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.

  • Review Article
  • Published:

Modulators of GABAA receptor-mediated inhibition in the treatment of neuropsychiatric disorders: past, present, and future

Subjects

Abstract

The predominant inhibitory neurotransmitter in the brain, γ-aminobutyric acid (GABA), acts at ionotropic GABAA receptors to counterbalance excitation and regulate neuronal firing. GABAA receptors are heteropentameric channels comprised from subunits derived from 19 different genes. GABAA receptors have one of the richest and well-developed pharmacologies of any therapeutic drug target, including agonists, antagonists, and positive and negative allosteric modulators (PAMs, NAMs). Currently used PAMs include benzodiazepine sedatives and anxiolytics, barbiturates, endogenous and synthetic neurosteroids, and general anesthetics. In this article, I will review evidence that these drugs act at several distinct binding sites and how they can be used to alter the balance between excitation and inhibition. I will also summarize existing literature regarding (1) evidence that changes in GABAergic inhibition play a causative role in major depression, anxiety, postpartum depression, premenstrual dysphoric disorder, and schizophrenia and (2) whether and how GABAergic drugs exert beneficial effects in these conditions, focusing on human studies where possible. Where these classical therapeutics have failed to exert benefits, I will describe recent advances in clinical and preclinical drug development. I will also highlight opportunities to advance a generation of GABAergic therapeutics, such as development of subunit-selective PAMs and NAMs, that are engendering hope for novel tools to treat these devastating conditions.

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

Access options

Buy this article

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

Fig. 1: Images of adult human brain sections showing in situ hybridization for various GABAA receptor subunits.
Fig. 2: Localization of α5 subunit-containing GABAA receptors.

Similar content being viewed by others

References

  1. Prince DA. Epileptogenic neurons and circuits. Adv Neurol. 1999;79:665–84.

    CAS  PubMed  Google Scholar 

  2. Gleichmann M, Chow VW, Mattson MP. Homeostatic disinhibition in the aging brain and Alzheimer’s disease. J Alzheimers Dis. 2011;24:15–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Li Y, Sun H, Chen Z, Xu H, Bu G, Zheng H. Implications of GABAergic neurotransmission in Alzheimer’s disease. Front Aging Neurosci. 2016;8:31.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Prévot T, Sibille E. Altered GABA-mediated information processing and cognitive dysfunctions in depression and other brain disorders. Mol Psychiatry. 2021;26:151–67.

    Article  PubMed  Google Scholar 

  5. Sigel E, Steinmann ME. Structure, function, and modulation of GABA(A) receptors. J Biol Chem. 2012;287:40224–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Pirker S, Schwarzer C, Wieselthaler A, Sieghart W, Sperk G. GABA(A) receptors: immunocytochemical distribution of 13 subunits in the adult rat brain. Neuroscience. 2000;101:815–50.

    Article  CAS  PubMed  Google Scholar 

  7. Atack JR, Alder L, Cook SM, Smith AJ, McKernan RM. In vivo labelling of α5 subunit-containing GABA(A) receptors using the selective radioligand [(3)H]L-655,708. Neuropharmacology. 2005;49:220–9.

    Article  CAS  PubMed  Google Scholar 

  8. Hörtnagl H, Tasan RO, Wieselthaler A, Kirchmair E, Sieghart W, Sperk G. Patterns of mRNA and protein expression for 12 GABAA receptor subunits in the mouse brain. Neuroscience. 2013;236:345–72.

    Article  PubMed  Google Scholar 

  9. Lüscher B, Keller CA. Regulation of GABAA receptor trafficking, channel activity, and functional plasticity of inhibitory synapses. Pharmacol Ther. 2004;102:195–221.

    Article  PubMed  Google Scholar 

  10. Comenencia-Ortiz E, Moss SJ, Davies PA. Phosphorylation of GABAA receptors influences receptor trafficking and neurosteroid actions. Psychopharmacology. 2014;231:3453–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Brickley SG, Mody I. Extrasynaptic GABA(A) receptors: their function in the CNS and implications for disease. Neuron. 2012;73:23–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Segal M, Barker JL. Rat hippocampal neurons in culture: voltage-clamp analysis of inhibitory synaptic connections. J Neurophysiol. 1984;52:469–87.

