwin AR (1973) Long-lasting potentiation of synaptic transmission in the dentate area of the unanaesthetized rabbit following stimulation of the perforant path. J Physiol 232: 357–374Google Scholar
  6. Bliss TVP, Lømo T (1973) Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path. J Physiol 232: 331–356Google Scholar
  7. Bonhaus DW, Perry WB, MacNamara JO (1990) Decreased density, but not number, of N-methyl-D-aspartate, glycine and phencyclidine sites in hippocampus of senescent rats. Brain Res 532: 82–86Google Scholar
  8. Coan E, Saywood W, Collingridge GL (1987) MK-801 blocks NMDA receptor-mediated synaptic transmission and long term potentiation in rat hippocampal slices. Neurosci Lett 80: 111–114Google Scholar
  9. Coan E, Irving AJ, Collingridge GL (1989) Low-frequency activation of the NMDA receptor system can prevent the induction of LTP. Neurosci Lett 105: 205–210Google Scholar
  10. Collingridge GL, Kehl S, McLennan HH (1983) Excitatory amino acids in synaptic transmission in the Schaffer collateral-commissural pathway of the rat hippocampus. J Physiol 334: 33–46Google Scholar
  11. Conzelman GM (1956) The physiological disposition of D-cycloserine in the human subject. Am Rev Tuberc Pul Dis 74: 739–746Google Scholar
  12. Conzelman GM, Jones RK (1956) On the physiological disposition of cycloserine in experimental animals. Am Rev Tuberc Pul Dis 74: 802–806Google Scholar
  13. Crane GE (1959) Cycloserine as an antidepressant agent. Am J Psychiat 115: 1025–1026Google Scholar
  14. Crane GE (1961) The psychotropic effects of cycloserine: a new use for an antibiotic. Compr Psychiat 2: 51–59Google Scholar
  15. Danysz W, Wroblewski JT, Costa E (1988) Learning impairment in rats by N-methyl-D-aspartate receptor antagonists. Neuropharmacol 27: 653–656Google Scholar
  16. Danysz W, Wroblewski JT (1989) Amnesic properties of glutamate receptor antagonists. Neurosci Res Commun 5: 9–14Google Scholar
  17. Davis S, Butcher SP, Morris RGM (1992) The NMDA receptor antagonist D-2-amino-5-phosphonopentanoate (D-AP5) impairs spatial learning and LTPin vivo at intracerebral concentrations comparable to those that block LTPin vitro. J Neurosci 12: 21–34Google Scholar
  18. Disterhoft JF, Thompson LT, Halperin GL, Lanthorn TH (1993) D-cycloserine enhances hippocampally-dependent eyeblink conditioning in aging as well as young rabbits. Soc Neurosci Abs 19: 413.2Google Scholar
  19. Dunn RW, Corbett R, Fielding S (1989) Effects of 5-HT1A receptor agonists and NMDA receptor antagonists in the social interaction test and elevated plus maze. Eur J Pharmacol 169: 1–10Google Scholar
  20. Emmett MR, Mick SJ, Rao TS, Iyengar S, Wood PL (1991) Actions of D-cycloserine at the N-methyl-D-aspartate-associated glycine receptor sitein vivo. Neuropharmacol 30: 1167–1171Google Scholar
  21. Epstein IG, Nair KGS, Mulinos MG, Haber A (1958–1959) Pyridoxine and its relation to cycloserine neurotoxicity. Antibiot Ann: 472–481Google Scholar
  22. Fishkin RJ, Ince ES, Carlezon WA Jr, Dunn RW (1993) D-Cycloserine attenuates scopolamine-induced learning and memory deficits in rats. Behav Neural Biol 59: 150–157Google Scholar
  23. Flood JF, Morley JE, Lanthorn TH (1992) Effect on memory processing by D-cycloserine, an agonist of the NMDA/glycine receptor. Eur J Pharmacol 221: 249–254Google Scholar
  24. Fox K, Sato H, Daw N (1989) The location and function of NMDA receptors in cat and kitten visual cortex. J Neurosci 9: 2443–2454Google Scholar
  25. Francis PT, Sims NR, Proctor AW, Bowen DM (1993) Cortical pyramidal neurone loss may cause glutamatergic hypoactivity and cognitive impairment in Alzheimer's disease: investigative and therapeutic perspectives. J Neurochem 60: 1589–1604Google Scholar
