Der Nervenarzt

, Volume 74, Issue 7, pp 543–551 | Cite as

Die Bedeutung von GABAA-Rezeptoren für Pathophysiologie und Therapie der Panikstörung



Gamma-Aminobuttersäure (GABA) ist der wichtigste inhibitorische Neurotransmitter im Zentralnervensystem. Eine Dysfunktion von GABAA-Rezeptoren spielt eine wichtige Rolle in der Pathophysiologie der Panikstörung. Allgemein bekannt ist die klinische Wirksamkeit von Benzodiazepinen in der Therapie der Panikstörung, Nebenwirkungen limitieren allerdings den Einsatz als Langzeittherapie. Antidepressiva, insbesondere selektive Serotoninwiederaufnahmehemmer, stellen Mittel der ersten Wahl in der Pharmakotherapie der Panikstörung dar. Neuere Untersuchungen konnten zeigen, dass die Erhöhung endogener GABA durch Blockade der GABA-Transaminase mit Vigabatrin oder durch Inhibition von GABA-Transportern mit Tiagabin ebenfalls anxiolytische Eigenschaften entfaltet. Diese neue Interventionsstrategie an der GABA-Bindungsstelle des GABAA-/Benzodiazepin-Rezeptor-Komplexes sowie Agonisten für die Benzodiazepinbindungsstelle mit Selektivität für bestimmte Untereinheiten des Rezeptors stellen interessante neuartige Perspektiven für die Weiterentwicklung der Pharmakotherapie der Panikstörung dar.


Panikstörung Angst GABAA-Rezeptor Benzodiazepine 


Gamma aminobutyric acid (GABA) is the most important inhibitory neurotransmitter in the central nervous system. Its action is exerted in the brain through GABAA receptors which belong to the family of ligand-gated ion channels. These GABAA receptors consist of various subunits and are targets for benzodiazepines, barbiturates, neuroactive steroids, and distinct anticonvulsive agents. Meanwhile, there is considerable evidence that a dysfunction of GABAA receptors plays an important role in the pathophysiology of panic disorder. The anxiolytic effects of benzodiazepines are widely used in the treatment of panic disorder. Nevertheless, side effects of benzodiazepines, e.g., dependency and withdrawal symptoms, limit their use as a long-term treatment. In the meantime, antidepressants, especially selective serotonin reuptake inhibitors, comprise first-line treatment in the pharmacotherapy of panic disorder. They interfere with the synthesis of endogenous neuroactive steroids that allosterically modulate GABAA receptor function. With regard to experimentally evoked panic attacks in patients with panic disorder and healthy controls, recent investigations demonstrated that enhancing endogenous GABA through the blockade of the GABA transaminase by vigabatrin or inhibition of GABA transporters by tiagabine may exert anxiolytic effects. This novel strategy targeting the GABA binding site of the GABAA/benzodiazepine receptor complex and specific agonists for the benzodiazepine binding site present interesting perspectives for the future pharmacotherapy of panic disorder.


