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Discriminative Stimulus Properties of Anxiolytic and Sedative Drugs: Pharmacological Specificity

  • D. J. Sanger
Part of the Psychopharmacology Series book series (PSYCHOPHARM, volume 4)

Abstract

In the first set of experiments rats were trained to discriminate a dose of 5 mg/kg chlordiazepoxide from saline. The chlordiazepoxide cue was antagonized by flumazepil (Ro 15–1788) and by CGS 8216, and generalized to a variety of anxiolytic and sedative drugs including the benzodiazepine receptor ligands zopiclone, suriclone, CL 218,872, CGS 9896, and ZK 91296. The novel Imidazopyridine hypnotic, Zolpidem, which also displaces benzodiazepines from their binding sites, failed to produce high levels of responding on the chlordiazepoxide-associated lever except at a dose which greatly reduced rates of lever pressing. In further experiments rats were trained to discriminate a dose of 2 mg/kg Zolpidem from saline. This dose produced reductions in response rates but an attempt to establish a lower dose of Zolpidem as a discriminative stimulus was largely unsuccessful. Zolpidem-appropriate responding was produced by pentobarbital, chlordiazepoxide, triazolam, CL 218,872, clorazepate, lorazepam, quazepam, and zopiclone but only at doses which reduced response rates. The Zolpidem cue was antagonized by flumazepil, CGS 9896, and ZK 91296. While the discriminative stimulus produced by chlordiazepoxide may be related to its anxiolytic action, the Zolpidem stimulus is probably more closely associated with sedation. It was also tentatively concluded that the stimulus properties of chlordiazepoxide and Zolpidem are produced by activity at different subtypes of benzodiazepine receptors.