    Article  CAS  PubMed  Google Scholar 

  13. Stell BM, Mody I. Receptors with different affinities mediate phasic and tonic GABA(A) conductances in hippocampal neurons. J Neurosci. 2002;22:RC223.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Wei W, Zhang N, Peng Z, Houser CR, Mody I. Perisynaptic localization of delta subunit-containing GABA(A) receptors and their activation by GABA spillover in the mouse dentate gyrus. J Neurosci. 2003;23:10650–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Farrant M, Kaila K. The cellular, molecular and ionic basis of GABA(A) receptor signalling. Prog Brain Res. 2007;160:59–87.

    Article  CAS  PubMed  Google Scholar 

  16. Whissell PD, Lecker I, Wang DS, Yu J, Orser BA. Altered expression of δ GABAA receptors in health and disease. Neuropharmacol. 2015;88:24–35.

    Article  CAS  Google Scholar 

  17. Farrant M, Nusser Z. Variations on an inhibitory theme: phasic and tonic activation of GABA(A) receptors. Nat Rev Neurosci. 6:215–29.

  18. Prenosil GA, Schneider Gasser EM, Rudolph U, Keist R, Fritschy JM, Vogt KE. Specific subtypes of GABAA receptors mediate phasic and tonic forms of inhibition in hippocampal pyramidal neurons. J Neurophysiol. 2006;96:846–57.

    Article  CAS  PubMed  Google Scholar 

  19. Glykys J, Mody I. Hippocampal network hyperactivity after selective reduction of tonic inhibition in GABA A receptor α5 subunit-deficient mice. J Neurophysiol. 2006;95:2796–807.

    Article  CAS  PubMed  Google Scholar 

  20. Zorrilla de San Martin J, Donato C, Peixoto J, Aguirre A, Choudhary V, De Stasi AM, et al. Alterations of specific cortical GABAergic circuits underlie abnormal network activity in a mouse model of Down syndrome. Elife 2020;9:e58731.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Skolnick P. Anxioselective anxiolytics: on a quest for the Holy Grail. Trends Pharmacol Sci. 2012;33:611–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Zhu S, Noviello CM, Teng J, Walsh RM Jr, Kim JJ, Hibbs RE. Structure of a human synaptic GABAA receptor. Nature. 2018;559:67–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Wingrove PB, Safo P, Wheat L, Thompson SA, Wafford KA, Whiting PJ. Mechanism of alpha-subunit selectivity of benzodiazepine pharmacology at gamma-aminobutyric acid type A receptors. Eur J Pharmacol. 2002;437:31–39.

    Article  CAS  PubMed  Google Scholar 

  24. Faure-Halley C, Graham D, Arbilla S, Langer SZ. Expression and properties of recombinant alpha1 beta2 gamma2 and alpha5 beta2 gamma2 forms of the rat GABAA receptor. Eur J Pharmacol. 1993;246:283–7.

    Article  CAS  PubMed  Google Scholar 

  25. Zhu S, Sridhar A, Teng J, Howard RJ, Lindahl E, Hibbs RE. Structural and dynamic mechanisms of GABAA receptor modulators with opposing activities. Nat Commun. 2022;13:4582.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Woods JH, Katz JL, Winger G. Benzodiazepines: use, abuse, and consequences. Pharmacol Rev. 1992;44:151–347.

