Role of the GABA—Benzodiazepine Receptor Complex in Stress

In Vivo Approaches and Potential Relevance to Childhood Psychopathology
  • Stephen I. Deutsch
  • Abraham Weizman
  • Ronit Weizman
  • Frank J. VocciJr.
  • Karin A. Kook


An appreciation of the structure and function of the GABAA-benzodiazepine receptor-chloride ionophore complex is necessary in order to understand the therapeutic mechanism of action of several major classes of anxiolytic and sedative-hypnotic drugs. The chapter provides the background necessary to appreciate these structural and functional considerations. Studies reporting that genetic differences in the density of central benzodiazepine receptors exist between strains of animals differing in the traits of emotionality and fearfulness are presented. The demonstration, isolation, and synthesis of several inverse agonists have spurred theoretical speculation about the existence of endogenous ligands for the benzodiazepine receptor, as well as a role for this receptor in normal and pathological responses to stress. This chapter selectively reviews studies describing the plasticity of the benzodiazepine-GABA receptor complex in response to environmental stress. Several of these stress paradigms were naturalistic ones showing that the application of specific stressors during the early stages of an animal’s development results in enduring changes in benzodiazepine receptor sensitivity and behavior in the adult animal. There are also data showing that the benzodiazepine receptor is involved in the mediation and modulation of aggressive behavior. The potential relevance of these observations to child psychiatry is obvious. Evidence implicating peripheral hormones in the regulation of central benzodiazepine receptor sensitivity in response to stress is presented. A stressinduced modification of the complex would suggest that adaptive responses may be accompanied by changes in γ-aminobutyric acid (GABA)ergic transmission that are mediated postsynaptically; some of these changes appear to occur rapidly (i.e., within 1 min of exposure to the stress) and may reflect post-translational modification of the complex. Most of the data on the benzodiazepine receptor and its modification by environmental stress were obtained with classical in vitro techniques, especially filtration-binding assays. These techniques are performed under conditions that are not physiological with respect to temperature and salt concentrations; they disrupt the local neuronal circuitry involved in the regulation of benzodiazepine receptor sensitivity in the intact animal. Therefore, an in vivo approach to the measurement of benzodiazepine receptors in intact animals that avoids the artifacts associated with in vitro and ex vivo techniques has been developed. The method involves the intravenous injection of a tracer quantity of the radiolabeled antagonist Ro 15-1788. Using this in vivo approach, a relationship was shown between benzodiazepine receptor occupancy and the pharmacological potencies of several benzodiazepines. The application of this method to studying the effects of environmental stress and the mechanism of stress-induced modifications of binding are also reviewed.


