Psychopharmacology

, Volume 110, Issue 3, pp 295–301 | Cite as

Pentobarbital-like discriminative stimulus effects of direct GABA agonists in rats

  • Doreen M. Grech
  • Robert L. Balster
Original Investigations

Abstract

The discriminative stimulus effects of direct and indirect-acting GABAergic drugs were investigated in rats trained to discriminate 5 mg/kg pentobarbital (PB) from saline under a two-lever fixed ratio (FR) 32 schedule of food reinforcement. PB and diazepam produced dose-dependent substitution for the training dose of PB with response rate reduction only at doses above those producing full substitution. Muscimol, thiomuscimol and 4,5,6,7-tetrahydroisoxazolo [5,4-c]-pyridin-3-ol (THIP) produced intermediate levels of pentobarbital-lever responding (40–60%), accompanied by dose-dependent decreases in rates of responding following THIP and muscimol administration. The GABAA agonist progabide and its metabolite 4-{[(4-chlorophenyl) (5-fluoro-2-hydroxyphenyl)methylene]amino}] butyric acid (SL 75102) also partially substituted for PB, producing means of 39–73% PB-lever responding. The GABAB agonist, baclofen, completely failed to substitute for PB even at doses that decreased rates of responding. These results show that the discriminative stimulus effects of indirect GABAA agonists, PB and diazepam, although similar to one another, differ from those of direct GABAA receptor agonists, which produced only partial substitution for PB. The GABAB agonist, baclofen, can be distinguished by lacking any ability to substitute for PB. These results contribute to a further understanding of the similarities and differences in the behavioral effects of different types of GABA agonists.