Panic disorder Anxiety GABAA receptor Benzodiazepines 


  1. 1.
    American Psychiatric Association (1994) Diagnostic and Statistical Manual of Mental Disorders, 4th edn. American Psychiatric Press, Washington DCGoogle Scholar
  2. 2.
    American Psychiatric Association (1998) Practice guideline for the treatment of patients with panic disorder. Am J Psychiatry 155:1–34Google Scholar
  3. 3.
    Arndt CF, Derambure P, Defoort-Dhellemmes S, Hache JC (1999) Outer retinal dysfunction in patients treated with vigabatrin. Neurology 52:1201–1205Google Scholar
  4. 4.
    Ballenger JC, Burrows GD, DuPont RL,Jr et al. (1988) Alprazolam in panic disorder and agoraphobia: results from a multicenter trial. I. Efficacy in short-term treatment. Arch Gen Psychiatry 45:413–422Google Scholar
  5. 5.
    Bandelow B, Zohar J, Hollander E, Kasper S, Möller H-J (2002) Guidelines for the pharmacological treatment of anxiety and obsessive-compulsive disorders. World J Biol Psychiatry 3:171–199Google Scholar
  6. 6.
    Barlow DH (1997) Cognitive-behavioral therapy for panic disorder: current status. J Clin Psychiatry 58:32–36Google Scholar
  7. 7.
    Boerner RJ, Möller H-J (1996) Pharmakotherapie der Panikstörung und/oder Agoraphobie. Psychopharmakotherapie 3:168–177Google Scholar
  8. 8.
    Carter RB, Wood PL, Wieland S et al. (1997) Characterization of the anticonvulsant properties of ganaxolone (CCD 1042; 3α-hydroxy-3-methyl-5α-pregnan-20-one), a selective high-affinity steroid modulator of the GABAA receptor. J Pharmacol Exp Ther 280:1284–1295Google Scholar
  9. 9.
    Changeux J-P, Devillers-Thiery A, Galzi J-L, Bertrand D (1992) New mutants to explore nicotinic receptor functions. Trends Pharmacol Sci 13:299–301Google Scholar
  10. 10.
    Collins I, Moyes C, Davey WB et al. (2002) 3-Heteroaryl-2-pyridones: benzodiazepine site ligands with functional selectivity for alpha 2/alpha 3-subtypes of human GABA(A) receptor-ion channels. J Med Chem 45:1887–1900Google Scholar
  11. 11.
    Crestani F, Löw K, Keist R, Mandelli M, Möhler H, Rudolph U (2001) Molecular targets for the myorelaxant action of diazepam. Mol Pharmacol 59:442–445Google Scholar
  12. 12.
    Crestani F, Martin JR, Möhler H, Rudolph U (2000) Resolving differences in GABAA receptor mutant mouse studies. Nat Neurosci 3:1059Google Scholar
  13. 13.
    Cross-national collaborative panic study. Second phase investigators (1992) Drug treatment of panic disorder. Comparative efficacy of alprazolam, imipramine, and placebo. Br J Psychiatry 160:191–202Google Scholar
  14. 14.
    Damianisch K, Rupprecht R, Lancel M (2001) The influence of subchronic administration of the neurosteroid allopregnanolone on sleep in the rat. Neuropsychopharmacology 25:576–584Google Scholar
  15. 15.
    Eke T, Talbot JF, Lawden MC (1997) Severe persistent visual field constriction associated with vigabatrin. Br Med J 314:180–181Google Scholar
  16. 16.
    Faulhaber J, Steiger A, Lancel M (1997) The GABAA agonist THIP produces slow wave sleep and reduces spindling activity in NREM sleep in humans. Psychopharmcology 130:285–291Google Scholar
  17. 17.
    Gasior M, Carter RB, Witkin JM (1999) Neuroactive steroids: potential therapeutic use in neurological and psychiatric disorders. Trends Pharmacol Sci 20:107–112Google Scholar
  18. 18.
    Gee KW, McCauley LD, Lan NC (1995) A putative receptor for neurosteroids on the GABAA receptor complex: the pharmacological properties and therapeutic potential of epalons. Crit Rev Neurobiol 9:207–227Google Scholar
  19. 19.
    Goddard AW, Mason GF, Almai A, Rothman DL, Behar KL, Petroff OAC, Charney DS, Krystal JH (2001) Reductions in occipital cortex GABA levels in panic disorder detected with 1H-magnetic resonance spectroscopy. Arch Gen Psychiatry 58:556–561Google Scholar
  20. 20.
    Griffin LD, Mellon SH (1999) Selective serotonin reuptake inhibitors directly alter activity of neurosteroidogenic enzymes. Proc Natl Acad Sci USA 96:13512–13517Google Scholar
  21. 21.
    Hales TG, Lambert JJ (1992) Modulation of GABAA and glycine receptors by clomethiazole. Eur J Pharmacol 210:239–246Google Scholar
  22. 22.
