Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Research Article
  • Published:

Common effects of chronically administered antipanic drugs on brainstem GABAA receptor subunit gene expression

Molecular Psychiatry volume 6, pages 404–412 (2001)Cite this article

Abstract

Panic disorder is an anxiety disorder that can be treated by long-term administration of tricyclic antidepressants such as imipramine, monoamine oxidase inhibitors such as phenelzine, or the selective serotonin reuptake inhibitor (SSRI) antidepressants. Clinical data also indicate that some benzodiazepines, such as alprazolam, are effective antipanic agents, and that their therapeutic onset is faster than that of antidepressants. Benzodiazepines are well known for their action at GABAA receptors, and preclinical data indicate that imipramine and phenelzine also interfere with the GABAergic system. In addition some clinical data lend support to decreased benzodiazepine-sensitive receptor function in panic disorder patients. Using imipramine, phenelzine and alprazolam, we investigated, in rats, the possibility that the therapeutic efficacy of antipanic agents stems from the remodeling of GABAergic transmission in the pons-medulla region. Of the 12 GABAA receptor subunit (α1–6, β1–3, γ1–3) steady-state mRNA levels investigated, we observed an increase in the levels of the α3-, β1- and γ2-subunit transcripts with all three antipanic agents tested. The effects of imipramine and phenelzine on these subunits occurred after 21 days of treatment, while alprazolam effects were observed after 3 days of administration. Histochemical data suggest that the α3β1γ2 subunits comprise a receptor subtype in the pons-medulla region. Therefore, we conclude that these molecular events parallel the therapeutic profile of the drugs examined. We further propose that these events may correspond to a remodeling of the GABAA receptor population, and may be useful markers for investigation of the antipanic properties of drugs.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  1. Weissman MM . Family genetic studies of panic disorder J Psychiatry Res 1993 27 (suppl 1): 69–78

    Article  Google Scholar 

  2. Reiman EM, Raichle ME, Robins E, Mintun MA, Fusselman MJ, Fox PT et al. Neuroanatomical correlates of a lactate-induced anxiety attack Arch Gen Psychiatry 1989 46: 493–500

    Article  CAS  Google Scholar 

  3. Gorman JM, Liebowitz MR, Fyer AJ, Stein J . A neuroanatomical hypothesis for panic disorder Am J Psychiatry 1989 146: 148–161

    Article  CAS  Google Scholar 

  4. Jacob RG, Furman JM, Durrant JD, Turner SM . Panic, agoraphobia, and vestibular dysfunction Am J Psychiatry 1996 153: 503–512

    Article  CAS  Google Scholar 

  5. Knott VJ, Bakish D, Barkley J . Brainstem evoked potentials in panic disorder J Psychiatry Neurosci 1994 19: 301–306

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Johnson MR, Lydiard RB, Ballenger JC . Panic disorder: pathophysiology and drug treatment Drugs 1995 49: 328–344

    Article  CAS  Google Scholar 

  7. Zacharko RM, Koszycki D, Mendella PD, Bradwejn J . Behavioral, neurochemical, anatomical and electrophysiological correlates of panic and neuropeptide colocalization Prog Neurobiol 1995 47: 371–423

    Article  CAS  Google Scholar 

  8. Bourin M, Baker GB, Bradwejn J . Neurobiology of panic disorder J Psychosom Res 1998 44: 163–180

    Article  CAS  Google Scholar 

  9. Ballenger JC . Long-term pharmacologic treatment of panic disorder J Clin Psychiatry 1991 52 (suppl 2): 18–23

    Google Scholar 

  10. Schweizer E, Rickels K, Weiss S, Zavodnick S . Maintenance drug treatment of panic disorder I: Results of a prospective, placebo controlled comparison of alprazolam and imipramine Arch Gen Psychiatry 1993 50: 51–60

    Article  CAS  Google Scholar 

  11. Korf J, Venema K . Desmethylimipramine enhances the release of endogenous GABA and other neurotransmitter amino acids from the rat thalamus J Neurochem 1983 40: 946–950

    Article  CAS  Google Scholar 

  12. Baker GB, Wong JTF, Yeung J, Coutts RT . Effects of the antidepressant phenelzine on brain levels of γ-aminobutyric acid J Affect Dis 1991 21: 207–211

    Article  CAS  Google Scholar 

  13. McKenna KF, McManus DJ, Baker GB, Coutts RT . Chronic administration of the antidepressant phenelzine and its N-acetyl analogue: effects on GABAergic function J Neural Transm 1994 41 (suppl): 115–122