Inverse Agonist Supramolecular Complex GABAergic Transmission Diazepam Binding Flunitrazepam Binding 
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.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Trullas R, Havoundjian H, Zamir N, et al : Environmentally-induced modification of the benzodiazepine/GABA receptor coupled chloride ionophore. Psychopharmacology 91:384–390, 1987PubMedCrossRefGoogle Scholar
  2. 2.
    Goeders NE, Kuhar MJ : Benzodiazepine receptor binding in vivo with [3H]Rol5-1788. Life Sci 37:345–355, 1985PubMedCrossRefGoogle Scholar
  3. 3.
    Miller LG, Greenblatt DJ, Paul SM, et al : Benzodiazepine receptor occupancy in vivo: Correlation with brain concentrations and pharmacodynamic actions. J Pharmacol Exp Ther 240:516–522, 1987PubMedGoogle Scholar
  4. 4.
    Haefely W, Pole P: Physiology of GABA enhancement by benzodiazepines and barbiturates, in Olsen RW Venter JC (eds): Benzodiazepine/GABA Receptors and Chloride Channels: Structural and Functional Properties. New York, Alan R. Liss, 1986, p 97Google Scholar
  5. 5.
    Olsen RW : GABA-benzodiazepine barbiturate receptor interactions. J Neurochem 37:1–13, 1981PubMedCrossRefGoogle Scholar
  6. 6.
    Braestrup C, Nielsen M, Olsen CE : Urinary and brain beta-carboline-3-carboxylates as potent inhibitors of brain benzodiazepine receptors. Proc Natl Acad Sci USA 77:2288–2292, 1980PubMedCrossRefGoogle Scholar
  7. 7.
    Ninan PT, Insel TR, Cohen RM, et al : Benzodiazepine receptor mediated experimental anxiety in primates. Science 218:1332–1334, 1982PubMedCrossRefGoogle Scholar
  8. 8.
    Dorow R, Horowski R, Paschelke G, et al : Severe anxiety induced by FG 7142, a (β-carboline ligand for benzodiazepine receptors. Lancet 9:98–99, 1983CrossRefGoogle Scholar
  9. 9.
    Mohler H, Richards JG : Agonist and antagonist benzodiazepine receptor interaction in vitro. Nature (Lond) 294:763–765, 1981CrossRefGoogle Scholar
  10. 10.
    Mohler H, Okada T : Benzodiazepine receptor: Demonstration in the central nervous system. Science 198:849–851, 1977PubMedCrossRefGoogle Scholar
  11. 11.
    Squires RF, Braestrup C : Benzodiazepine receptors in rat brain. Nature (Lond) 266:732–734, 1977CrossRefGoogle Scholar
  12. 12.
    Tallman JF, Thomas JW, Gallager DW : GABAergic modulation of benzodiazepine binding site sensitivity. Nature (Lond) 274:383–385, 1978CrossRefGoogle Scholar
  13. 13.
    Study RE, Barker JL : Diazepam and (—) pentobarbital: Fluctuation analysis reveals different mechanisms for potentiation of GABA responses in cultured central neurons. Brain Res 268:171–176, 1981Google Scholar
  14. 14.
    Braestrup C, Nielsen M : GABA reduces binding of [3H]-methyl-(β-carboline-3-carboxylate to brain benzodiazepine receptors. Nature (Lond) 294:472–474, 1981CrossRefGoogle Scholar
  15. 15.
    Borea PA, Supavilai P, Karobath M : Differential modulation of etazolate or pentobarbital enhanced [3H]-muscimol binding by benzodiazepine agonists and inverse agonists. Brain Res 280:383–386, 1983PubMedCrossRefGoogle Scholar
  16. 16.
    Barker JL, Owen DG : Electrophysiological pharmacology of GABA and diazepam in cultured CNS neurons, in Olsen RW Venter JC(eds): Benzodiazepine/GABA Receptors and Chloride Channels: Structural and Functional Properties. New York, Alan R. Liss, 1986, p 135Google Scholar
  17. 17.
    Honore T, Nielsen M, Braestrup C : Barbiturate shift as a tool for determination of efficacy of benzodiazepine-receptor ligands. Eur J Pharmacol 100:103–107, 1984PubMedCrossRefGoogle Scholar
  18. 18.
    Wong EHF, Snowman AM, Leeb-Lundberg LMF : Bariturates allosterically inhibit GABA antagonist and benzodiazepine inverse agonist binding. Eur J Pharmacol 102:205–212, 1984PubMedCrossRefGoogle Scholar
  19. 19.
    Skolnick P, Paul SM, Barker JL : Pentobarbital potentiates GABA-enhanced [3H]-diazepam binding to benzodiazepine receptors. Eur J Pharmacol 65:125–127, 1980PubMedCrossRefGoogle Scholar
  20. 20.