  26. Handelmann GE, Mueller LL, Cordi AA (1988) Glycinergic compounds facilitate memory formation and retrieval in rats. Soc Neurosci Abs 14: 249Google Scholar
  27. Hanngren H, Hansson E, Ullberg S (1962) An autoradiographic study of the distribution of tritium-labeled cycloserine in mice. Antibiot Chemother 12: 46–54Google Scholar
  28. Haring R, Stanton PK, Scheidler MA, Moskal JR (1991) Glycine-like modulation of N-methyl-D-aspartate receptors by a monoclonal antibody that enhances long-term potentiation. J Neurochem 57: 323–332Google Scholar
  29. Harris E, Ganong AH, Cotman CW (1984) Long-term potentiation in the hippocampus involves activation of N-methyl-D-aspartate receptors. Brain Res 323: 132–137Google Scholar
  30. Henderson G, Johnson JW, Ascher P (1990) Competitive antagonists and partial agonists at the glycine modulatory site of the mouse N-methyl-D-aspartate receptor. J Physiol 430: 189–212Google Scholar
  31. Herberg LJ, Rose IC (1990) Effects of D-cycloserine and cycloleucine, ligands for the NMDA-associated strychnine-insensitive glycine site, on brain-stimulation reward and spontaneous locomotion. Pharmacol Biochem Behav 36: 735–738Google Scholar
  32. Hood WF, Compton RP, Monahan JB (1989) D-Cycloserine: a ligand for the N-methyl-D-aspartate coupled glycine receptor has partial agonist characteristics. Neurosci Lett 98: 91–95Google Scholar
  33. Huang YY, Colino A, Selig DK, Malenka RC (1992) The influence of prior synaptic activity on the induction of long-term potentiation. Science 255: 730–733Google Scholar
  34. Izumi Y, Clifford DB, Zorumski CF (1990) Glycine antagonists block the induction of long-term potentiation in CA1 of the rat hippocampal slice. Neurosci Lett 112: 251–256Google Scholar
  35. Izumi Y, Clifford DB, Zorumski CF (1992a) Low concentrations of N-methyl-D-aspartate inhibit the induction of long-term potentiation in rat hippocampal slices. Neurosci Lett 137: 245–248Google Scholar
  36. Izumi Y, Clifford DB, Zorumski CF (1992b) Inhibition of long-term potentiation by NMDA-mediated nitric oxide release. Science 257: 1273–1276Google Scholar
  37. Johnson JW, Ascher P (1987) Glycine potentiates the NMDA response in cultured mouse brain neurons. Nature 325: 529–531Google Scholar
  38. Jones RW, Wesnes KA, Kirby J (1991) Effects of NMDA modulation in scopolamine dementia. Ann NY Acad Sci 640: 241–244Google Scholar
  39. Kelso SR, Ganong AH, Brown TH (1986) Hebbian synapses in hippocampus. Proc Natl Acad Sci USA 83: 5326–5330Google Scholar
  40. Kito S, Miyoshi R, Nomoto T (1990) Influence of age on NMDA receptor complex in rat brain studied by in vitro autoradiography. J Histochem Cytochem 38: 1725–1731Google Scholar
  41. Kleckner NW, Dingledine R (1988) Requirement for glycine in activation of NMDA-receptors expressed inXenopus oocytes. Science 241: 835–837Google Scholar
  42. Larson J, Wong D, Lynch G (1986) Patterned stimulation at the theta frequency is optimal for the induction of hippocampal long-term potentiation. Brain Res 368: 347–350Google Scholar
  43. Leander JD, Rathburn RC, Zimmerman DM (1988) Anticonvulsant effects of phencyclidine-like drugs: relation to N-methyl-D-aspartic acid antagonism. Brain Res 454: 368–372Google Scholar
  44. Lehmann J, Williams ME, Mathis C, Wolfson E, Wahhab S, Nair SN (1993) Learning impairment of rats following traumatic brain injury: effects of D-cycloserine, haloperidol and diazepam. (submitted)Google Scholar
  45. Levy WB, Steward O (1979) Synapses as associative memory elements in the hippocampal formation. Brain Res 175: 233–245Google Scholar
  46. Levy WB, Steward O (1983) Temporal contiguity requirements for long-term associative potentiation/depression in the hippocampus. Neuroscience 8: 791–797Google Scholar
