Advertisement

Pharmacological Evidence for Full Agonist Activity of Abecarnil at Certain GABAA Receptors

  • M. Serra
  • C. A. Ghiani
  • C. Motzo
  • G. Biggio
Part of the Psychopharmacology Series book series (PSYCHOPHARM, volume 11)

Abstract

It is now well established that the degree of activation of the central γ-aminobutyric acid type A (GABAA)-receptor complex is predictive of the pharmacological efficacy and clinical profile of the agonist ligands for benzodiazepine recognition sites (see review Biggio and Costa 1990; Biggio et al. 1992). Accordingly, anxiolytic and anticonvulsant drugs which enhance the function of GABAergic transmission with a low intrinsic activity are classified as “partial agonists,” i.e., compounds able to reduce the risk of tolerance, dependence, and unwanted effects attributed to “full agonists.”

Keywords

GABAA Receptor Partial Agonist Full Agonist GABAergic Transmission GABAergic Synapse 
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.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Biggio G, Costa E (eds) (1983) Benzodiazepine recognition-site ligands: biochemistry and pharmacology. Raven, New YorkGoogle Scholar
  2. Biggio G, Costa E (eds) (1986) GABAergic transmission and anxiety. Adv Biochem Psych 41Google Scholar
  3. Biggio G, Costa E (eds) (1990) GAB A- and benzodiazepine-receptor subtypes. Adv Biochem Psych 46Google Scholar
  4. Biggio G, Brodie BB, Guidotti A, Costa E (1977) Mechanism by which diazepam, muscimol and other drugs change the content of cyclic GMP in cerebellar cortex. Proc Natl Acad Sci USA 74:3592–3596PubMedCrossRefGoogle Scholar
  5. Biggio G, Concas A, Serra M, Salis M, Corda MG, Nurchi V, Crisponi C, Gessa GL (1984) Stress and p-carbolines decrease the density of low affinity GABA binding: an effect reversed by diazepam. Brain Res 305:13–18PubMedCrossRefGoogle Scholar
  6. Biggio G, Concas A, Corda MG, Serra M (1989) Enhancement of GABAergic transmission by Zolpidem, an imidazopyridine with preferential affinity for type I benzodiazepine receptors. Eur J Pharmacol 161:173–180PubMedCrossRefGoogle Scholar
  7. Biggio G, Concas A, Corda MG, Giorgi O, Sanna E, Serra M (1990) GABAergic and dopaminergic transmission in the rat cerebral cortex: effect of stress, anxiolytic and anxiogenic drugs. Pharmacol Ther 48:121–142PubMedCrossRefGoogle Scholar
  8. Biggio G, Concas A, Costa E (eds) (1992) GABAergic synaptic transmission molecular, pharmacological and clinical aspects. Adv Biochem Psych 47Google Scholar
  9. Concas A, Serra M, Atsoggiu T, Biggio G (1988) Foot-shock stress and anxiogenic β-carbolines increase t-[35S]butylbicyclophosphorothionate binding in the rat cerebral cortex, an effect opposite to anxiolytics and y-aminobutyric acid mimetics. J Neurochem 51:1868–1876PubMedCrossRefGoogle Scholar
  10. Concas A, Sanna E, Mascia MP, Serra M, Biggio G (1990) Diazepam enhances bicuculline-induced increase of [35S]TBPS binding in unwashed membrane preparations from rat cerebral cortex. Neurosci Lett 112:87–91PubMedCrossRefGoogle Scholar
  11. Concas A, Mascia MP, Sanna E, Santoro G, Serra M, Biggio G (1991) “in vivo” administration of valproate decreases t-[35S]butylbicyclophosphorothionate binding in the rat brain. Naunyn Schmiede bergs Arch Pharmacol 343:269–300Google Scholar
  12. Concas A, Sanna E, Cuccheddu T, Mascia MP, Santoro G, Maciocco E, Biggio G (1993) Carbon dioxide inhalation, stress and anxiogenic drugs reduce the function of GAB A- receptor complex in the rat brain. Prog Neuropsychopharmacol Biol Psychiatry 17 (in press)Google Scholar