    CAS  PubMed  Google Scholar 

  27. Tan KR, Rudolph U, Lüscher C. Hooked on benzodiazepines: GABAA receptor subtypes and addiction. Trends Neurosci. 2011;34:188–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Tan KR, Brown M, Labouèbe G, Yvon C, Creton C, Fritschy JM, et al. Neural bases for addictive properties of benzodiazepines. Nature. 2010;463:769–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Sieghart W, Ramerstorfer J, Sarto-Jackson I, Varagic Z, Ernst M. A novel GABA(A) receptor pharmacology: drugs interacting with the α(+) β(-) interface. Br J Pharmacol. 2012;166:476–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Lu X, Zorumski CF, Mennerick S. Lack of Neurosteroid Selectivity at δ vs. γ2-Containing GABAA Receptors in Dentate Granule Neurons. Front Mol Neurosci. 2020;23:13.6

    Google Scholar 

  31. Maguire JL, Mennerick S. Neurosteroids and GABAA receptors. Neuropsychopharmacol Rev. 2023, In this issue.

  32. Herd MB, Belelli D, Lambert JJ. Neurosteroid modulation of synaptic and extrasynaptic GABA(A) receptors. Pharmacol Ther. 2007;116:20–34.

    Article  CAS  PubMed  Google Scholar 

  33. Wohlfarth KM, Bianchi MT, Macdonald RL. Enhanced neurosteroid potentiation of ternary GABA(A) receptors containing the δ subunit. J Neurosci. 2002;22:1541–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Mihalek RM, Banerjee PK, Korpi ER, Quinlan JJ, Firestone LL, Mi ZP, et al. Attenuated sensitivity to neuroactive steroids in gamma-aminobutyrate type A receptor delta subunit knockout mice. Proc Natl Acad Sci USA. 1999;96:12905–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Blanco MJ, La D, Coughlin Q, Newman CA, Griffin AM, Harrison BL, et al. Breakthroughs in neuroactive steroid drug discovery. Bioorg Med Chem Lett. 2018;28:61–70.

    Article  CAS  PubMed  Google Scholar 

  36. Althaus AL, Ackley MA, Belfort GM, Gee SM, Dai J, Nguyen DP, et al. Preclinical characterization of zuranolone (SAGE-217), a selective neuroactive steroid GABAA receptor positive allosteric modulator. Neuropharmacology. 2020;181:108333.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Clayton AH, Lasser R, Nandy I, Sankoh AJ, Jonas J, Kanes SJ. Zuranolone in major depressive disorder: results from MOUNTAINA phase 3, multicenter, double-blind, randomized, placebo-controlled trial. J Clin Psychiatry. 2023a;84:22m14445.

    Article  PubMed  Google Scholar 

  38. Clayton AH, Lasser R, Parikh SV, Iosifescu DV, Jung J, Kotecha M, et al. Zuranolone for the treatment of adults with major depressive disorder: a randomized, placebo-controlled phase 3 trial. Am J Psychiatry. 2023:180:676–84.

    Article  PubMed  Google Scholar 

  39. McGrath M, Hoyt H, Pence A, Forman SA, Raines DE. Selective actions of benzodiazepines at the transmembrane anaesthetic binding sites of the GABAA receptor: In vitro and in vivo studies. Br J Pharmacol. 2021;178:4842–58.

    Article  CAS  PubMed  Google Scholar 

  40. Forman SA, Miller KW. Anesthetic sites and allosteric mechanisms of action on Cys-loop ligand-gated ion channels. Can J Anaesth. 2011;58:191–205.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Rahman M, Zhu D, Lindblad C, Johansson IM, Holmberg E, Isaksson M, et al. GABA-site antagonism and pentobarbital actions do not depend on the α-subunit type in the recombinant rat GABA receptor. Acta Physiol. 2006;187:479–88.

    Article  CAS  Google Scholar 

  42. Hevers W, Lüddens H. The diversity of GABAA receptors. Pharmacological and electrophysiological properties of GABAA channel subtypes. Mol Neurobiol. 1998;18:35–86.

    Article  CAS  PubMed  Google Scholar 

  43. Ansseau M, Doumont A, Cerfontaine JL, Mantanus H, Rousseau JC, Timsit Berthier M. Self-reports of anxiety level and EEG changes after a single dose of benzodiazepines. Double-blind comparison of two forms of oxazepam. Neuropsychobiology. 1984;12:255–9.