  47. Lewis WC, Calden G, Thurston JR, Gilson WE (1957) Psychiatric and neurological reactions to cycloserine in the treatment of tuberculosis. Dis Chest 32: 172–182Google Scholar
  48. Luby ED, Cohen RC, Rosenbaum B, Gottlieb JS, Kelly R (1959) Study of a new schizophrenomimetic drug — Sernyl. Arch Neurol Psychiat 81: 363–369Google Scholar
  49. Magnusson KR, Cotman CW (1993) Effects of aging on NMDA and MK-801 binding sites in mice. Brain Res 604: 334–337Google Scholar
  50. Mandell GL, Sande MA (1985) In: Gilman AG, Goodman LS, Gilman A (eds) Goodman and Gilman's: the pharmacological basis of therapeutics. MacMillan, New York, pp 1199–1218Google Scholar
  51. Maragos WF, Greenamyre JT, Penney JB Jr, Young AB (1987) Glutamate dysfunction in Alzheimer's disease: an hypotheses. TINS 10: 65–68Google Scholar
  52. Marvizon JC, Lewin AH, Skolnick P (1989) 1-Aminocyclopropane carboxylic acid: a potent and selective ligand for the glycine modulatory site of the N-methyl-D-aspartate receptor complex. J Neurochem 52: 992–994Google Scholar
  53. McBain CJ, Kleckner NW, Wyrick S, Dingledine R (1989) Structural requirements for activation of the glycine coagonist site of N-methyl-D-aspartate receptors expressed inXenopus oocytes. Mol Pharmacol 36: 556–565Google Scholar
  54. Monaghan DT, Geddes JW, Yao D, Chung C, Cotman CW (1987) [3H]TCP binding sites in Alzheimer's disease. Neurosci Lett 73: 197–200Google Scholar
  55. Monahan JB, Handelmann GE, Hood WF, Cordi AA (1989) D-Cycloserine, a positive modulator of the N-methyl-D-aspartate receptor, enhances performance of learning tasks in rats. Pharmacol Biochem Behav 34: 649–653Google Scholar
  56. Mondadori C, Weiskrantz L, Buerki H, Petschke F, Fagg GE (1989) NMDA receptor antagonists can enhance or impair learning performance in animals. Exp Brain Res 75: 449–454Google Scholar
  57. Morris RGM, Anderson E, Lynch G (1986) Selective impairment of learning and blockade of long-term potentiation by an N-methyl-D-aspartate receptor antagonist, D-AP5. Nature 319: 774–776Google Scholar
  58. Morton RF, McKenna MH, Charles E (1955–56) Studies on the absorption, diffusion and excretion of cycloserine. Antibiot Ann: 169–172Google Scholar
  59. Moyer JR Jr, Deyo RA, Disterhoft JF (1990) Hippocampectomy disrupts trace eyeblink conditioning in rabbits. Behav Neurosci 104: 243–252Google Scholar
  60. Nair KGS (1957) Cycloserine combination therapy discussion. Transact 16th Vet Admin Conf Chemotherap Tuberculosis 16: 53Google Scholar
  61. Nair KGS, Epstein IG, Baron H, Mulinos MG (1955–56) Absorption, distribution and excretion of D-cycloserine in man. Antibiot Ann: 136–140Google Scholar
  62. O'Keefe J, Nadel L (1978) The hippocampus as a cognitive map. Clarendon, OxfordGoogle Scholar
  63. Oliver MW, Kessler M, Larson J, Schottler F, Lynch G (1990) Glycine site associated with the NMDA receptor modulates long-term potentiation. Synapse 5: 265–270Google Scholar
  64. Pellymounter MA, Beatty G, Gallagher M (1990) Hippocampal 3H-CPP binding and spatial learning deficits in aged rats. Psychobiology 18: 298–304Google Scholar
  65. Peterson C, Cotman CW (1989) Strain-dependent decrease in glutamate binding to the N-methyl-D-aspartate acid receptor during aging. Neurosci Lett 104: 309–313Google Scholar
  66. Peterson SL (1992) 7-Chlorokynurenic acid antagonizes the anticonvulsant activity of D-cycloserine in maximal electroshock seizures. Epilep Res 13: 73–81Google Scholar
  67. Pittaluga A, Fedele E, Risiglione C, Raiteri M (1993) Age-related decrease of the NMDA receptor-mediated noradrenaline release in rat hippocampus and partial restoration by D-cycloserine. Eur J Pharmacol 231: 129–134Google Scholar
  68. Quartermain D, Mower J, Rafferty MF, Herting RL, Lanthorn TH (1994) Acute but not chronic activation of the NMDA coupled glycine receptor with D-cycloserine facilitates learning and retention. Eur J Pharmacol (in press)Google Scholar
