Psychopharmacology

, Volume 170, Issue 2, pp 215–224 | Cite as

Evaluation of the phencyclidine-like discriminative stimulus effects of novel NMDA channel blockers in rats

Original Investigation

Abstract

Rationale

Because of their potential therapeutic effects, N-methyl-d-aspartate (NMDA) receptor antagonists have been investigated for clinical use. Unfortunately, many channel-blocking antagonists have been associated with the production of side effects, including motor impairment and phencyclidine (PCP)-like subjective effects.

Objective

This study investigated the relationship between NMDA receptor channel blockade and production of PCP-like side effects by evaluating a variety of NMDA channel blockers with different binding characteristics for the production of PCP-like discriminative stimulus effects.

Methods

The NMDA channel blockers were tested in rats trained to discriminate 2 mg/kg PCP, i.p., from saline using a standard two-lever drug discrimination procedure with responding under a fixed ratio (FR) 32 schedule of food reinforcement.

Results

The high-affinity channel blockers PD 138289, PD 137889 and FR 115427, produced full, dose-dependent substitution for PCP. Of the moderate-affinity channel blockers, MRZ 2/579 fully substituted for PCP while 1-(4-methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline, 8-(2-methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline and alaproclate produced partial substitution. Drugs with the lowest affinity for the channel site and/or higher affinity for non-NMDA CNS sites, antazoline, idazoxan, 1-phenyl-1,2,3,4-tetrahydroisoquinoline, α-benzyl-N-methylphenethylamine and orphenadrine, failed to substitute for PCP.

Conclusions

The results demonstrate that the cellular actions of the individual channel-blocking NMDA antagonists, in particular affinity for the channel site and NMDA receptor specificity, are important determinants of their discriminative stimulus effects. While higher affinity channel blockers show a correlation between affinity and PCP-like discriminative stimulus effects, behavioral disruption through action at non-NMDA receptors probably prevents achieving sufficient concentrations of the lower affinity compounds at NMDA receptors to produce PCP-like discriminative stimulus effects.

Keywords

Phencyclidine NMDA receptor antagonists Drug discrimination Side effects Rats 

Notes

Acknowledgements

Portions of this study were presented previously at the annual Society for Neuroscience Meeting New Orleans, Louisiana (October 1997), and/or reported in K.L. Nicholson's Ph.D. Dissertation (September 1998). Research supported by NIDA grants DA-01442 and DA-07027. Special thanks to Drs. Chris Parsons and Wojciech Danysz of Merz Pharmaceuticals GmbH for providing MRZ 2/579; Drs. Christopher Bigge and Peter Boxer of Parke-Davis Pharmaceutical Research Division for providing PD 138289 and PD 137889; Dr. Nakanishi of the Fujisawa Pharmaceutical Co. for providing FR 115427; Drs. Nancy Gray, Patricia Contreras, and Brian Cheng of G.D. Searle & Co. for providing the other tetrahydroisoqionolines, 8-MPTIQ, 1-MPTIQ, and 1-PTIQ; and Dr. John Woodward of VCU for providing the BNMPA. The technical assistance of Hua Li is greatly appreciated.