    Hauser CAE, Wetzel CHR, Berning B, Gerner FM, Rupprecht R (1997) Flunitrazepam has an inverse agonistic effect on recombinant α6β2γ2 GABAA-receptors via a flunitrazepam-binding site. J Biol Chem 272:11723–11727Google Scholar
  23. 23.
    Hevers S, Lüddens H (1998) The diversity of GABAA receptors. Pharmacological and electrophysiologi cal properties of GABAA channel subtypes. Mol Neurobiol 18:35–86Google Scholar
  24. 24.
    Lambert JJ, Belelli D, Hill-Venning C, Peters JA (1995) Neurosteroids and GABAA receptor function. Trends Pharmacol Sci 16:295–303Google Scholar
  25. 25.
    Lancel M, Crönlein TAM, Faulhaber J (1996) Role of GABAA receptors in sleep regulation. Differential effects of muscimol and midazolam on sleep in rats. Neuropsychopharmacology 15:63–74Google Scholar
  26. 26.
    Lancel M, Faulhaber J, Deisz RA (1998) Effect of the GABA uptake inhibitor tiagabine on sleep and EEG power spectra in the rat. Br J Pharmacol 123:1471–1477Google Scholar
  27. 27.
    Lancel M, Ruigt GSF, Deisz RA (1999) Role of GABAA receptors in the regulation of sleep: initial sleep responses to peripherally administered modulators and agonists. Sleep 22:33–42Google Scholar
  28. 28.
    Leppik IE (1995) Tiagabine: the safety landscape. Epilepsia 36:10–13Google Scholar
  29. 29.
    Löw K, Crestani F, Keist R et al. (2000) Molecular and neuronal substrate for the selective attenuation of anxiety. Science 290:131–134Google Scholar
  30. 30.
    Malizia AL, Cunningham VJ, Bell CJ, Liddle PF, Jones T, Nutt DN (1998) Decreased brain GABAA-benzodiazepine receptor binding in panic disorder. Arch Gen Psychiatry 55:715–720Google Scholar
  31. 31.
    Maricq AV, Peterson AS, Brake AJ, Myers RM, Julius D (1991) Primary structure and functional expression of the 5HT3 receptor, a serotonin-gated ion channel. Science 254:432–437Google Scholar
  32. 32.
    Mathias S, Wetter TC, Steiger A, Lancel M (2001) The GABA uptake inhibitor tiagabine promotes slow wave sleep in normal elderly subjects. Neurobiol Aging 22:247–253Google Scholar
  33. 33.
    Michelson LK, Marchione K (1991) Behavioral, cognitive, and pharmacological treatments of panic disorder with agoraphobia: critique and synthesis. J Consult Clin Psychol 59:100–114Google Scholar
  34. 34.
    Monaghan EP, McAuley JW, Data JL (1999) Ganaxolone: a novel positive allosteric modulator of the GABA(A) receptor complex for the treatment of epilepsy. Expert Opin Investig Drugs 8:1663–1671Google Scholar
  35. 35.
    Möhler H, Fritschy J-M, Rudolph U (2002) A new benzodiazepine pharmacology. J Pharmacol Exp Ther 300:2–8Google Scholar
  36. 36.
    Nutt DJ, Glue P, Lawson C, Wilson S (1990) Flumazenil provocation of panic attacks: evidence for altered benzodiazepine receptor sensitivity in panic disorders. Arch Gen Psychiatry 47:917–925Google Scholar
  37. 37.
    Nutt DJ, Malizia AL (2001) New insights into the role of the GABAA-benzodiazepine receptor in psychiatric disorder. Br J Psychiatry 179:390–396Google Scholar
  38. 38.
    Olsen RW, Tobin AJ (1990) Molecular biology of GABAA receptors. FASEB J 4:1469–1480Google Scholar
  39. 39.
    Paul SM, Purdy RH (1992) Neuroactive steroids. FASEB J 6:2311–2322.Google Scholar
  40. 40.
    Puia G, Santi MR, Vicini S et al. (1990) Neurosteroids act on recombinant human GABAA receptors. Neuron 4:759–765Google Scholar
  41. 41.
    Romeo E, Ströhle A, Spalletta G et al. (1998) Effects of antidepressant treatment on neuroactive steroids in major depression. Am J Psychiatry 155:910–913Google Scholar
  42. 42.
    Roy-Byrne PP, Cowley DS, Greenblatt DJ (1990) Reduced benzodiazepine sensitivity in panic disorder. Arch Gen Psychiatry 47:534–538Google Scholar
  43. 43.
    Rudolph U, Crestani F, Benke D et al. (1999) Benzodiazepine actions mediated by specific γ-aminobutyric acidA receptor subtypes. Nature 401:796–797Google Scholar
  44. 44.
    Rudolph U, Crestani F, Möhler H (2001) GABAA receptor subtypes: dissecting their pharmacological functions. Trends Pharmacol Sci 22:188–194Google Scholar
  45. 45.
    Rupprecht R, Holsboer F (1999) Neuroactive steroids: mechanisms of action and neuropsychopharmacological perspectives. Trends Neurosci 22:410–416Google Scholar