Key words

Drug discrimination Pentobarbital GABA (gamma-aminobutyric acid) Muscimol THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c] pyridin-3-ol) Thiomuscimol Progabide SL 75102 (4-{[(4-chlorophenyl)(5-fluoro-2-hydroxyphenyl) methylene]amino} butyric acid) Baclofen Diazepam 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Ator NA (1991) Discriminative-stimulus effects of the GABAA agonist THIP and the GABAB agonist baclofen. Soc Neurosci Abstr 465:8Google 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 226:776–782Google Scholar
  3. Ator NA, Griffiths RR (1986) Discriminative stimulus effects of atypical anxiolytics in baboons and rats. J Pharmacol Exp Ther 237:393–403Google Scholar
  4. Ator NA, Griffiths RR (1989) Differential generalization to pentobarbital in rats trained to discriminate lorazepam, chlordiazepoxide, diazepam, or triazolam. Psychopharmacology 98:20–30Google Scholar
  5. Balster RL, Moser VC (1987) Pentobarbital discrimination in the mouse. Alcohol Drug Res 7:233–242Google Scholar
  6. Beneditto MA, Leite VR (1981) Baclofen as an anticonvulsant in experimental models of convulsions. Exp Neurol 72:346–351Google Scholar
  7. Bennett DA, Amrick CL (1986) 2-Amino-7-phosphoheptanoic acid produces discriminative stimulus and anticonflict effects similar to diazepam. Life Sci 39:2455–2461Google Scholar
  8. Bowery NG (1982) Baclofen: 10 years on. TIPS 3:400–403Google 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 37:113–123Google Scholar
  10. de Vry J, Slangen JL (1986) Effects of training dose on discrimination of chlordiazepoxide, pentobarbital and ethanol in rats. Psychopharmacology 88:341–345Google Scholar
  11. deWit H, Griffiths RR (1991) Testing the abuse liability of anxiolytic and hypnotic drugs in humans. Drug Alcohol Depend 28:83–111Google Scholar
  12. Falch E, Krogsgaard-Larsen P (1982) The binding of the GABA agonist [3H] THIP to rat brain synaptic membranes. J Neurochem 38:1123–1129Google Scholar
  13. Garcha HS, Rose IC, Stolerman IP (1985) Midazolam cue in rats: generalization tests with anxiolytic and other drugs. Psychopharmacology 87:233–237Google Scholar
  14. Gray JA, Mellanby J, Buckland C (1984) Behavioral studies of the role of GABA in anxiolytic drug action. Neuropharmacology 23:827Google Scholar
  15. Griffiths RR, Roache JD, Ator NA, Lamb RJ, Lukas SE (1985) Similarities in reinforcing and discriminative stimulus effects of diazepam, triazolam and pentobarbital in animals and humans. In: Balster RL, Seiden LS (eds) Behavioral pharmacology: the current status. Liss, New York, pp 419–431Google Scholar
  16. Haefely W, Kyburz E, Gerecke M, Mohler H (1985) Recent advances in the molecular pharmacology of benzodiazepine receptors and in the structure-activity relationships of their agonists and antagonists. Adv Drug Res 14:153–311Google Scholar
  17. Haug T (1983) Neuropharmacological specificity of the diazepam stimulus complex: effects of agonists and antagonists. Eur J Pharmacol 93:221–227Google Scholar
  18. 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 31:514–516Google Scholar
  19. Herling S, Valentino RJ, Winger GD (1980) Discriminative stimulus effects of pentobarbital in pigeons. Psychopharmacology 71:21–28Google Scholar
  20. Hill DR, Bowery NG (1981)3H-Baclofen and3H-GABA bind to bicuculline insensitive GABAB sites in rat brain. Nature 290:149–152Google Scholar
  21. Järbe TUC (1976) Characteristics of pentobarbital discrimination in the gerbil: transfer and antagonism. Psychopharmacology 49:33–40Google Scholar
  22. Johanson CE (1991) Discriminative stimulus effects of diazepam in humans. J Pharmacol Exp Ther 257:634–643Google Scholar
  23. Kemp JA, Marshall GR, Woodruff GN (1986) Quantitative evaluation of the potencies of GABA-receptor agonists and antagonists using the rat hippocampal slice preparation. Br J Pharmacol 87:677–684Google Scholar
  24. Lloyd KG, Arbilla S, Beaumont K, Briley M, De Montis G, Scatton B, Langer SZ, Bartholini G (1981)γ-Aminobutyric acid (GABA) receptor stimulation. II. Specificity of progabide (SL 76002) and SL 75102 for the GABA receptor. J Pharmacol Exp Ther 220:672–677Google Scholar
  25. Lloyd KG, Morselli PL, Depoortere H, Fourneir V, Zivkovic B, Scatton B, Brockkamp L, Worms P, Bartholini G (1982) The potential use of GABA agonists in psychiatric disorders: Evidence from studies with progabide in animal models and clinical trials. Pharmacol Biochem Behav 18:957–966Google Scholar
  26. Nielsen EB, Valentine JD, Holohean AM, Appel JB (1983) Benzodiazepine receptor-mediated discriminative cues: effects of GABAergic drugs and inverse agonists. Life Sci 33:2213–2220Google Scholar
  27. Olsen RW, Ticku MK, VanNess PC, Greenlee D (1978) Effects of drugs on gamma-aminobutyric acid receptors, uptake, release and synthesis in vitro. Brain Res 139:277–294Google Scholar
  28. Overton DA (1966) State-dependent learning produced by depressant and atropine-like drugs. Psychopharmacology 10:6–31Google Scholar
  29. Rastogi SK, Ticku MK (1986) Anticonsulsant profile of drugs which facilitate GABAergic transmission on convulsions mediated by GABAergic mechanisms. Neuropharmacology 25:175–185Google Scholar
  30. Rauch RJ, Stolerman IP (1987) Midazolam cue in rats: effects of drugs acting on GABA and 5-hydroxytryptamine systems, anticonvulsants and sedatives. J Psychopharmacol 2:71–80Google Scholar
  31. Sanger DJ (1985) GABA and the behavioral effects of anxiolytic drugs. Life Sci 36:1503–1513Google Scholar
  32. Sanger DJ (1988) Discriminative stimulus properties of anxiolytic and sedative drugs: pharmacological specificity. In: Colpaert FC, Balster RL (eds) Transduction mechanisms of drug stimuli. Springer, Berlin Heidelberg New York, pp 73–84Google Scholar
  33. 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 235:456–462Google Scholar
  34. Stolerman IP, Garcha HS, Rose IC (1986) Midazolam cue in rats: effects of Ro 15-1788 and picrotoxin. Psychopharmacology 89:183–188Google Scholar
  35. Twyman RE, Rogers CJ, MacDonald RL (1989) Differential regulation ofgamma-aminobutyric acid receptor channels by diazepam and phenobarbital. Ann Neurol 25:213–220Google Scholar
  36. Willetts J, Balster RL (1989) Pentobarbital-like discriminative stimulus effects of N-methyl-d-aspartate antagonists. J Pharmacol Exp Ther 249:436–443Google Scholar
  37. Winger GD, Herling S (1982) Discriminative stimulus effects of pentobarbital in rhesus monkeys: tests of stimulus generalization and duration of action. Psychopharmacology 76:172–176Google Scholar
  38. Worms P, Depoortere H, Lloyd KG (1979) Neuropharmacological spectrum of muscimol. Life Sci 25:607–614Google Scholar
  39. Worms P, Depoortere H, Durand A, Morselli PL, Lloyd KG, Bartholini G (1982)γ-Aminobutyric acid (GABA) receptor stimulation. 1. Neuropharmacological profiles of progabide (SL 76002) and SL 75102, with emphasis on their anticonvulsant spectra. J Pharmacol Exp Ther 220:660–671Google Scholar
  40. Young R (1991) Discriminative stimulus properties of benzodiazepines and several new anxiolytics. In: Glenon 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. (ADM) 92-1878, US Government Printing Office, Washington, pp 117–130Google Scholar

Copyright information

© Springer-Verlag 1993

Authors and Affiliations

  • Doreen M. Grech
    • 1
  • Robert L. Balster
    • 1
  1. 1.Department of Pharmacology and ToxicologyMedical College of Virginia, Virginia Commonwealth UniversityRichmondUSA

Personalised recommendations