  69. Rupniak NM, Duchowski M, Tye SJ, Cook G, Iversen SD (1992) Failure of D-cycloserine to reverse cognitive disruption induced by scopolamine or phencyclidine in primates. Life Sci 50: 1959–1962Google Scholar
  70. Schuster GM, Schmidt WJ (1992) D-cycloserine reverses the working memory impairment of hippocampal-lesioned rats in a spatial learning task. Eur J Pharmacol 224: 97–98Google Scholar
  71. Simeon J, Fink M, Itil TM, Ponce D (1970) d-Cycloserine therapy of psychosis by symptom provocation. Comprehen Psychiat 11: 80–88Google Scholar
  72. Sirviö J, Ekonsalo T, Riekkinen P Jr, Lahtinen H, Riekkinen P Sr (1992) D-Cycloserine, a modulator of the N-methyl-D-aspartate receptor, improves spatial learning in rats treated with muscarinic antagonist. Neurosci Lett 146: 215–218Google Scholar
  73. Skolnick P, Marvizon JC, Jackson BW, Monn JM, Rice K, Lewin C (1989) Blockade of N-methyl-D-aspartate induced convulsions by 1-aminocyclopropanecarboxylates. Life Sci 45: 1647–1655Google Scholar
  74. Spencer JN, Payne HG (1956) Cycloserine: experimental studies. Antibiot Chemother 6: 708–717Google Scholar
  75. Stringer JL, Greenfield J, Hackett JT, Guyenet PG (1983) Blockade of long-term potentiation by phencyclidine andσ opiates in the hippocampus in vivo and in vitro. Brain Res 280: 127–138Google Scholar
  76. Thiels E, Weisz DJ, Berger TW (1991)In vivo modulation of N-methyl-D-aspartate receptor-dependent long-term potentiation by the glycine modulatory site. Neurosci 46: 501–509Google Scholar
  77. Thomson AW (1990) Glycine is a coagonist at the NMDA receptor/channel complex. Prog Neurobiol 35: 53–74Google Scholar
  78. Thompson LT, Disterhoft JF (1991) The NMDA receptor/channel complex and associative learning: opposite effects of PCP and D-cycloserine. Soc Neurosci Abs 17: 486Google Scholar
  79. Thompson LT, Moskal JR, Disterhoft JF (1992) Hippocampally-dependent learning facilitated by a monoclonal antibody or D-cycloserine. Nature 359: 638–641Google Scholar
  80. Trullas R, Skolnick P (1990) Functional antagonists at the NMDA receptor complex exhibit antidepressant actions. Eur J Pharmacol 185: 1–10Google Scholar
  81. Trullas R, Jackson B, Skolnick P (1989) Anxiolytic properties of 1-aminocyclopropane-carboxylic acid, a ligand at strychnine-insensitive glycine receptors. Pharmacol Biochem Behav 34: 313–316Google Scholar
  82. Walker DL, Gold PE (1991) Effects of the novel NMDA anatgonist, NPC 12626, on long-term potentiation, learning and memory. Brain Res 549: 213–221Google Scholar
  83. Watanabe Y, Himi T, Saito H, Abe K (1992) Involvment of glycine site associated with the NMDA receptor in hippocampal long-term potentiation and acquisition of spatial memory in rats. Brain Res 582: 58–64Google Scholar
  84. Watson GB, Lanthorn TH (1990) Pharmacological characteristics of cyclic homologues of glycine at the N-methyl-D-aspartate receptor-associated glycine site. Neuropharmacol 29: 727–730Google Scholar
  85. Watson GB, Bolanowski MA, Baganoff MP, Deppler CL, Lanthorn TH (1990) D-Cycloserine acts as a partial agonist at the glycine modulatory site of the NMDA receptors expressed inXenopus oocytes. Brain Res 510: 158–160Google Scholar
  86. Wenk GL, Walker LC, Price DL, Cork LC (1991) Loss of NMDA, but not GABA-A, binding in the brains of aged rats and monkeys. Neurobiol Aging 12: 93–98Google Scholar
  87. Winson J (1978) Loss of hippocampal theta rhythm results in spatial memory deficit in the rat. Science 201: 160–163Google Scholar

Copyright information

© Springer-Verlag 1994

Authors and Affiliations

  • T. H. Lanthorn
    • 1
  1. 1.Lightning NeurotechGurneeUSA

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