    Schofield PR, Darlison MG, Fujita N, et al : Sequence and functional expression of the of GABAA receptor shows a ligand-gated receptor super-family. Nature (Lond) 328:221–227, 1987CrossRefGoogle Scholar
  21. 20a.
    Pritchett DB, Luddens H, Seeburg PH: Type I and type II GABAA-benzodiazepine receptors produced in transfected cells. Science 245:1389–1392, 1989PubMedCrossRefGoogle Scholar
  22. 21.
    Havoundjian H, Paul SM, Skolnick P : Rapid, stress-induced modification of the benzodiazepine receptorcoupled chloride ionophore. Brain Res 375:401–406, 1986PubMedCrossRefGoogle Scholar
  23. 22.
    Havoundjian H, Paul SM, Skolnick P : Acute, stress-induced changes in the benzodiazepine/GABA receptor complex are confined to the chloride ionophore. J Pharmacol Exp Ther 237:787–793, 1986PubMedGoogle Scholar
  24. 23.
    Schwartz RD, Wess MJ, Labarca R, et al : Acute stress enhances the activity of the GABA-gated chloride ion channel in brain. Brain Res 411:151–155, 1987PubMedCrossRefGoogle Scholar
  25. 24.
    Robertson HA, Martin IL, Candy JM : Differences in benzodiazepine receptor binding in Maudsley reactive and Maudsley non-reactive rats. Eur J Pharmacol 50:455–457, 1978PubMedCrossRefGoogle Scholar
  26. 25.
    Tamborska E, Insel T, Marangos PH : “Peripheral” and “central” type benzodiazepine receptors in Maudsley rats. Eur J Pharmacol 126:281–287, 1986PubMedCrossRefGoogle Scholar
  27. 26.
    Robertson HA: Benzodiazepine receptors in “emotional” and “non-emotional” mice: Comparison of four strains. Eur J Pharmacol 56:163–166, 1979PubMedCrossRefGoogle Scholar
  28. 27.
    Lippa AS, Klepner CA, Yunger L, et al : Relationship between benzodiazepine receptors and experimental anxiety in rats. Pharmacol Biochem Behav 9:853–856, 1978PubMedCrossRefGoogle Scholar
  29. 28.
    Lane JD, Crenshaw CM, Guerin GF, et al : Changes in biogenic amine and benzodiazepine receptors correlated with conditioned emotional response and its reversal by diazepam. Eur J Pharmacol 83:183–190, 1982PubMedCrossRefGoogle Scholar
  30. 29.
    Braestrup C, Nielsen M, Nielsen E, et al : Benzodiazepine receptors in brain as affected by different experimental stresses: The changes are small and not unidirectional. Psychopharmacology 65:273–277, 1979PubMedCrossRefGoogle Scholar
  31. 30.
    Essman M, Valzelli L : Brain benzodiazepine receptor changes in the isolated aggressive mouse. Pharmacol Res Commun 13:665–671, 1981PubMedCrossRefGoogle Scholar
  32. 31.
    Petkov VV, Yanev S : Brain benzodiazepine receptor changes in rats with isolation syndrome. Pharmacol Res Commun 14:739–744, 1982PubMedCrossRefGoogle Scholar
  33. 32.
    Fride E, Dan Y, Gavish M, et al : Prenatal stress impairs maternal behavior in a conflict situation and reduces hippocampal benzodiazepine receptors. Life Sci 36:2103–2109, 1985PubMedCrossRefGoogle Scholar
  34. 33.
    Bodnoff SR, Suranyi-Cadotte B, Quirion R : Postnatal handling reduces novelty-induced fear and increases [3H]flunitrazepam binding in rat brain. Eur J Pharmacol 144:105–107, 1987PubMedCrossRefGoogle Scholar
  35. 34.
    Soubrie P, Thiebot M, Jobert A, et al : Decreased convulsant potency of picrotoxin and pentetrazol and enhanced [3H]flunitrazepam cortical binding following stressful manipulations in rats. Brain Res 189:505–517, 1980PubMedCrossRefGoogle Scholar
  36. 35.
    LeFur A, Guilloux F, Mitrani N, et al : Relationship between plasma corticosteroids and benzodiazepines in stress. J Pharmacol Exp Ther 211:305–308, 1979Google Scholar
  37. 36.
    Skerritt JH, Trisdikoon P, Johnston GAR : Increased GABA binding in mouse brain following acute swim stress. Brain Res 215:398–403, 1981PubMedCrossRefGoogle Scholar
  38. 37.
    Medina, J, Novas M, Wolfman C, et al : Benzodiazepine receptors in rat cerebral cortex and hippocampus undergo rapid and reversible changes after acute stress. Neuroscience 9:331–335, 1983PubMedCrossRefGoogle Scholar
  39. 38.
    Drugan RC, Maier SF, Skolnick P, et al : An anxiogenic benzodiazepine receptor ligand induces learned helplessness. Eur J Pharmacol 113:453–457, 1985PubMedCrossRefGoogle Scholar