    Article  CAS  PubMed  Google Scholar 

  44. Lambert PM, Ni R, Benz A, Rensing NR, Wong M, Zorumski CF, et al. Non-sedative cortical EEG signatures of allopregnanolone and functional comparators. Neuropsychopharmacology. 2023;48:371–9.

    Article  CAS  PubMed  Google Scholar 

  45. Fernandez LMJ, Lüthi A. Sleep spindles: mechanisms and functions. Physiol Rev. 2020;100:805–68.

    Article  PubMed  Google Scholar 

  46. Fogerson PM, Huguenard JR. Tapping the brakes: cellular and synaptic mechanisms that regulate thalamic oscillations. Neuron. 2016;92:687–704.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Sohal VS, Huguenard JR. Inhibitory interconnections control burst pattern and emergent network synchrony in reticular thalamus. J Neurosci. 2003;23:8978–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Lancel M. Role of GABAA receptors in the regulation of sleep: initial sleep responses to peripherally administered modulators and agonists. Sleep. 1999;22:33–42.

    Article  CAS  PubMed  Google Scholar 

  49. Carrier J, Semba K, Deurveilher S, Drogos L, Cyr-Cronier J, Lord C, et al. Sex differences in age-related changes in the sleep-wake cycle. Front Neuroendocrinol. 2017;47:66–85.

    Article  PubMed  Google Scholar 

  50. Lancel M, Faulhaber J, Schiffelholz T, Romeo E, Di Michele F, Holsboer F, et al. Allopregnanolone affects sleep in a benzodiazepine-like fashion. J Pharmacol Exp Ther. 1997;282:1213–8.

    CAS  PubMed  Google Scholar 

  51. Smith SS, Shen H, Gong QH, Zhou X. Neurosteroid regulation of GABA(A) receptors: focus on the alpha4 and delta subunits. Pharmacol Ther. 2007;116:58–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Pessoa L. How many brain regions are needed to elucidate the neural bases of fear and anxiety? Neurosci Biobehav Rev. 2023;146:105039.

    Article  PubMed  Google Scholar 

  53. Purdy RH, Morrow AL, Moore PH Jr, Paul SM. Stress-induced elevations of gamma-aminobutyric acid type A receptor-active steroids in the rat brain. Proc Natl Acad Sci USA. 1991;88:4553–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Pinna G, Dong E, Matsumoto K, Costa E, Guidotti A. In socially isolated mice, the reversal of brain allopregnanolone down-regulation mediates the anti-aggressive action of fluoxetine. Proc Natl Acad Sci USA. 2003;100:2035–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Walton NL, Antonoudiou P, Barros L, Dargan T, DiLeo A, Evans-Strong A, et al. Impaired endogenous neurosteroid signaling contributes to behavioral deficits associated with chronic stress. Biol Psychiatry. 2023;S0006-3223:00050–1.

    Google Scholar 

  56. Hantsoo L, Epperson CN. Allopregnanolone in premenstrual dysphoric disorder (PMDD): Evidence for dysregulated sensitivity to GABAA receptor modulating neuroactive steroids across the menstrual cycle. Neurobiol Stress. 2020;12:100213.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Gulinello M, Gong QH, Li X, Smith SS. Short-term exposure to a neuroactive steroid increases α4 GABA(A) receptor subunit levels in association with increased anxiety in the female rat. Brain Res. 2001;910:55–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Maguire JL, Stell BM, Rafizadeh M, Mody I. Ovarian cycle-linked changes in GABA(A) receptors mediating tonic inhibition alter seizure susceptibility and anxiety. Nat Neurosci. 2005;8:797–804.

    Article  CAS  PubMed  Google Scholar 

  59. Bäckström T, Das R, Bixo M. Positive GABAA receptor modulating steroids and their antagonists: Implications for clinical treatments. J Neuroendocrinol. 2022;34:e13013.