  13. Corda MG, Giorgi O, Longoni B, Ongini E, Montaldo S, Biggio G (1988) Preferential affinity of [3H]2-oxo-quazepam for type I benzodiazepine recognition sites in the human brain. Life Sci 42:189–197PubMedCrossRefGoogle Scholar
  14. Gallager DW (1978) Benzodiazepines: potentiation of a GABA inhibitory response in the dorsal raphe nucleus. Eur J Pharmacol 49:133–143PubMedCrossRefGoogle Scholar
  15. Gee KW, Lawrence LJ, Yamamura HJ (1986) Modulation of the chloride ionophore by benzodiazepine-receptor ligands: influence of γ-aminobutyric acid and ligand efficacy. Mol Pharmacol 30:218–225PubMedGoogle Scholar
  16. Giorgi O, Corda MG, Fernandez A, Biggio G (1989) The p-carboline derivative ZK 93426 and FG 7142 fail to precipitate abstinence signs in diazepam-dependent cats. Pharmacol Biochem Behav 32:671–675PubMedCrossRefGoogle Scholar
  17. Gonsalves SF, Gallanger DW (1987) Timecourse for development of anticonvulsant tolerance and GABAergic subsensitivity after chronic diazepam. Brain Res 405:94PubMedCrossRefGoogle Scholar
  18. Greenblatt DJ, Shader RI (1976) Benzodiazepines in clinical pracitice. Raven, New YorkGoogle Scholar
  19. Haefely W (1984) Pharmacological profile of two benzodiazepine partial agonists: Ro 16–6028 and Ro 17–1812. Clinical Neuropharmacol 7 [Suppl 1]:670–671 (abstract S363)Google Scholar
  20. Haefely W, Martin JR, Schoch P (1990) Novel anxiolytics that act as partial agonists of benzodiazepine receptors. TIPS 11:452–456PubMedGoogle Scholar
  21. Horton WR (1980) GABA and seizure induced by inhibitors of glutamic acid decarboxylase. Brain Res Bull 5:605–608CrossRefGoogle Scholar
  22. Horton WR, Chapman AG, Meldrum BS (1979) Isoniazid, as a glutamic acid decarboxylase inhibitor. J Neurochem 33:745–750PubMedCrossRefGoogle Scholar
  23. Löscher W, Honack D, Scherke R, Hashem A, Frey HH (1990) Pharmacokinetics, anticonvulsant efficacy and adverse effects of the β-carboline abecarnil, a novel ligand for benzodiazepine receptors, after acute and chronic administration in dogs. J Pharmacol Exp Ther 255:541–548PubMedGoogle Scholar
  24. Luddens H, Wisden W (1991) Function and pharmacology of multiple GABAA-receptor subunits. TIPS 12:49–51PubMedGoogle Scholar
  25. Lukas SE, Griffiths RR (1982) Precipitated withdrawal by benzodiazepine-receptor antagonist (Ro 15–1788) after 7 days of diazepam. Science 217:1161–1163PubMedCrossRefGoogle Scholar
  26. Marley RJ, Gallanger DW (1989) Chronic diazepam treatment produces regionally specific changes in GABA-stimulated chloride influx. Eur J Pharmacol 159:217–223PubMedCrossRefGoogle Scholar
  27. Murphy SM, Owen RT, Tyrer PJ (1984) Withdrawal symptoms after six weeks treatment with diazepam. Lancet 2:1389PubMedCrossRefGoogle Scholar
  28. Ongini E, Marzanatti M, Bamonte F, Monopoli A, Guzzon V (1985) A β-carboline antagonizes benzodiazepine actions but does not precipitate the abstinence syndrome in cats. Psychopharmacology (Berlin) 86:132–136CrossRefGoogle Scholar
  29. Polc P, Haefely W (1976) Effects of two benzodiazepines, phenobarbitone and baclofen on synaptic transmission in the cat cuneate nucleus. Naunyn Schmiedebergs Arch Pharmacol 294:121–131PubMedCrossRefGoogle Scholar
  30. Pritchett DB, Seeburg PH (1990) γ-aminobutyric acidA receptor α5-subunit creates novel type II benzodiazepine receptor pharmacology. J Neurochem 54:1802–1804PubMedCrossRefGoogle Scholar