  40. 39.
    Drugan RC, Ryan SM, Minor TR, et al : Librium prevents the analgesia and shuttlebox escape deficit typically observed following inescapable shock. Pharmacol Biochem Behav 21:749–754, 1984PubMedCrossRefGoogle Scholar
  41. 40.
    DeSouza E, Goeders NE, Kuhar MJ : Benzodiazepine receptors in rat brain are altered by adrenalectomy. Brain Res 381:176–181, 1986CrossRefGoogle Scholar
  42. 41.
    Goeders NE, DeSouza EB, Kuhar MJ : Benzodiazepine receptor GABA ratios: Regional differences in rat brain and modulation by adrenalectomy. Eur J Pharmacol 129:363–366, 1986PubMedCrossRefGoogle Scholar
  43. 42.
    Majewska MD, Harrison NL, Schwartz RD, et al : Steroid hormone metabolites are barbiturate-like modulators of the GABA receptor. Science 232:1004–1007, 1986PubMedCrossRefGoogle Scholar
  44. 43.
    Morrow AL, Suzdak PD, Paul SM : Steroid hormone metabolites potentiate GABA receptor-mediated chloride ion flux with nanomolar potency. Eur J Pharmacol 142:483–485, 1987PubMedCrossRefGoogle Scholar
  45. 44.
    Schambelan M, Biglieri EG : Deoxycorticosterone production and regulation in man. J Clin Endocrinol Metab 34:695–703, 1972PubMedCrossRefGoogle Scholar
  46. 45.
    Lai H, Kumar B, Forster MJ : Enhancement of learning and memory in mice by a benzodiazepine antagonist. FASEB J 2()11):2707–2711, 1988Google Scholar
  47. 46.
    Kumar BA, Forster MJ, Lai H : CGS 8216, a benzodiazepine receptor antagonist, enhances learning and memory in mice. Brain Res 460()1): 195–198, 1988PubMedCrossRefGoogle Scholar
  48. 47.
    Novas ML, Wolfman C, Medina JH, et al : Proconvulsant and “anxiogenic” effects of n-butyl beta carboline-3-carboxylate, an endogenous benzodiazepine binding inhibitor from brain. Pharmacol Biochem Behav 30()2):331–336, 1988PubMedCrossRefGoogle Scholar
  49. 48.
    De Bias AL, Sangameswaran L : Demonstration and purification of an endogenous benzodiazepine from the mammalian brain with a monoclonal antibody to benzodiazepines. Life Sci 39()21): 1927–1936, 1986CrossRefGoogle Scholar
  50. 49.
    Sangameswaran L, Fales HM, Friedrich P, et al : Purification of a benzodiazepine from bovine brain and detection of benzodiazepine-like immunoreactivity in human brain. Proc Natl Acad Sci (USA) 83()23): 9236–9240, 1986CrossRefGoogle Scholar
  51. 50.
    Wildmann J, Ranalder U : Presence of lorazepam in the blood plasma of drug free rats. Life Sci 43 (15): 1257–1260, 1988CrossRefGoogle Scholar
  52. 51.
    Wildman J : Increase of natural benzodiazepines in wheat and potato during germination. Biochem Biophys Res Commun 157()3): 1436–1443, 1988CrossRefGoogle Scholar
  53. 52.
    Deutsch SI, Miller LG, Weizman R, et al : Characterization of specific [3H]Rol5-1788 binding in vivo. Psychopharm Bull 23:469–472, 1987Google Scholar
  54. 53.
    Miller LG, Thompson ML, Greenblatt DJ, et al : Rapid increase in brain benzodiazepine receptor binding following defeat stress in mice. Brain Res 414:395–400, 1987PubMedCrossRefGoogle Scholar

Copyright information

© Plenum Publishing Corporation 1990

Authors and Affiliations

  • Stephen I. Deutsch
    • 1
    • 2
  • Abraham Weizman
    • 3
    • 4
  • Ronit Weizman
    • 5
    • 6
  • Frank J. VocciJr.
    • 7
  • Karin A. Kook
    • 8
  1. 1.Psychiatry ServiceVeterans Administration Medical CenterUSA
  2. 2.Department of PsychiatryGeorgetown University School of MedicineUSA
  3. 3.Geha Psychiatric HospitalBeilinson Medical CenterPetah TiqvaIsrael
  4. 4.Sackler Faculty of MedicineTel Aviv UniversityTel AvivIsrael
  5. 5.Pediatric DepartmentHasharon HospitalPetah TiqvaIsrael
  6. 6.Sackler Faculty of MedicineTel Aviv UniversityTel AvivIsrael
  7. 7.Medications Development Program, Division of Preclinical ResearchNational Institute on Drug AbuseRockvilleUSA
  8. 8.Division of Neuropharmacological Drug ProductsFood and Drug AdministrationRockvilleUSA

Personalised recommendations