Psychopharmacology

, Volume 114, Issue 4, pp 573–582

Sensitive and rapid behavioral differentiation ofN-methyl-d-aspartate receptor antagonists

  • Mark J. Ginski
  • Jeffrey M. Witkin
Original Investigations

Abstract

Behavioral effects of PCP-type noncompetitive antagonists ofN-methyl-d-aspartate (NMDA) receptors overlap with those of a host of other centrally acting compounds. In the present experiment, locomotor activity and performance on an inverted screen test in untrained mice were used to differentiate PCP-type non-competitive NMDA antagonists from other drug classes. These uncompetitive NMDA antagonists [PCP, dizocilpine, (−)-MK-801, TCP, (+)-SKF 10,047, dextrorphan, ketamine] produced dose-related increases in locomotor activity and the percentage of mice falling off an inverted, elevated wire mesh screen. Both effects demonstrated stereoselectivity, occurred at comparable dose levels, and were within the range of doses producing other biological effects (e.g., anticonvulsant). The potencies of these drugs for producing behavioral effects were positively correlated with affinities for PCP ([3H]MK-801) but not σ([3H]SKF 10,047) receptors. Although muscarinic antagonists (benactyzine, atropine) produced effects in the same direction, locomotor stimulation was small and occurred at lower doses than those inducing screen failures. Competitive NMDA antagonists (LY 274614, LY 233536, CPP, NPC 12626), σ receptor ligands (DTG, dextromethorphan), postsynaptic dopamine agonists (quinpirole, SKF 38393) and antagonists (haloperidol, SCH 39166), and some depressant compounds (morphine, diazepam) increased failures on the screen test but decreased locomotor activity. Ligands of the polyamine regulatory site of the NMDA receptor (ifenprodil, SL 82.0715-10) and the AMPA receptor antagonist NBQX decreased locomotor activity without increasing screen failures. An antagonist of the strychnine-insensitive glycine receptor (7-chlorokynurenic acid) did not affect performance on either test. Psychomotor stimulants (cocaine and methamphetamine) stimulated locomotor activity without affecting screen performance. The only false positives occurred with barbiturates (pentobarbital, phenobarbital). Nonetheless, the present procedure demonstrates excellent sensitivity and power for rapid discrimination of uncompetitive NMDA antagonists.