    Google Scholar 

  14. Popov N, Matthies H . Some effects of monoamine oxidase inhibitors on the metabolism of γ-aminobutyric acid in rat brain J Neurochem 1969 16: 899–907

    Article  CAS  Google Scholar 

  15. McManus DJ, Baker GB, Martin IL, Greenshaw AJ, McKenna KF . Effects of the antidepressant/antipanic drug phenelzine on GABA concentrations and GABA-transaminase activity in rat brain Biochem Pharmacol 1992 43: 2486–2489

    Article  CAS  Google Scholar 

  16. Tesar GE, Rosenbaum JF, Pollack MH, Otto MW, Sachs GS, Herman JB et al. Double-blind, placebo-controlled comparison of clonazepam and alprazolam for panic disorder J Clin Psychiatry 1991 52: 69–76

    CAS  PubMed  Google Scholar 

  17. Burrows GD, Judd FK, Norman TR . Long-term drug treatment of panic disorder J Psychiatry Res 1993 27 (suppl 1): 111–125

    Article  Google Scholar 

  18. Barnard EA, Skolnick P, Olsen RW, Mohler H, Sieghart W, Biggio G et al. International Union of Pharmacology. XV. Subtypes of gamma-aminobutyric acidA receptors: classification on the basis of subunit structure and receptor function Pharmacol Rev 1998 50: 291–313

    CAS  PubMed  Google Scholar 

  19. Roy-Byrne P, Wingerson DK, Radant A, Greenblatt DJ, Cowley DS . Reduced benzodiazepine sensitivity in patients with panic disorder: comparison with patients with obsessive-compulsive disorder and normal subjects Am J Psychiatry 1996 153: 1444–1449

    Article  CAS  Google Scholar 

  20. Cowley DS, Roy-Byrne PP, Radant A, Ritchie JC, Greenblatt DJ, Nemeroff CB et al. Benzodiazepine sensitivity in panic disorder: effects of chronic alprazolam treatment Neuropsychopharmacology 1995 12: 147–157

    Article  CAS  Google Scholar 

  21. Kuikka JT, Pitakänen A, Lepola U et al. Abnormal regional benzodiazepine receptor uptake in the prefrontal cortex in patients with panic disorder Nucl Med Commun 1995 16: 273–280

    Article  CAS  Google Scholar 

  22. Schlegel S, Steinert H, Bokish A, Hahn K, Schloesser R, Benkert O . Decreased benzodiazepine receptor binding in panic disorder measured by IOMAZENIL-SPECT. A preliminary report Eur Arch Psychiatry Clin Neurosci 1994 244: 49–51

    Article  CAS  Google Scholar 

  23. Kaschka W, Feistel H, Ebert D . Reduced benzodiazepine receptor binding in panic disorders measured by iomazenil SPECT J Psychiatry Res 1995 29: 427–434

    Article  CAS  Google Scholar 

  24. Malizia AL, Cunningham VJ, Bell CM, Liddle PF, Rajeswaran S, Jones T et al. Decreased brain GABAA-benzodiazepine receptor binding in panic disorder J Psychopharmacol 1997 11 (suppl 3): A26

    Google Scholar 

  25. Rimón R, Lepola U, Halonen T, Riekkinen P . Cerebrospinal fluid gamma-aminobutyric acid in patients with panic disorder Biol Psychiatry 1995 38: 737–741

    Article  Google Scholar 

  26. Petty F, Steinberg J, Kramer GL, Fulton M, Moeller FG . Desipramine does not alter plasma GABA in patients with major depression J Affect Dis 1993 29: 53–56

    Article  CAS  Google Scholar 

  27. Roy-Byrne PP, Cowley DS, Hommer D, Greenblatt DJ, Kramer G, Petty F . Effect of acute and chronic benzodiazepines on plasma GABA in anxious patients and controls Psychopharmacology 1992 109: 153–156

    Article  CAS  Google Scholar 

  28. Sieghart W . Structure and pharmacology of γ-aminobutyric acidA receptor subtypes Pharmacol Rev 1995 47: 181–234

    CAS  PubMed  Google Scholar 

  29. Burt DR . GABAA receptor-activated chloride channels. In: Guggino WB (ed) Current Topics in Membranes, vol 42 Academic Press: London 1994 215–263

    Google Scholar 

  30. Pritchett DB, Lüddens H, Seeburg PH . Type I and type II GABAA-benzodiazepine receptors produced in transfected cells Science 1989 245: 1389–1392

    Article  CAS  Google Scholar 

  31. Pritchett DB, Sontheimer H, Shivers BD, Ymer S, Kettenmann H, Schofield PR et al. Importance of a novel GABAA receptor subunit for benzodiazepine pharmacology Nature 1989 338: 582–585