References

  1. Balster RL (1989) Substitution and antagonism in rats trained to discriminate (+)-N-allylnormetazocine from saline. J Pharmacol Ther 249:749–756Google Scholar
  2. Balster RL (1991a) Discriminative stimulus properties of phencyclidine and other NMDA antagonists. In: Glennon RA, Järbe TUC, Frankenheim J (eds) Drug discrimination: applications to drug abuse research. National Institute on Drug Abuse Research Monograph Series 116, DHHS Publication No. ADXM 92-1878. U.S. Government Printing Office, Washington, pp 163–180Google Scholar
  3. Balster RL (1991b) Drug abuse potential evaluation in animals. Br J Addict 86:549–1558PubMedGoogle Scholar
  4. Balster RL, Willetts J (1996) Phencyclidine: a drug of abuse and a tool for neuroscience research. In: Schuster CR, Kuhar MJ (eds) Pharmacological aspects of drug dependence: towards an integrated neurobehavioral approach. Handbook of experimental pharmacology, vol 118. Springer, Berlin Heidelberg New York, pp 233–262Google Scholar
  5. Beardsley PM, Hayes BA, Balster RL (1990) The self-administration of MK-801 can depend upon drug-reinforcement history and its discriminative stimulus properties are phencyclidine-like in rhesus monkeys. J Pharmacol Ther 252:953–959Google Scholar
  6. Bigge CF, Johnson G, Hays SJ, Malone TC, Ortwine DF, Boxer PA, Marcoux FW, Coughenour LL (1992) Development of polycyclic amines as potent noncompetitive NMDA antagonists. In: Kamenka J-M, Domino EF (eds) Multiple sigma and PCP receptor ligands: mechanisms for neuromodulation and neuroprotection? NPP Books, Ann Arbor, pp 1–20Google Scholar
  7. Bigge CF, Malone TC, Hays SJ, Johnson G, Novak PM, Lescosky LJ, Retz DM, Ortwine DF, Probert AW Jr, Coughenour LL, Boxer PA, Robichaud LJ, Brahce LJ, Shillis JL (1993) Synthesis and pharmacological evaluation of a 4α-phenanthrenamine derivatives acting at the phencyclidine binding site of the N-methyl-d-aspartate receptor. J Med Chem 36:1977–1995PubMedGoogle Scholar
  8. Bliss CI (1967) Statistics in biology. McGraw-Hill, New YorkGoogle Scholar
  9. Brady KT, Balster RL, May EL (1982a) Stereoisomers of N-allylnormetazocine: phencyclidine-like behavioral effects in squirrel monkeys and rats. Science 215:178–180PubMedGoogle Scholar
  10. Brady KT, Woolverton WL, Balster RL (1982b) Discriminative stimulus and reinforcing properties of etoxadrol and dexoxadrol in monkeys. J Pharmacol Exp Ther 220:56–62PubMedGoogle Scholar
  11. Doshay LJ, Constable K (1957) Treatment of paralysis agitans with orphenadrine (Disipal). Results in 176 cases. J Am Med Assoc 163:1352–1357Google Scholar
  12. Finch JW (1959) Clinical trial of orphenadrine in skeletal muscle disorders. Clin Med Surg 6:195–198Google Scholar
  13. Frost SJ, Eccleston D, Marshall EF, Hassanyeh F (1984) Alaproclate: an open clinical study in depressive illness. Psychopharmacology 83:285–287PubMedGoogle Scholar
  14. Geter-Douglass B, Witkin JM (1999) Behavioral effects and anticonvulsant efficacies of low-affinity, uncompetitive NMDA antagonists in mice. Psychopharmacology 146:280–289Google Scholar
  15. Grant KA, Colombo G, Grant J, Rogawski MA (1996) Dizocilpine-like discriminative stimulus effects of low-affinity uncompetitive NMDA antagonists. Neuropharmacology 35:1709–1719Google Scholar
  16. Gray NM, Cheng BK, Mick SJ, Lair CM, Contrereas PC (1989) Phencyclidine-like effects of tetrahydroisoquinolines and related compounds. J Med Chem 32:1242–1248PubMedGoogle Scholar
  17. Hays SJ, Novak PM, Ortwine DF, Bigge CF, Colbry NL, Johnson G, Lescosky LJ, Malone TC, Michael A, Reily MD, Coughenour LL, Brahce LJ, Shillis JL, Probert A Jr (1993) Synthesis and pharmacological evaluation of hexahydrofluorenamines as noncompetitive antagonists at the N-methyl-d-aspartate receptor. J Med Chem 36:654–670PubMedGoogle Scholar