Key words

NMDA receptor antagonists Dissociative anesthetics Behavioral effects Locomotor activity Mice 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Abood LG, Biel JH (1962) Anticholinergic psychotomimetic agents. Int Rev Neurobiol 4:217–273Google Scholar
  2. Addae JL, Stone TW (1988) Effects of anticonvulsants on responses to excitatory amino acids applied topically to rat cerebral cortex. Gen Pharmacol 19:455–462Google Scholar
  3. Balster RL (1987) The behavioral pharmacology of phencyclidine. In: Meltzer HY (ed) Psychopharmacology: the third generation of progress. Raven Press, New York, pp 1573–1579Google Scholar
  4. Balster RL, Wessinger WD (1983) Central nervous system depressant effects of phencyclidine. In: Kamenka JM, Domino EF, Geneste P (eds) Phencyclidine and related arylcyclohexylamines: present and future applications. NPP Books, Ann Arbor, Mich., pp 291–309Google Scholar
  5. Balster RL, Willetts J (1988) Receptor mediation of the discriminative stimulus properties of phencyclidine and sigma-opioid agonists. In: Colpaert FC, Balster RL (eds) Transduction mechanisms of drug stimuli. Springer, Berlin Heidelberg New York, pp 122–135Google Scholar
  6. Boast CA, Pastor G (1987) Characterization of motor activity patterns induced byN-methyl-d-aspartate antagonists in gerbils. Pharmacol Biochem Behav 27:553–557Google Scholar
  7. Bourson A, Tricklebank MD (1991) The discriminative stimulus properties of the glycine/NMDA receptor antagonist L-687,414. Fundam Clin Pharmacol 5:443Google Scholar
  8. Brady KT, Balster RL, May EL (1982) Discriminative stimulus properties of stereoisomers ofN-allylnormetazocine in phencyclidine-trained squirrel monkeys. Science 215:178–180Google Scholar
  9. Burns RS, Lerner SE (1981) The effects of phencyclidine in man: a review. In: Domino EF (ed) PCP (phencyclidine): historical and current perspectives. NPP Books, Ann Arbor, Mich., pp 449–470Google Scholar
  10. Carlsson M, Carlsson A (1989) The NMDA antagonists MK-801 causes marked locomotor stimulation in monoamine-depleted mice. J Neural Transm 75:221–226Google Scholar
  11. Carlsson M, Carlsson, A (1990) Interactions between glutamatergic and monoaminergic systems within the basal ganglia — implications for schizophrenia and Parkinson's disease. Trends Neurosci 13:272–276Google Scholar
  12. Carter AJ (1992) Glycine antagonists: regulation of the NMDA receptor-channel complex by the strychnine-insensitive glycine site. Drugs Future 17:595–613Google Scholar
  13. Chen G (1965) Evaluation of phencyclidine-type cataleptic activity. Arch Int Pharmacodyn 157:193–201Google Scholar
  14. Chen G, Ensor CR, Russell D, Bohner B (1959) The pharmacology of 1-(1-phenyl-cyclohexyl)piperidine HCl. J Pharmacol Exp Ther 149:71–78Google Scholar
  15. Choi D (1988) Glutamate neurotoxicity and diseases of the nervous system. Neuron 1:623–634Google Scholar
  16. Clineschmidt BV, Martin GE, Bunting PR, Papp NL (1982) Central sympathomimetic activity of (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (MK-801), a substance with potent anticonvulsant, central sympathomimetic, and apparent anxiolytic properties. Drug Dev Res 2:135–145Google Scholar
  17. Collins GGS, Anson J (1987) Effects of barbiturates on responses evoked by excitatory amino acids in slices of rat olfactory cortex. Neuropharmacology 26:167–171Google Scholar
  18. Coughenour LL, McLean JR, Parker RB (1977) A new device for the rapid measurement of impaired motor function in mice. Pharmacol Biochem Behav 6:351–353Google Scholar
  19. Domino EF, Luby ED (1981) Abnormal mental states induced by phencyclidine as a model of schizophrenia. In: Domino EF (ed) PCP (phencyclidine): historical and current perspectives. NPP Books, Ann Arbor, Mich., pp 401–418Google Scholar
  20. Downs, DA, Wiley JA, Labay RJ, Meltzer LT (1988) Drug effects on phencylidine-induced locomotor stimulation and ataxia in mice. In: Domino EF, Kamenka J-M (eds) Sigma and phencylidine-like compounds as molecular probes in biology. NPP Books, Ann Arbor, Mich., pp 545–554Google Scholar