    Article  CAS  Google Scholar 

  32. Fritschy JM, Mohler H . GABAA-receptor heterogeneity in the adult rat brain: differential regional and cellular distribution of seven major subunits J Comp Neurol 1995 359: 154–194

    Article  CAS  Google Scholar 

  33. Wisden W, Laurie DJ, Monyer H, Seeburg PH . The distribution of 13 GABAA receptor subunit mRNAs in the rat brain I. Telencephalon, diencephalon, mesencephalon J Neurosci 1992 12: 1040–1062

    Article  CAS  Google Scholar 

  34. Sperk G, Schwarzer C, Tsunashima K, Fuchs K, Sieghart W . GABA(A) receptor subunits in the rat hippocampus I: immunocytochemical distribution of 13 subunits Neuroscience 1997 80: 987–1000

    Article  CAS  Google Scholar 

  35. Chen S, Huang X, Zeng XJ, Sieghart W, Tietz EI . Benzodiazepine-mediated regulation of alpha1, alpha2, beta1–3 and gamma2 GABA(A) receptor subunit proteins in the rat brain hippocampus and cortex Neuroscience 1999 93: 33–44

    Article  CAS  Google Scholar 

  36. Zeng XJ, Tietz EI . Benzodiazepine tolerance at GABAergic synapses on hippocampal CA1 pyramidal cells Synapse 1999 31: 263–277

    Article  CAS  Google Scholar 

  37. Tanay VA-MI, Glencorse TA, Greenshaw AJ, Baker GB, Bateson AN . Chronic administration of antipanic drugs alter rat brainstem GABAA receptor subunit mRNA levels Neuropharmacology 1996 35: 1475–1482

    Article  CAS  Google Scholar 

  38. Lin L-H, Whiting P, Harris RA . Molecular determinants of general anesthetic action: role of GABAA receptor structure J Neurochem 1993 60: 1548–1553

    Article  CAS  Google Scholar 

  39. Lai C-T, Tanay VA-MI, Bateson AN, Martin IL, Baker GB . A rapid, sensitive procedure to determine buspirone levels in rat brains using gas chromatography with nitrogen-phosphorus detection J Chromatogr B: Biomed Appl 1997 704: 175–179

    Article  CAS  Google Scholar 

  40. Tanay VA-MI, Tancowny BP, Glencorse TA, Bateson AN . The quantitative analysis of multiple mRNA species using oligonucleotide probes in an S1 nuclease protection assay Mol Biotechnol 1997 7: 217–229

    Article  CAS  Google Scholar 

  41. Holt RA, Bateson AN, Martin IL . Chronic treatment with diazepam or abecarnil differently affects the expression of GABAA receptor subunit mRNAs in the rat cortex Neuropharmacology 1996 35: 1457–1463

    Article  CAS  Google Scholar 

  42. Lai C-T, Tanay VA-MI, Charrois GJR, Baker GB, Bateson AN . Effects of phenelzine and imipramine on the steady-state levels of mRNAs that encode glutamic acid decarboxylase (GAD67 and GAD65), the GABA transporter GAT-1 and GABA transminase in rat cortex Naunyn-Schmiedeberg's Arch Pharmacol 1998 357: 32–38

    Article  CAS  Google Scholar 

  43. Heninger G, Saito N, Tallman JF, Garett KM, Vitek MP, Duman RS et al. Effects of continuous diazepam administration on GABAA subunit mRNA in rat brain J Mol Neurosci 1990 2: 101–107

    Article  CAS  Google Scholar 

  44. Holt RA, Bateson AN, Martin IL . Chronic zolpidem treatment alters GABAA receptor mRNA levels in the rat cortex Eur J Pharmacol 1997 329: 129–132

    Article  CAS  Google Scholar 

  45. Calkin PA, Barnes EM . γ-aminobutyric acid A (GABAA) agonists down-regulate GABAA/benzodiazepine receptor polypeptides from the surface of chick cortical neurons J Biol Chem 1994 269: 1548–1553

    CAS  PubMed  Google Scholar 

  46. Alexander PE, Alexander DD . Alprazolam treatment for panic disorders J Clin Psychiatry 1986 47: 301–304

    CAS  PubMed  Google Scholar 

  47. Ballenger JC, Burrows GD, Dupont RL, Lesser IM, Noyes R, Pecknold JC et al. Alprazolam in panic disorder and agoraphobia: results from a multicenter trial: I Efficacy in short-term treatment Arch Gen Psychiatry 1988 45: 413–422