  46. 46.
    Rupprecht R, Holsboer F (2001) Neuroactive steroids in neuropsychopharmacology. Int Rev Neurobiol 46:461–477Google Scholar
  47. 47.
    Rupprecht R, Reul JMHM, Trapp T et al. (1993) Progesterone receptor-mediated effects of neuroactive steroids. Neuron 11:523–530Google Scholar
  48. 48.
    Sandford JJ, Forshall S, Bell C et al. (2001) Crossover trial of pagoclone and placebo in patients with DSM-IV panic disorder. J Psychopharmacol 15:205–208Google Scholar
  49. 49.
    Sayin Ü, Purali N, Özkan T, Altug T, Büyükdevrim S (1992) Vigabatrin has an anxiolytic effect in the elevated plus-maze test of anxiety. Pharmacol Biochem Behav 43:529–535Google Scholar
  50. 50.
    Schmitt U, Hiemke C (1999) Effects of GABA-transporter (GAT) inhibitors on rat behaviour in open-field and elevated plus-maze. Behav Pharmacol 10:131–137Google Scholar
  51. 51.
    Schmitt U, Lüddens H, Hiemke C (2000) Behavioral effects of GABA(A) receptor stimulation and GABA-transporter inhibition. Pharmacol Biochem Behav 65:351–356Google Scholar
  52. 52.
    Shear MK, Weiner K (1997) Psychotherapy for panic disorder. J Clin Psychiatry 58:38–43Google Scholar
  53. 53.
    Sieghart W (1992) GABAA receptors: ligand-gated Cl-ion channels modulated by multiple drug-binding sites. Trends Pharmacol Sci 13:446–450Google Scholar
  54. 54.
    Sieghart W (2000) Unraveling the function of GABAA receptor subtypes. Trends Pharmacol Sci 21:411–413Google Scholar
  55. 55.
    Ströhle A, Kellner M, Yassouridis A, Holsboer F, Wiedemann K (1998) Effect of flumazenil in lactate-sensitive patients with panic disorder. Am J Psychiatry 155:610–612Google Scholar
  56. 56.
    Ströhle A, Romeo E, di Michele F, Pasini A, Yassouridis A, Holsboer F, Rupprecht R (2002) GABAA receptor modulatory neuroactive steroid composition in panic disoder and during paroxetine treatment. Am J Psychiatry 159:145–147Google Scholar
  57. 57.
    Ströhle A, Romeo E, di Michele F et al. (2002) Induced panic attacks shift GABAA receptor modulatory steroid composition in patients with panic disorder: preliminary results. Archives of General Psychiatry (im Druck)Google Scholar
  58. 58.
    Uzunova V, Sheline Y, Davis JM, Rasmusson A, Uzunov DP, Costa E, Guidotti A (1998) Increase in the cerebrospinal fluid content of neurosteroids in patients with unipolar major depression who are receiving fluoxetine or fluvoxamine. Proc Natl Acad Sci USA 95:3239–3244Google Scholar
  59. 59.
    Vanover KE, Rosenzweig-Lipson S, Hawkinson JE et al. (2000) Characterization of the anxiolytic properties of a novel neuroactive steroid, Co 2–6749 (GMA-839; WAY-141839; 3α, 21-Dihydroxy-3β-trifluoromethyl-19-nor-5β-pregnan-20-one), a selective modulator of γ-aminobutyric acidA receptors. J Pharmacol Exp Ther 295:337–345Google Scholar
  60. 60.
    Wieland HA, Lüddens H, Seeburg PH (1992) A single histidine in GABAA receptors is essential for benzodiazepine agonist binding. J Biol Chem 267:1426–1429Google Scholar
  61. 61.
    Wieland S, Belluzzi J, Hawkinson JE et al. (1997) Anxiolytic and anticonvulsant activity of a synthetic neuroactive steroid Co 3–0593. Psychopharmcol 134:46–54Google Scholar
  62. 62.
    Wisden W, Seeburg PH (1992) GABAA receptor channels: from subunits to functional entities. Curr Opin Neurobiol 2:263–269Google Scholar
  63. 63.
    Zwanzger P, Baghai T, Boerner RJ, Möller H-J, Rupprecht R (2001) Anxiolytic effects of vigabatrin in panic disorder. J Clin Psychopharmacol 21:539–540Google Scholar
  64. 64.
    Zwanzger P, Baghai TC, Schüle C, Minov C, Padberg F, Möller H-J, Rupprecht R (2001) Tiagabine improves panic and agoraphobia in panic disorder patients. J Clin Psychiatry 62:656–657Google Scholar
  65. 65.
    Zwanzger P, Baghai TC, Schüle C et al. (2001) Vigabatrin decreases cholecystokinin-tetrapeptide (CCK-4) induced panic in healthy volunteers. Neuropsychopharmacology 25:699–703Google Scholar

Copyright information

© Springer-Verlag 2003

Authors and Affiliations

  1. 1.Klinik für Psychiatrie und Psychotherapie der Ludwig-Maximilians-Universität München
  2. 2.Klinik für Psychiatrie und Psychotherapie, Nußbaumstraße 7, 80336 München

Personalised recommendations