    Article  PubMed  Google Scholar 

  60. Timby E, Bäckström T, Nyberg S, Stenlund H, Wihlbäck AN, Bixo M. Women with premenstrual dysphoric disorder have altered sensitivity to allopregnanolone over the menstrual cycle compared to controls-a pilot study. Psychopharmacology. 2016;233:2109–17.

    Article  CAS  PubMed  Google Scholar 

  61. Bixo M, Ekberg K, Poromaa IS, Hirschberg AL, Jonasson AF, Andréen L, et al. Treatment of premenstrual dysphoric disorder with the GABAA receptor modulating steroid antagonist Sepranolone (UC1010)A randomized controlled trial. Psychoneuroendocrinology. 2017;80:46–55.

    Article  CAS  PubMed  Google Scholar 

  62. Maeng S, Zarate CA Jr. The role of glutamate in mood disorders: results from the ketamine in major depression study and the presumed cellular mechanism underlying its antidepressant effects. Curr Psychiatry Rep. 2007;9:467–74.

    Article  PubMed  Google Scholar 

  63. Thompson SM, Kallarackal AJ, Kvarta MD, Van Dyke AM, LeGates TA, Cai X. An excitatory synapse hypothesis of depression. Trends Neurosci. 2015;38:279–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Sanacora G, Yan Z, Popoli M. The stressed synapse 2.0: pathophysiological mechanisms in stress-related neuropsychiatric disorders. Nat Rev Neurosci. 2022;23:86–103.

    Article  CAS  PubMed  Google Scholar 

  65. Thompson SM. Plasticity of synapses and reward circuit function in the genesis and treatment of depression. Neuropsychopharmacology. 2023;48:90–103.

    Article  PubMed  Google Scholar 

  66. Brambilla P, Perez J, Barale F, Schettini G, Soares JC. GABAergic dysfunction in mood disorders. Mol Psychiatry. 2003;8:721–37.

    Article  CAS  PubMed  Google Scholar 

  67. Luscher B, Shen Q, Sahir N. The GABAergic deficit hypothesis of major depressive disorder. Mol Psychiatry. 2011;16:383–406.

    Article  CAS  PubMed  Google Scholar 

  68. Sanacora G, Gueorguieva R, Epperson CN, Wu YT, Appel M, Rothman DL, et al. Subtype-specific alterations of gamma-aminobutyric acid and glutamate in patients with major depression. Arch Gen Psychiatry. 2004;61:705–13.

    Article  CAS  PubMed  Google Scholar 

  69. Gabbay V, Mao X, Klein RG, Ely BA, Babb JS, Panzer AM, et al. Anterior cingulate cortex γ-aminobutyric acid in depressed adolescents: relationship to anhedonia. Arch Gen Psychiatry. 2012;69:139–49.

    Article  CAS  PubMed  Google Scholar 

  70. Ghosal S, Hare B, Duman RS. Prefrontal cortex GABAergic deficits and circuit dysfunction in the pathophysiology and treatment of chronic stress and depression. Curr Opin Behav Sci. 2017;14:1–8.

    Article  PubMed  PubMed Central  Google Scholar 

  71. Godlewska BR, Near J, Cowen PJ. Neurochemistry of major depression: a study using magnetic resonance spectroscopy. Psychopharmacology. 2015;232:501–7.

    Article  CAS  PubMed  Google Scholar 

  72. Mann JJ, Oquendo MA, Watson KT, Boldrini M, Malone KM, Ellis SP, et al. Anxiety in major depression and cerebrospinal fluid free gamma-aminobutyric acid. Depress Anxiety. 2014;31:814–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Prescot A, Sheth C, Legarreta M, Renshaw PF, McGlade E, Yurgelun-Todd D. Altered cortical GABA in female veterans with suicidal behavior: sex differences and clinical correlates. Chronic Stress. 2018;2:2470547018768771.

    Article  PubMed  PubMed Central  Google Scholar 

  74. Petty F, Kramer GL, Gullion CM, Rush AJ. Low plasma gamma-aminobutyric acid levels in male patients with depression. Biol Psychiatry. 1992;32:354–63.