  31. Pritchett DB, Sontheimer H, Shivers BD, Ymer S, Kettenmann H, Schofield PR, Seeburg PH (1989a) Importance of a novel GAJBA-receptor subunit for benzodiazepine pharmacology. Nature 338:582–585PubMedCrossRefGoogle Scholar
  32. Pritchett DB, Luddens H, Seeburg PH (1989b) Type I and Type II GABAA-benzodiazepine receptors produced in transfected cells. Science 245:1389–1392PubMedCrossRefGoogle Scholar
  33. Rickeis K, Case WG, Downing RW, Winokur A (1983) A long-term diazepam therapy and clinical outcome. JAMA 250:767–771CrossRefGoogle Scholar
  34. Rosenberg HC, Chiu TH (1982) An antagonist-induced benzodiazepine abstinence syndrome. Eur J Pharmacol 81:153–157PubMedCrossRefGoogle Scholar
  35. Sanna E, Concas A, Serra M, Santoro G, Biggio G (1991) “ex vivo” binding of t-[35S]butylbicyclophosphorotionate: a biochemical tool to study the pharmacology of ethanol at the γ-aminobutyric acid-coupled chloride channel. J Pharmacol Exp Ther 256:922–928PubMedGoogle Scholar
  36. Sanna E, Cuccheddu T, Serra M, Concas A, Biggio G (1992) Carbon dioxide inhalation reduces the function of GABA A receptors in the rat brain. Eur J Pharmacol (in press)Google Scholar
  37. Schopf J (1983) Withdrawal phenomena after long-term administration of benzodiazepines: a review of recent investigations. Pharmacopsychiatry 16:1–8CrossRefGoogle Scholar
  38. Serra M, Sanna E, Biggio G (1989) Isoniazid, an inhibitor of GABAergic transmission, enhances [35S]TBPS binding in rat cerebral cortex. Eur J Pharmacol 164:385–388PubMedCrossRefGoogle Scholar
  39. Serra M, Sanna E, Concas A, Foddi MC, Biggio G (1991) Foot-shock stress enhances the increase of [35S]TBPS binding in the rat cerebral cortex and the convulsions induced by isoniazid. Neurochem Res 16:17–22PubMedCrossRefGoogle Scholar
  40. Skerrit JH, Willow M, Johnston GAR (1982) Diazepam enhancement of low affinity GABA binding to rat brain membranes. Neurosci Lett 29:63–66CrossRefGoogle Scholar
  41. Squires RF, Casida JE, Richardson M, Saederup E (1983) 35S-t-butylbicyclophosphorotionate binds with high affinity to brainpecific sites coupled to γ-aminobutyric acidA and ion recognition sites. Mol Pharmacol 23:326–336PubMedGoogle Scholar
  42. Stephens DN, Schneider HH, Kehr W, Andrews JS, Rettig KJ, Turski L, Schmiechen R, Turner JD, Jensen LH, Petersen EN, Honore’ T, Bondo Hansen J (1990) Abecarnil, a metabolically stable, anxioselective β-carboline acting at benzodiazepine receptors. J Pharmacol Exp Ther 253:334–343PubMedGoogle Scholar
  43. Supavilai P, Karobath M (1984) t-butylbicyclophosphorotionate binding sites are constituents of the y-aminobutyric acid benzodiazepine-receptor complex. J Neurosci 4:1193–1200PubMedGoogle Scholar
  44. M. Serra et aL: Pharmacological Evidence for Full Agonist ActivityGoogle Scholar
  45. Turski L, Stephens DN, Jensen LH, Petersen EN, Meldrum BS, Patel S, Bondo Hansen J, Löscher W, Schneider HH, Schmiechen R (1990) Anticonvulsant action of the β-carboline abecarnil: studies in rodents and baboon, papio papio. J Pharmacol Exp Ther 253:344–352PubMedGoogle Scholar
  46. Woods SW, Charney DS, Loke J, Goodman WK, Redmond DE, Heninger GR (1986) Carbon dioxide sensitivity in panic anxiety. Arch Gen Psychiatry 43:900–909PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1993

Authors and Affiliations

  • M. Serra
    • 1
  • C. A. Ghiani
    • 1
  • C. Motzo
    • 1
  • G. Biggio
    • 1
  1. 1.Department of Experimental Biology “Bernardo Loddo”University of CagliariItaly

Personalised recommendations