    Article  CAS  Google Scholar 

  48. Davidson JRT . Use of benzodiazepines in panic disorder J Clin Psychiatry 1997 58 (suppl 2): 26–28

    Google Scholar 

  49. Bradwejn J . Benzodiazepines for the treatment of panic disorder and generalized anxiety disorder: clinical issues and future directions Can J Psychiatry 1993 38 (suppl 4): S109–S113

    Google Scholar 

  50. Rosenberg R . Drug treatment of panic disorder Pharmacol Toxicol 1993 72: 344–353

    Article  CAS  Google Scholar 

  51. Araki T, Tohyama M . Region-specific expression of GABAA receptor α3 and α4 subunit mRNAs in the rat brain Mol Brain Res 1992 12: 293–314

    Article  CAS  Google Scholar 

  52. Tohyama M, Oyamada H . Gene expression of neuroreceptors in the locus coeruleus of the rat Micros Res Tech 1994 29: 200–203

    Article  CAS  Google Scholar 

  53. Araki T, Sato M, Kiyama H, Manabe Y, Tohyama M . Localization of GABAA-receptor γ2-subunit mRNA-containing neurons in the rat central nervous system Neuroscience 1992 47: 45–61

    Article  CAS  Google Scholar 

  54. Luque JM, Malherbe P, Richards JG . Localization of GABAA receptor subunit mRNAs in the rat locus coeruleus Mol Brain Res 1994 24: 219–226

    Article  CAS  Google Scholar 

  55. Malherbe P, Sigel E, Baur R, Persohn E, Richards JG, Möhler H . Functional expression and sites of gene transcription of a novel α subunit of the GABAA receptor in rat brain FEBS Lett 1990 260: 261–265

    Article  CAS  Google Scholar 

  56. Ducic I, Caruncho HJ, Zhu WJ, Vicini S, Costa E . γ-Aminobutyric acid gating of Cl−channels in recombinant GABAA receptors J Pharmacol Exp Therapeut 1995 272: 438–445

    CAS  Google Scholar 

  57. Ebert B, Wafford KA, Whiting PJ, Krogsgaard-Larsen P, Kemp JA . Molecular pharmacology of γ-aminobutyric acid type A receptor agonist and partial agonist in oocytes injected with different α, β, and γ receptor subunit combinations Mol Pharmacol 1994 46: 957–963

    CAS  PubMed  Google Scholar 

  58. Sigel E, Baur R, Trube G, Möhler H, Malherbe P . The effect of subunit composition of rat brain GABAA receptor on channel function Neuron 1990 5: 703–711

    Article  CAS  Google Scholar 

  59. Sigel E, Baur R, Kellenberger S, Malherbe P . Point mutations affecting antagonist affinity and agonist dependent gating of GABAA receptor channels EMBO J 1992 11: 2017–2023

    Article  CAS  Google Scholar 

  60. Wafford KA, Whiting PJ, Kemp JA . Differences in affinity and efficacy of benzodiazepine receptor ligands at recombinant γ-aminobutyric acidA receptor subtypes Mol Pharmacol 1993 43: 240–244

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Many thanks to Brian Tancowny and Christine Selzler for their help with the animal procedures. The authors are also grateful to Gail Rauw for her expert technical assistance with the drug analyses. This work has been supported by the Canadian Psychiatric Research Foundation, the Alberta Mental Health Research Fund and the Medical Research Council of Canada. VA-MIT was in receipt of a studentship from the Alberta Mental Health Research Fund and ANB is an Alberta Heritage Foundation for Medical Research Scholar.

Author information

Authors and Affiliations

  1. Department of Pharmacology, Faculty of Medicine, University of Alberta, Edmonton, T6G 2H7, Alberta, Canada

    VA-MI Tanay, G B Baker & A N Bateson

  2. Department of Psychiatry, Faculty of Medicine, University of Alberta, Edmonton, T6G 2H7, Alberta, Canada

    A J Greenshaw, G B Baker & A N Bateson

  3. Division of Neuroscience, Faculty of Medicine, University of Alberta, Edmonton, T6G 2H7, Alberta, Canada

    A J Greenshaw, G B Baker & A N Bateson

Authors
  1. VA-MI Tanay
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A J Greenshaw
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. G B Baker
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A N Bateson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to A N Bateson.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tanay, VM., Greenshaw, A., Baker, G. et al. Common effects of chronically administered antipanic drugs on brainstem GABAA receptor subunit gene expression. Mol Psychiatry 6, 404–412 (2001). https://doi.org/10.1038/sj.mp.4000879

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.mp.4000879

Keywords

This article is cited by

Search

Advanced search

Quick links