    Article  CAS  PubMed  Google Scholar 

  75. Hasler G, van der Veen JW, Tumonis T, Meyers N, Shen J, Drevets WC. Reduced prefrontal glutamate/glutamine and gamma-aminobutyric acid levels in major depression determined using proton magnetic resonance spectroscopy. Arch Gen Psychiatry. 2007;64:193–200.

    Article  CAS  PubMed  Google Scholar 

  76. Bhagwagar Z, Wylezinska M, Jezzard P, Evans J, Boorman E, Matthews M., et al. Low GABA concentrations in occipital cortex and anterior cingulate cortex in medication-free, recovered depressed patients. Int J Neuropsychopharmacol. 2008;11:255–60.

    Article  CAS  PubMed  Google Scholar 

  77. Esel E, Kose K, Hacimusalar Y, Ozsoy S, Kula M, Candan Z, et al. The effects of electroconvulsive therapy on GABAergic function in major depressive patients. J ECT. 2008;24:224–8.

    Article  CAS  PubMed  Google Scholar 

  78. Karolewicz B, Maciag D, O’Dwyer G, Stockmeier CA, Feyissa AM, Rajkowska G. Reduced level of glutamic acid decarboxylase-67 kDa in the prefrontal cortex in major depression. Int J Neuropsychopharmacol. 2010;13:411–20.

    Article  CAS  PubMed  Google Scholar 

  79. Pehrson AL, Sanchez C. Altered gamma-aminobutyric acid neurotransmission in major depressive disorder: a critical review of the supporting evidence and the influence of serotonergic antidepressants. Drug Des Dev Ther. 2015;9:603–24.

    Article  CAS  Google Scholar 

  80. Merali Z, Du L, Hrdina P, Palkovits M, Faludi G, Poulter MO, et al. Dysregulation in the suicide brain: mRNA expression of corticotropin-releasing hormone receptors and GABA(A) receptor subunits in frontal cortical brain region. J Neurosci. 2004;24:1478–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Choudary PV, Molnar M, Evans SJ, Tomita H, Li JZ, Vawter MP, et al. Altered cortical glutamatergic and GABAergic signal transmission with glial involvement in depression. Proc Natl Acad Sci USA. 2005;102:15653–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Kugaya A, Sanacora G, Verhoeff NP, Fujita M, Mason GF, Seneca NM, et al. Cerebral benzodiazepine receptors in depressed patients measured with [123I]iomazenil SPECT. Biol Psychiatry. 2003;54:792–9.

    Article  CAS  PubMed  Google Scholar 

  83. Klumpers UM, Veltman DJ, Drent ML, Boellaard R, Comans EF, Meynen G, et al. Reduced parahippocampal and lateral temporal GABAA-[11C]flumazenil binding in major depression: preliminary results. Eur J Nucl Med Mol Imaging. 2010;37:565–74.

    Article  CAS  PubMed  Google Scholar 

  84. Cheetham SC, Crompton MR, Katona CL, Parker SJ, Horton RW. Brain GABAA/benzodiazepine binding sites and glutamic acid decarboxylase activity in depressed suicide victims. Brain Res. 1988;460:114–23.

    Article  CAS  PubMed  Google Scholar 

  85. Pandey GN, Conley RR, Pandey SC, Goel S, Roberts RC, Tamminga CA, et al. Benzodiazepine receptors in the post-mortem brain of suicide victims and schizophrenic subjects. Psychiatry Res. 1997;71:137–49.

    Article  CAS  PubMed  Google Scholar 

  86. de Aguiar Neto FS, Rosa JLG. Depression biomarkers using non-invasive EEG: a review. Neurosci Biobehav Rev. 2019;105:83–93.

    Article  PubMed  Google Scholar 

  87. Marcu GM, Szekely-Copîndean RD, Radu AM, Bucuță MD, Fleacă RS, Tănăsescu C, et al. Resting-state frontal, frontlateral, and parietal α asymmetry: a pilot study examining relations with depressive disorder type and severity. Front Psychol. 2023;14:1087081.