Keywords

Discriminative Stimulus Stimulus Property Discriminative Stimulus Effect Sedative Drug Generalization Test 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. Arbilla S, Depoortere H, George P, Langer SZ (1985) Pharmacological profile of Zolpidem at benzodiazepine receptors and electrocorticogram in rats. Naunyn Schmiedeberg’s Arch Pharmacol 330:248–251CrossRefGoogle Scholar
  2. Ator NA, Griffiths RR (1983) Lorazepam and pentobarbital drug discrimination in baboons: cross-drug generalization and interaction with Ro 15–1788. J Pharmacol Exp Ther 226:776–782PubMedGoogle Scholar
  3. Ator NA, Griffiths RR (1985) Lorazepam and pentobarbital discrimination: interactions with CGS 8216 and caffeine. Eur J Pharmacol 107:169–181PubMedCrossRefGoogle Scholar
  4. Ator NA, Griffiths RR (1986) Discriminative stimulus effects of atypical anxiolytics in baboons and rats. J Pharmacol Exp Ther 237:393–403PubMedGoogle Scholar
  5. Barry H III, Krimmer EC (1979) Differential stimulus attributes of chlordiazepoxide and pentobarbital. Neuropharmacology 18:991–998PubMedCrossRefGoogle Scholar
  6. Bennett DA, Petrack B (1984) CGS 9896: a nonbenzodiazepine, nonsedating potential anxiolytic. Drug Dev Res 4:75–82CrossRefGoogle Scholar
  7. Bernard PS, Bennett DA, Pastor G, Yokoyama N, Liebman JM (1985) CGS 9896: agonist-antagonist benzodiazepine receptor activity revealed by anxiolytic, anticonvulsant and muscle relaxation assessment in rodents. J Pharmacol Exp Ther 235:98–105PubMedGoogle Scholar
  8. Bindra D, Nyman K, Wise J (1965) Barbiturate-induced dissociation of acquisition and extinction: role of movement-initiating processes. J Comp Physiol Psychol 60:223–228PubMedCrossRefGoogle Scholar
  9. Colpaert FC, Desmedt LKC, Janssen PAJ (1976) Discriminative stimulus properties of benzodiazepines, barbiturates and pharmacologically related drugs: relation to some intrinsic and anticonvulsant effects. Eur J Pharmacol 37:113–123PubMedCrossRefGoogle Scholar
  10. Dantzer R, Perio A (1982) Behavioral evidence for partial antagonistic properties of Ro 15–1788, a benzodiazepine receptor antagonist. Eur J Pharmacol 81:655–658PubMedCrossRefGoogle Scholar
  11. Depoortere H, Zivkovic B, Lloyd KG, Sanger DJ, Perrault G, Langer SZ, Bartholini G (1986) Zolpidem, a novel non-benzodiazepine hypnotic. I. Neuropharmacological and behavioral effects. J Pharmacol Exp Ther 237:649–658PubMedGoogle Scholar
  12. De Vry J, Slangen JL 1986 Effects of chlordiazepoxide training dose on the mixed agonist-antagonist properties of benzodiazepine receptor antagonist Ro 15–1788, in a drug discrimination procedure. Psyehopharmacology 88:177–183CrossRefGoogle Scholar
  13. De Vry J, Slangen JL 1986 Effects of training dose on discrimination and cross-generalization of chlordiazepoxide, pentobarbital and ethanol in the rat. Psychopharmacology 88:341–345PubMedGoogle Scholar
  14. De Vry J, Slangen JL 1986 Differential interactions between chlordiazepoxide, pentobarbital and benzodiazepine antagonists Ro 15–1788 and CGS 8216 in a drug discrimination procedure. Pharmacol Biochem Behav 24:999–1005PubMedCrossRefGoogle Scholar
  15. Garcha HS, Rose IC, Stolerman IP (1985) Midazolam cue in rats: generalization tests with anxiolytic and other drugs. Psychopharmacology 87:233–237PubMedCrossRefGoogle Scholar
  16. Haug T (1983) Neuropharmacological specificity of the diazepam stimulus complex: effects of agonists and antagonists. Eur J Pharmacol 93:221–227PubMedCrossRefGoogle Scholar
  17. Haug T, Gotestam KG (1982) The diazepam stimulus complex: specificity in a rat model. Eur J Pharmacol 80:225–230PubMedCrossRefGoogle Scholar
  18. Hendry JS, Balster RL, Rosecrans JA (1983) Discriminative stimulus properties of buspirone compared to central nervous system depressants in rats. Pharmacol Biochem Behav 19:97–101PubMedCrossRefGoogle Scholar
  19. Herling S, Shannon HE (1982) Ro 15–1788 antagonizes the discriminative stimulus effects of diazepam in rats but not similar effects of pentobarbital. Life Sci 31:2105–2112PubMedCrossRefGoogle Scholar
  20. Jarbe TUC (1976) Characteristics of pentobarbital discrimination in the gerbil: transfer and antagonism. Psychopharmacology 49:33–40PubMedGoogle Scholar
  21. Johansson JO, Jarbe JUC 1975 Antagonism of pentobarbital induced discrimination in the gerbil. Psychopharmacologia 41:225–228PubMedCrossRefGoogle Scholar