  18. Heresco-Levy U, Javitt DC (1998) The role of N-methyl-d-aspartate (NMDA) receptor-mediated neurotransmission in the pathophysiology and therapeutics of psychiatric syndromes. Eur Neuropsychopharmacol 8:141–152CrossRefPubMedGoogle Scholar
  19. Hesselink MB, Parsons CG, Wollenburg C, Danysz W (1999) Brain distribution of an uncompetitive NMDA receptor antagonist: comparison to its in vitro potency in electrophysiological studies. Naunyn Schmiedebergs Arch Pharmacol 360:144–550CrossRefPubMedGoogle Scholar
  20. Hoddes SH (1964) Orphenadrine citrate in the treatment of muscular pain. Practitioner 193:76–80Google Scholar
  21. Hodgkiss JP, Sherriffs HJ, Cottrell DA, Shirakawa K, Kelly JS, Kuno A, Ohkubo M, Butcher SP, Olverman HJ (1993) Neurochemical and electrophysiological studies on FR 115427, a novel non-competitive NMDA receptor antagonist. Eur J Pharmacol 240:219–227CrossRefPubMedGoogle Scholar
  22. Holtzman SG (1990) Discriminative stimulus effects of drugs: relationship to potential for abuse. In: Adler MA, Cowan A (eds) Testing and evaluation of drugs of abuse. Wiley-Liss, New York, pp 193–210Google Scholar
  23. Hu P-S, Ross SB (1997) NMDA receptor-mediated increase in cyclic GMP in the rat cerebellum in vivo is blocked by alaproclate and GEA-857. Pharmacol Tox 80:97–102PubMedGoogle Scholar
  24. Hunskaar S, Donnell D (1991) Clinical and pharmacological review of the efficacy of orphenadrine and its combination with paracetamol in painful conditions. J Int Med Res 19:71–87PubMedGoogle Scholar
  25. Jackson A, Sanger DJ (1988) Is the discriminative stimulus produced by phencyclidine due to an interaction with N-methyl-d-aspartate receptors? Psychopharmacology 96:87–92Google Scholar
  26. Jones HE, Li H, Balster RL (1998) Failure of ibogaine to produce phencyclidine-like discriminative stimulus effects in rats and monkeys. Pharmacol Biochem Behav 59:413–418CrossRefPubMedGoogle Scholar
  27. Jordan S, Jackson HC, Nutt DJ, Handley SL (1996) Discriminative stimulus produced by the imidazole I2 site ligand 2-BFI. J Psychopharmacol 10:273–278Google Scholar
  28. Katsuta K, Nakanishi H, Shirakawa K, Yoshida K, Takagi K, Tamura A (1995) The neuroprotective effect of the novel noncompetitive NMDA antagonist, FR 115427 in focal cerebral ischemia in rats. J Cereb Blood Flow Metab 15:345–348PubMedGoogle Scholar
  29. Kleven MS, Koek W (1998) Discriminative stimulus effects of 8-hydroxy-2-(di-n-propylamino)tetralin in pigeons and rats: species similarities and differences. J Pharmacol Exp Ther 284:238–249PubMedGoogle Scholar
  30. Kolasa K, Kleinrok Z, Rajtar G, Juszkiewicz M (1984) Effects of histamine and H1- and H2-receptor antagonists on wet-dog-shake episodes in rats induced with tranylcypromine and 5-methoxytryptamine. Acta Physiol Pol 35:225–230PubMedGoogle Scholar
  31. Kornhuber J, Parsons CG, Hartmann S, Retz W, Kamolz S, Thome J, Riederer P (1995) Orphenadrine is an uncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist: binding and patch clamp studies. J Neural Trans 102:237–246Google Scholar
  32. Kozlowksi MR, Browne RG, Vinick FJ (1986) Discriminative stimulus properties of phencyclidine (PCP)-related compounds: correlations with 3H-PCP binding potency measured autoradiographically. Pharmacol Biochem Behav 25:1051–1058CrossRefPubMedGoogle Scholar
  33. Lindberg UH, Thorberg SO, Bengtsson S, Renyi AL, Ross SB, Ogren SO (1978) Inhibitors of neuronal monoamine uptake. 2. Selective inhibition of 5-hydroxytryptamine uptake by alpha-amino acid esters of phenethyl alcohols. J Med Chem 21:448–456Google Scholar
  34. Liu Y, Belayev L, Zhao W, Busto R, Ginsberg MD (2000) MRZ 2/579, a novel uncompetitive N-methyl-d-aspartate antagonist, reduces infarct volume and brain swelling and improves neurological deficit after focal cerebral ischemia in rats. Brain Res 862:111–119CrossRefPubMedGoogle Scholar