  21. Evoniuk GE, Hertzman RP, Skolnick P (1991) A rapid method for evaluating the behavioral effects of phencyclidine-like dissociative anesthetics in mice. Psychopharmacology 105:125–128Google Scholar
  22. Ferkany JW, Kyle DJ, Willetts J, Rzeszotarski WJ, Guzewska ME, Ellenberger SR, Jones SM, Sacaan AI, Snell LD, Borosky S, Jones BE, Johnson KM, Balster RL, Burchett K, Kawasaki K, Hoch DB, Dingeldine R (1989) Pharmacological profile of NPC 12626, a novel, competitiveN-methyl-d-aspartate receptor antagonist. J Pharmacol Exp Ther 250:100–109Google Scholar
  23. Finney DJ (1964) Statistical methods in biological assay, 2nd edn. Hafner, New YorkGoogle Scholar
  24. Genovese RF, Xi-Chun LM (1991) Effects of MK-801 stereoisomers on schedule-controlled behavior in rats. Psychopharmacology 105:477–480Google Scholar
  25. Greenberg BD, Segal DS (1985) Acute and chronic behavioral interactions between phencyclidine and amphetamine: evidence for a dopaminergic role in some PCP-induced behaviors. Pharmacol Biochem Behav 23:99–105Google Scholar
  26. Holtzman SG (1980) Phencyclidine-like discriminative effects of opioids in the rat. J Pharmacol Exp Ther 214:614–619Google Scholar
  27. Irifune M, Shimizu T, Nomoto M (1991) Ketamine-induced hyperlocomotion associated with alteration of presynaptic components of dopamine neurons in the nucleus accumbens of mice. Pharmacol Biochem Behav 40:399–407Google Scholar
  28. Iversen SD, Singh L, Oles RJ, Preston C, Tricklebank MD (1988) Pharmacological profile of theN-methyl-d-aspartate (NMDA) receptor antagonist, MK-801. In: Domino EF, Kamenka JM (eds) Sigma and phencyclidine-like compounds as molecular probes in biology. NPP Books, Ann Arbor, Mich., p 373Google Scholar
  29. Jackson A, Sanger DJ (1988) Is the discriminative stimulus produced by phencyclidine due to an interaction withN-methyl-d-aspartate receptors? Psychopharmacology 96:87–92Google Scholar
  30. Ketchum JS, Sidell FR, Crowell EB Jr, Aghajanian GK, Hayes AH Jr (1973) Atropine, scopolamine, ditran: comparative pharmacology and antagonists in man. Psychopharmacologia 28:121–145Google Scholar
  31. Koek W, Colpaert FC (1990) Selective blockade ofN-methyl-d-aspartate (NMDA)-induced convulsions by NMDA antagonists and putative glycine antagonists: relationship with phencyclidine-like behavioral effects. J Pharmacol Exp Ther 252:349–357Google Scholar
  32. Koek W, Colpaert FC (1992)N-Methyl-d-aspartate antagonism and phencylidine like activity: behavioral effects of glycine site ligands. In: Kamenka JM, Domino EF (eds) Multiple sigma and PCP receptor ligands: mechanisms for neuromodulation and neuroprotection. NPP Books, Ann Arbor, Mich., pp 655–671Google Scholar
  33. Koek W, Woods JH (1988) Correlations between phencylidine-like activity andN-methyl-d-aspartate antagonism: Behavioral evidence. In: Domino EF, Kamenka JM (eds) Sigma and phencyclidine-like compounds as molecular probes in biology. NPP Books, Ann Arbor, Mich., pp 357–372Google Scholar
  34. Koek W, Woods JH, Rice KC, Jacobson AE, Huguenin PN, Burke TR Jr (1984) Phencyclidine-induced catelepsy in pigeons: specificity and stereoselectivity. Eur J Pharmacol 106:635–638Google Scholar
  35. Koek W, Woods JH, Ornstein P (1986) Phencyclidine-like behavioral effects in pigeons induced by systemic administration of the excitatory amino acid antagonist, 2-amino-5-phosphonovalerate. Life Sci 39:973–979Google Scholar
  36. Koek W, Colpaert FC, Woods JH, Kamenka JM (1989) The phenycyclidine (PCP) analogN-[1-(2-benzo(b)thiophenyl)cyclohexyl]piperidine (BTCP) shares cocaine-like but not other characteristic behavioral effects with PCP, ketamine and MK-801. J Pharmacol Exp Ther 250:1019–1027Google Scholar
  37. Koek W, Woods JH, Colpaert FC (1990)N-Methyl-d-aspartate antagonism and phencyclidine-like activity: a drug discrimination analysis. J Pharmacol Exp Ther 253:1017–1024Google Scholar