  22. Johansson JO, Jarbe JUC (1975b) Diazepam as a discriminative cue: its antagonism by beme-gride. Eur J Pharmacol 30:372–375PubMedCrossRefGoogle Scholar
  23. Klepner CA, Lippa AS, Benson DI, Sano MC, Beer B (1979) Resolution of two biochemically and pharmacologically distinct benzodiazepine receptors. Pharmacol Biochem Behav 11:457–462PubMedCrossRefGoogle Scholar
  24. McElroy JF, Feldman RS (1982) Generalization between benzodiazepine- and triazolopyridazine-elicited discriminative cues. Pharmacol Biochem Behav 17:709–713PubMedCrossRefGoogle Scholar
  25. Nicholson AN, Pascoe PA (1986) Hypnotic activity of an imidazo-pyridine (Zolpidem). Br J Clin Pharmacol 21:205–211PubMedGoogle Scholar
  26. Nielsen EB, Valentine JD, Holohean AM, Appel JB (1983) Benzodiazepine receptor mediated discriminative cues: effects of GABA-ergic drugs and inverse agonists. Life Sci 33:2213–2220PubMedCrossRefGoogle Scholar
  27. Oka M, Yamada K, Yoshida K, Shimizu M (1980) Avoidance enhancement and discriminative response control by anxiolytics with drugs acting on the GABA system. Jpn J Pharmacol 30:325–336PubMedCrossRefGoogle Scholar
  28. Overton DA (1966) State-dependent learning produced by depressant and atropine-like drugs. Psychopharmacologia 10:6–31PubMedCrossRefGoogle Scholar
  29. Petersen EN, Jensen LH, Honore T, Braestrup C, Kehr W, Stephens DN, Wachtel H, Seidelman D, Schmiechen R (1984) ZK 91296, a partial agonist at benzodiazepine receptors. Psychopharmacology 83:240–248PubMedCrossRefGoogle Scholar
  30. Randall LO, Schallek W, Sternbach LH, Ning RY (1974) Chemistry and pharmacology of the 1,4-benzodiazepines. In: Gordon M (ed) Psychopharmacological agents, vol 4, part III. Academic, New York, pp 175–281Google Scholar
  31. Sanger DJ (1985) GABA and the behavioral effects of anxiolytic drugs. Life Sci 36:1503–1513PubMedCrossRefGoogle Scholar
  32. Sanger DJ, Zivkovic B (1986) The discriminative stimulus properties of Zolpidem, a novel imidazopyridine hypnotic. Psychopharmacology 89:317–322PubMedGoogle Scholar
  33. Sanger DJ, Zivkovic B (1987) Discriminative stimulus properties of chlordiazepoxide and Zolpidem. Agonist and antagonist effects of CGS 9896 and ZK 91296. Neuropharmacology 26:499–505PubMedCrossRefGoogle Scholar
  34. Sanger DJ, Joly D, Zivkovic B (1985) Behavioral effects of non-benzodiazepine anxiolytic drugs: a comparison of CGS 9896 and zopiclone with chlordiazepoxide. J Pharmacol Exp Ther 232:831–837PubMedGoogle Scholar
  35. Schechter MD (1984) Specific antagonism of the behavioral effects of chlordiazepoxide and pentobarbital in the rat. Prog Neuro-Psychopharm Biol Psychiatry 8:359–364Google Scholar
  36. Shannon HE, Davis SL (1984) CGS 8216 noncompetitively antagonizes the discriminative effects of diazepam in rats. Life Sci 34:2589–2596PubMedCrossRefGoogle Scholar
  37. Shannon HE, Herling S (1983a) Discriminative stimulus effects of diazepam in rats: evidence for a maximal effect. J Pharmacol Exp Ther 227:160–166PubMedGoogle Scholar
  38. Shannon HE, Herling S (1983b) Antagonism of the discriminative effects of diazepam by pyrazoloquinolines in rats. Eur J Pharmacol 92:155–157PubMedCrossRefGoogle Scholar
  39. Sieghart W, Schuster A (1984) Affinity of various ligands for benzodiazepine receptors in rat cerebellum and hippocampus. Biochem Pharmacol 33:4033–4038PubMedCrossRefGoogle Scholar
  40. Spealman RD (1985) Discriminative stimulus effects of midazolam in squirrel monkeys: comparison with other drugs and antagonism by Ro 15–1788. J Pharmacol Exp Ther 235:456–462PubMedGoogle Scholar
  41. Stolerman IP, Garcha HS, Rose IC (1986) Midazolam cue in rats: effects of flumazepil (Ro 15–1788) and picrotoxin. Psychopharmacology 89:183–188PubMedCrossRefGoogle Scholar
  42. Williams M (1984) Molecular aspects of the action of benzodiazepine and non-benzodiazepine anxiolytics: a hypothetical allosteric model of the benzodiazepine receptor complex. Prog Neuro-Psychopharm Biol Psychiatry 8:209–247CrossRefGoogle Scholar
  43. Yokoyama N, Ritter B, Neubert A (1982) 2-Arylpyrazolo[4,3-c]-quinolin-3-ones: novel agonist, partial agonist and antagonist of benzodiazepines. J Med Chem 25:337–339PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1988

Authors and Affiliations

  • D. J. Sanger
    • 1
  1. 1.Laboratoires d’Etudes et de Recherches Synthélabo (L.E.R.S.)BagneuxFrance

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