  35. Marona-Lewicka D, Nichols DE (1998) Drug discrimination studies of the interoceptive cues produced by selective serotonin uptake inhibitors and selective serotonin releasing agents. Psychopharmacology 138:67–75Google Scholar
  36. Millan MJ, Dekeyne A, Papp M, La Rochelle CD, MacSweeny C, Peglion J-L, Brocco M (2001) S33005, a novel ligand at both serotonin and norepinephrine transporters. II. Behavioral profile in comparison with venlafaxine, reboxetine, citalopram, and clomipramine. J Pharmacol Exp Ther 298:581–591PubMedGoogle Scholar
  37. Mindham RHS, Gaind R, Anstee BH, Rimmer L (1972) Comparison of amantadine, orphenadrine, and placebo in the control of phenothiazine-induced Parkinsonism. Psychol Med 2:406–413PubMedGoogle Scholar
  38. Moore KA, Lichtman AH, Poklis A, Borzelleca JF (1995) α-Benzyl-N-methylphenethylamine (BNMPA), an impurity of illicit methamphetamine synthesis: pharmacological evaluation and interaction with methamphetamine. Drug Alcohol Depend 39:83–89CrossRefPubMedGoogle Scholar
  39. Moore KA, Mirshahi T, Compton DR, Poklis A, Woodward JJ (1996) Pharmacological characterization of BNMPA (α-benzyl-N-methylphenethylamine), an impurity of illicit methamphetamine synthesis. Eur J Pharmacol 311:133–139CrossRefPubMedGoogle Scholar
  40. Nakanishi H, Katsuta K, Ueda Y, Takasugi H, Kuno A, Ohkubo M, Ogita K, Yoneda Y, Shirakawa K, Yoshida K (1995) Behavioral studies on FR 115427, a novel selective N-methyl-d-asparatate antagonist. Psychopharmacology 117:172–177PubMedGoogle Scholar
  41. Nicholson KL, Jones HE, Balster RL (1998) Evaluation of the reinforcing and discriminative stimulus properties of the low-affinity N-methyl-d-aspartate channel blocker memantine. Behav Pharmacol 9:231–243PubMedGoogle Scholar
  42. Nicholson KL, Hayes BA, Balster RL (1999) Evaluation of the reinforcing properties and phencyclidine-like discriminative stimulus effects of dextromethorphan and dextrorphan in rats and rhesus monkeys. Psychopharmacology 146:49–59PubMedGoogle Scholar
  43. Noguchi S, Inukai T, Kuno T, Tanaka C (1992) The suppression of olfactory bulbectomy-induced muricide by antidepressants and antihistamines via histamine H1 receptor blocking. Physiol Behav 51:1123–1127CrossRefPubMedGoogle Scholar
  44. Ohkubo M, Kuno A, Katsuta K, Ueda Y, Shirakawa K, Nakanishi H, Nakanishi I, Kinoshita T, Takasugi H (1996) Studies on cerebral protective agents. IX. Synthesis of novel 1,2,3,4-tetrahydroisoquinolines as N-methyl-d-aspartate antagonists. Chem Pharmacol Bull 44:95–102Google Scholar
  45. Olmos G, Ribera J, Garcia-Sevilla JA (1996) Imidazoli(di)ne compounds interact with the phencyclidine site of NMDA receptors in the rat brain. Eur J Pharmacol 310:273–276CrossRefPubMedGoogle Scholar
  46. Palmer GC (2001) Neuroprotection by NMDA receptor antagonists in a variety of neuropathologies. Curr Drug Targets 2:241–271PubMedGoogle Scholar
  47. Parsons CG, Quack G, Bresink I, Baran L, Przegalinski E, Kostowski W, Krzascik P, Hartmann S, Danysz W (1995) Comparison of the potency, kinetics and voltage-dependency of a series of uncompetitive NMDA receptor antagonists in vitro with anticonvulsive and motor impairment activity in vivo. Neuropharmacology 34:1239–1258CrossRefPubMedGoogle Scholar
  48. Parsons CG, Danysz W, Quack G (1998) Glutamate in CNS disorders as a target for drug development? Drug News Perspect 11:523–569Google Scholar
  49. Parsons CG, Danysz W, Bartmann A, Spielmanns P, Frankiewicz T, Hesselink M, Eilbacher B, Quack G (1999) Amino-alkyl-cyclohexanes are novel uncompetitive NMDA receptor antagonists with strong voltage-dependency and fast blocking kinetics: in vitro and in vivo characterization. Neuropharmacology 38:85–108CrossRefPubMedGoogle Scholar
  50. Parsons CG, Danysz W, Quack G (2000) Memantine and the amino-alkyl-cyclohexane MRZ 2/579 are moderate affinity uncompetitive NMDA receptor antagonists—in vitro characterisation. Amino Acids 19:157–166CrossRefPubMedGoogle Scholar