    Article  PubMed  PubMed Central  Google Scholar 

  88. Bajbouj M, Lisanby SH, Lang UE, Danker-Hopfe H, Heuser I, Neu P. Evidence for impaired cortical inhibition in patients with unipolar major depression. Biol Psychiatry. 2006;59:395–400.

    Article  PubMed  Google Scholar 

  89. Levinson AJ, Fitzgerald PB, Favalli G, Blumberger DM, Daigle M, Daskalakis ZJ. Evidence of cortical inhibitory deficits in major depressive disorder. Biol Psychiatry. 2010;67:458–64.

    Article  CAS  PubMed  Google Scholar 

  90. Jeng JS, Li CT, Lin HC, Tsai SJ, Bai YM, Su TP, et al. Antidepressant-resistant depression is characterized by reduced short- and long-interval cortical inhibition. Psychol Med. 2020;50:1285–91.

    Article  PubMed  Google Scholar 

  91. Castricum J, Birkenhager TK, Kushner SA, Elgersma Y, Tulen JHM. Cortical inhibition and plasticity in major depressive disorder. Front Psychiatry. 2022;13:777422.

    Article  PubMed  PubMed Central  Google Scholar 

  92. Lissemore JI, Mulsant BH, Rajji TK, Karp JF, Reynolds CF, Lenze EJ, et al. Cortical inhibition, facilitation and plasticity in late-life depression: effects of venlafaxine pharmacotherapy. J Psychiatry Neurosci. 2021;46:E88–96.

    Article  PubMed  PubMed Central  Google Scholar 

  93. Lipman RS, Covi L, Rickels K, McNair DM, Downing R, Kahn RJ, et al. Imipramine and chlordiazepoxide in depressive and anxiety disorders. I. Efficacy in depressed outpatients. Arch Gen Psychiatry. 1986;43:68–77.

    Article  CAS  PubMed  Google Scholar 

  94. Rickels K, London J, Fox I, Hassman H, Csanalosi I, Weise C. Adinazolam, diazepam, imipramine, and placebo in major depressive disorder: a controlled study. Pharmacopsychiatry. 1991;24:127–31.

    Article  CAS  PubMed  Google Scholar 

  95. Petty F, Trivedi MH, Fulton M, Rush AJ. Benzodiazepines as antidepressants: does GABA play a role in depression? Biol Psychiatry. 1995;38:578–91.

    Article  CAS  PubMed  Google Scholar 

  96. Lipman RS, Covi L, Rickels K, McNair DM, Downing R, Kahn RJ, et al. Imipramine and chlordiazepoxide in depressive and anxiety disorders: I. Efficacy in depressed outpatients. Arch Gen Psychiatry. 1986;43:68–77.

    Article  CAS  PubMed  Google Scholar 

  97. Birkenhäger TK, Moleman P, Nolen WA. Benzodiazepines for depression? A review of the literature. Int Clin Psychopharmacol. 1995;10:181–95.

    Article  PubMed  Google Scholar 

  98. Suppes T, Chisholm KA, Dhavale D, Frye MA, Altshuler LL, McElroy SL, et al. Tiagabine in treatment refractory bipolar disorder: a clinical case series. Bipolar Disord. 2002;4:283–9.

    Article  CAS  PubMed  Google Scholar 

  99. Carpenter LL, Schecter JM, Tyrka AR, Mello AF, Mello MF, Haggarty R, et al. Open-label tiagabine monotherapy for major depressive disorder with anxiety. J Clin Psychiatry. 2006;67:66–71.

    Article  CAS  PubMed  Google Scholar 

  100. Rosenthal M. Tiagabine for the treatment of generalized anxiety disorder: a randomized, open-label, clinical trial with paroxetine as a positive control. J Clin Psychiatry. 2003;64:1245–9.