  38. Kulkarni SK, Ticku MK (1989) Interactions between GABAergic anticonvulsants and the NMDA receptor antagonist MK 801 against MES- and picrotoxin-induced convulsions in rats. Life Sci 44:1317–1323Google Scholar
  39. Leander JD, Wood CR, Zimmerman DM, Dykstra LA (1986) Phencyclidine-type catalepsy in the pigeon: an update on Chen's work. Drug Dev Res 7:75–85Google Scholar
  40. Leander JD, Lawson RR, Ornstein PL, Zimmerman DM (1988)N-Methyl-d-aspartic acid induced lethality in mice: selective antagonism by phencylidine-like drugs. Brain Res 448:115–120Google Scholar
  41. Liljequist S (1991) Genetic differences in the effects of competitive and non-competitive NMDA receptor antagonists on locomotor activity in mice. Psychopharmacology 104:17–21Google Scholar
  42. Litchfield JT, Wilcoxon F (1949) A simplified method of evaluating dose-effect experiments. J Pharmacol Exp Ther 95:99–113Google Scholar
  43. Lodge D, Anis NA (1982) Effects of phencyclidine on excitatroy amino acid activation of spinal interneurons in the cat. Eur J Pharmacol 77:203–204Google Scholar
  44. Lodge D, Johnson KM (1990) Noncompetitive excitatory amino acid receptor antagonists. In: Lodge D, Collingridge GL (eds) The Pharmacology of Excitatory Amino Acids. Elsevier Trends, Cambridge, 1990, pp 13–18Google Scholar
  45. Löscher W, Hönack D (1992) The behavioural effects of MK-801 in rats: involvement of dopaminergic, serotonergic and noradrenergic systems. Eur J Pharmacol 215:199–208Google Scholar
  46. Lucki I (1990) Behavioral responses associated with serotonin receptors. In: Barrett JE, Thompson T, Dews PB (eds) Advances in behavioral pharmacology, vol. 7. Lawrence Erlbaum, Hillsdale, N.J., pp 119–148Google Scholar
  47. Macdonald RL, Barker JL (1979) Anticonvulsant and anesthetic barbiturates: different postsynaptic actions in cultured mammalian neurons. Neurology 29:432–447Google Scholar
  48. Martin JR, Berman MH, Krewsun I, Small SF (1979) Phencyclidine-induced stereotyped behavior and serotonergic syndrome in rat. Life Sci 24:1699–1704Google Scholar
  49. Marwaha J, Palmer M, Hoffer B, Freedman R, Rice K, Paul S, Skolnick P (1981) Differential electrophysiological and behavioral responses to optically active derivatives of phencyclidine. Naunyn-Schmiedeberg's Arch Pharmacol 315:203–209Google Scholar
  50. Meldrum B (1985) Possible therapeutic applications of antagonists of excitatory amino acid neurotransmitters. Clin Sci 68:113–123Google Scholar
  51. National Institute on Drug Abuse (1990) National Household Survey on Drug Abuse: Population Estimates 1990. US Department of Health and Human Services Publication NO (ADM) 91–1732Google Scholar
  52. Olney J (1989) Excitatory amino acids and neuropsychiatric disorders. Biol Psychiatry 26:505–525Google Scholar
  53. Ornstein P, Zimmerman DM, Hynes III MD, Leander JD (1987) Anticonvulsant, motor impairment and stimulatory effects of NMDA antagonists and phencylidine-like compounds in mice. In: Hicks TP, Lodge D, McLennan H (eds) Excitatory amino acid transmission. Liss, New York, pp 123–126Google Scholar
  54. Sanger DJ, Jackson A (1989) Effects of phencyclidine and otherN-methyl-d-aspartate antagonists on the schedule-controlled behavior of rats. J Pharmacol Exp Ther 248:1215–1221Google Scholar
  55. Sanger DJ, Joly D (1991) The effects of NMDA antagonists on punished exploration in mice. Behav Pharmacol 2:57–63Google Scholar
  56. Seidleck B, Thurkauf A, Witkin JM (1994) Evaluation of ADCI against convulsant and locomotor stimulant effects of cocaine: Comparison with the structural analogs, dizocilpine and carbamazepine. Pharmacol Biochem Behav (in press)Google Scholar
  57. Shannon HE (1982) Phencyclidine-like discriminative stimuli of (+)- and (-)-N-allylnormetazocine in rats. Eur J Pharmacol 84:225–228Google Scholar
  58. Skolnick P, Marvizon J, Jackson B, Monn J, Rice K, Lewin A (1989) Blockade ofN-methyl-d-aspartate induced convulsions by 1-aminocyclopropanecarboxylates. Life Sci 45:1647–1655Google Scholar