  51. Popik P, Kozela E, Danysz W (2000) Clinically available NMDA receptor antagonists memantine and dextromethorphan reverse existing tolerance to the antinociceptive effects of morphine in mice. Naunyn Schmiedebergs Arch Pharmacol 361:425–432CrossRefPubMedGoogle Scholar
  52. Rogawski MA (1993) Therapeutic potential of excitatory amino acid antagonists: channel blockers and 2,3-benzodiazepines. Trends Pharmacol Sci 14:325–331PubMedGoogle Scholar
  53. Sanger DJ (1989) Discriminative stimulus effects of the alpha 2-adrenoceptor antagonist idazoxan. Psychopharmacology 99:117–121PubMedGoogle Scholar
  54. Sanger DJ, Terry P, Katz JL (1992) Memantine has phencyclidine-like but not cocaine-like discriminative stimulus effects in rats. Behav Pharmacol 3:265–268PubMedGoogle Scholar
  55. Shelton KL, Balster RL (1994) Ethanol drug discrimination in rats: substitution with GABA agonists and NMDA antagonists. Behav Pharmacol 5:441–451PubMedGoogle Scholar
  56. Sherriffs HJ, Shirakawa K, Kelly JS, Olverman HJ, Kuno A, Ohkubo M, Butcher SP (1993) Characterization of the binding of [3H]FR 115427, a novel noncompetitive NMDA receptor antagonist, to rat brain membranes. Eur J Pharmacol 24:319–324Google Scholar
  57. Slifer BL, Balster RL (1985) Phencyclidine-like discriminative stimulus properties of the stereoisomers of dioxadrol. Subst Alcohol Actions Misuse 5:273–280Google Scholar
  58. Sukhotina IA, Bespalov AY (2000) Effects of the NMDA receptor channel blockers memantine and MRZ 2/579 on morphine withdrawal-facilitated aggression in mice. Psychopharmacology 149:345–350CrossRefPubMedGoogle Scholar
  59. Svensson BE, Ross SB (1995) Alaproclate interaction with the NMDA receptor ion channel complex as studied by its effects on [3H]-MK801 binding. Soc Neurosci Abstr 21:352Google Scholar
  60. Svensson BE, Werkman TR, Rogawski MA (1994) Alaproclate effects on voltage-dependent K+ channels and NMDA receptors: studies in cultured rat hippocampal neurons and fibroblast cells transformed with Kv1.2 K+ channel cDNA. Neuropharmacology 33:795–804Google Scholar
  61. Syvälahti EK, Kunelius R, Lauren L (1988) Effects of antiparkinsonian drugs on muscarinic receptor binding in rat brain, heart and lung. Pharmacol Toxicol 62:90–94PubMedGoogle Scholar
  62. Wenk GL, Baker LM, Stoehr JD, Hauss-Wegrzyniak B, Danysz W (1998) Neuroprotection by novel antagonists at the NMDA receptor channel and glycineB sites. Eur J Pharmacol 347:183–187PubMedGoogle Scholar
  63. Wilkinson A, Courtney M, Westlind-Danielsson A, Hallnemo G, Akerman KEO (1994) Alaproclate acts as a potent, reversible, noncompetitive antagonist of the NMDA receptor coupled ion flow. J Pharmacol Exp Ther 271:1314–1319Google Scholar
  64. Willetts J, Balster RL (1988a) The discriminative stimulus effects of N-methyl-d-aspartate antagonists in phencyclidine-trained rats. Neuropharmacology 27:1249–1256PubMedGoogle Scholar
  65. Willetts J, Balster RL (1988b) Phencyclidine-like discriminative stimulus properties of MK-801 in rats. Eur J Pharmacol 146:167–169CrossRefPubMedGoogle Scholar
  66. Witkin JM, Gasior M, Heifets B, Tortella FC (1999) Anticonvulsant efficacy of N-methyl-d-aspartate antagonists against convulsions induced by cocaine. J Pharmacol Exp Ther 289:703–711PubMedGoogle Scholar
  67. Ybema CE, Slangen JL, Olivier B, Mos J (1993) Dose-dependent discriminative stimulus properties of 8-OH-DPAT. Behav Pharmacol 4:610–624PubMedGoogle Scholar
  68. Zajaczkowski W, Quack G, Danysz W (1996) Infusion of (+)-MK-801 and memantine—contrasting effects on radial maze learning in rats with entorhinal cortex lesion. Eur J Pharmacol 296:239–246CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2003

Authors and Affiliations

  1. 1.Department of Pharmacology and ToxicologyMedical College of Virginia, Virginia Commonwealth UniversityRichmondUSA

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