  59. Snedecor GW, Cochran WG (1967) Statistical methods, 6th ed. Iowa State University Press, Ames, Iowa, pp 135–171Google Scholar
  60. Székely JI, Sharpe LG, Jaffe JH (1991) Induction of phencyclidine-like behavior in rats by dextrorphan but not dextromethorphan. Pharmacol Biochem Behav 40:381–386Google Scholar
  61. Teichbert VI, Tal N, Goldberg O, Luini A (1984) Barbiturates, alcohols and the CNS excitatory neurotransmission: specific effects on the kainate and quisqualate receptors. Brain Res 291:285–292Google Scholar
  62. Tortella FC, Marley RJ, Witkin JM (1992) NMDA modulators protect against convulsions resistant to other anticonvulsants. NIDA Research Monograph 105, Problems of Drug Dependence 119:290Google Scholar
  63. Tricklebank MD, Singh L, Oles RJ, Preston C, Iversen SD (1989) The behavioural effects of MK-801: a comparison with antagonists acting non-competitively and competitively at the NMDA receptor. Eur J Pharmacol 167:127–135Google Scholar
  64. Trullas R, Skolnick P (1990) Functional antagonists at the NMDA receptor complex exhibit antidepressant actions. Eur J Pharmacol 185:1–10Google Scholar
  65. Waters DH, Walczak D (1980) Cholinergic and dopaminergic involvement in phenobarbital-induced locomotor activity in mice. Neuropharmacology 19:543–547Google Scholar
  66. Wiley JL, Balster RL (1992) Preclinical evaluation ofN-methyl-d-aspartate antagonists for antianxiety effects: a review. In: Kamenka JM, Domino EF (eds) Multiple sigma and PCP receptor ligands: mechanisms for neuromodulation and neuroprotection. NPP Books, Ann Arbor, Mich., pp 801–815Google Scholar
  67. Willetts J, Balster RL (1988) The discriminative stimulus effects ofN-methyl-d-aspartate antagonists in phencyclidine-trained rats. Neuropharmacology 27:1249–1256Google Scholar
  68. Willetts J, Balster RL (1989) Pentobarbital-like discriminative stimulus effects ofN-methyl-d-aspartate antagonists. J Pharmacol Exp Ther 249:438–443Google Scholar
  69. Willetts J, Bobelis, DJ, Balster RL (1989) Drug discrimination based on the competitiveN-methyl-d-aspartate antagonist, NPC 12626. Psychopharmacology 99:458–462Google Scholar
  70. Willets J, Balster RL, Leander JD (1990) Behavioral pharmacology of NMDA receptor antagonists. In: Lodge D, Collingridge GL (eds) The Pharmacology of Excitatory Amino Acids. Elsevier Trends, Cambridge, 1990, pp 62–67Google Scholar
  71. Willetts J, Tokarz ME, Balster RL (1991) Pentobarbital-like effects ofN-methyl-d-aspartate antagonists in mice. Life Sci 48:1795–1798Google Scholar
  72. Wilmot CA (1989) Excitatory amino acid antagonists: behavioral and biochemical approaches for the development of new central nervous system therapeutic agents. Drug Dev Res 17:339–365Google Scholar
  73. Witkin JM, Steele TD (1992) Effects of strychnine-insensitive glycine receptor ligands on discriminative stimulus effects ofN-methyl-d-aspartate (NMDA) channel antagonists. Soc Neurosci Abstr 18:447Google Scholar
  74. Witkin JM, Tortella FC (1991) Modulators ofN-methyl-d-aspartate protect against diazepam- or phenobarbital-resistant cocaine convulsions. Life Sci 48: PL51-PL56Google Scholar
  75. Witkin JM, Genovese RF, Witkin KM, Chiang PK (1992) Behavioral effects of some diphenyl-substituted antimuscarinics: comparison with cocaine and atropine. Pharmacol Biochem Behav 41:377–384Google Scholar
  76. Wong EHF, Knight AR, Woodruff GN (1988) [3H]MK-801 labels a site on theN-methyl-d-aspartate receptor channel complex in rat brain membranes. J Neurochem 50:274–281Google Scholar
  77. Zukin SR, Zukin RS (1979) Specific phencyclidine binding in rat central nervous system. Proc Natl Acad Sci USA 76:5372–5376Google Scholar

Copyright information

© Springer-Verlag 1994

Authors and Affiliations

  • Mark J. Ginski
    • 1
  • Jeffrey M. Witkin
    • 1
  1. 1.Drug Development Group, Psychobiology Section, Addiction Research CenterNational Institute on Drug AbuseBaltimoreUSA

Personalised recommendations