    Article  CAS  PubMed  Google Scholar 

  101. Ring HA, Heller AJ, Farr IN, Reynolds EH. Vigabatrin: rational treatment for chronic epilepsy. J Neurol Neurosurg Psychiatry. 1990;53:1051–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Levinson DF, Devinsky O. Psychiatric adverse events during vigabatrin therapy. Neurology 1999;53:1503–11.

    Article  CAS  PubMed  Google Scholar 

  103. Gunduz-Bruce H, Silber C, Kaul I, Rothschild AJ, Riesenberg R, Sankoh AJ, et al. Trial of SAGE-217 in patients with major depressive disorder. N Engl J Med. 2019;381:903–11.

    Article  CAS  PubMed  Google Scholar 

  104. Ten Doesschate F, van Waarde JA, van Wingen GA. Non-superiority of zuranolone (SAGE-217) at the longer-term. J Affect Disord. 2021;291:329–30.

    Article  PubMed  Google Scholar 

  105. Meltzer-Brody S, Kanes SJ. Allopregnanolone in postpartum depression: role in pathophysiology and treatment. Neurobiol Stress. 2020;12:100212.

    Article  PubMed  PubMed Central  Google Scholar 

  106. Pennell KD, Woodin MA, Pennell PB. Quantification of neurosteroids during pregnancy using selective ion monitoring mass spectrometry. Steroids. 2015;95:24–31.

    Article  CAS  PubMed  Google Scholar 

  107. Maguire J, Mody I. GABA(A)R plasticity during pregnancy: relevance to postpartum depression. Neuron 2008;59:207–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Deligiannidis KM, Fales CL, Kroll-Desrosiers AR, Shaffer SA, Villamarin V, Tan Y, et al. Resting-state functional connectivity, cortical GABA, and neuroactive steroids in peripartum and peripartum depressed women: a functional magnetic resonance imaging and spectroscopy study. Neuropsychopharmacology. 2019;44:546–54.

    Article  CAS  PubMed  Google Scholar 

  109. Epperson CN, Rubinow DR, Meltzer-Brody S, Deligiannidis KM, Riesenberg R, Krystal AD, et al. Effect of brexanolone on depressive symptoms, anxiety, and insomnia in women with postpartum depression: Pooled analyses from 3 double-blind, randomized, placebo-controlled clinical trials in the HUMMINGBIRD clinical program. J Affect Disord. 2023;320:353–9.

    Article  CAS  PubMed  Google Scholar 

  110. Melzer-Brody S. Neuropsychopharmacology Reviews, 2024, In this issue.

  111. Deligiannidis KM, Meltzer-Brody S, Gunduz-Bruce H, Doherty J, Jonas J, Li S, et al. Effect of zuranolone vs placebo in postpartum depression: a randomized clinical trial. JAMA Psychiatry. 2021;78:951–9.

    Article  PubMed  Google Scholar 

  112. Melón L, Hammond R, Lewis M, Maguire J. A novel, synthetic, neuroactive steroid is effective at decreasing depression-like behaviors and improving maternal care in preclinical models of postpartum depression. Front Endocrinol. 2018;9:703.

    Article  Google Scholar 

  113. Manber R, Chambers AS. Insomnia and depression: a multifaceted interplay. Curr Psychiatry Rep. 2009;11:437–42.

    Article  PubMed  Google Scholar 

  114. Felder JN, Epel ES, Neuhaus J, Krystal AD, Prather AA. Randomized controlled trial of digital cognitive behavior therapy for prenatal insomnia symptoms: effects on postpartum insomnia and mental health. Sleep 2022;45:zsab280.

    Article  PubMed  Google Scholar 

  115. Smucny J, Dienel SJ, Lewis DA, Carter CS. Mechanisms underlying dorsolateral prefrontal cortex contributions to cognitive dysfunction in schizophrenia. Neuropsychopharmacology. 2022;47:292–308.

    Article  PubMed  Google Scholar 

  116. Dienel SJ, Schoonover KE, Lewis DA. Cognitive dysfunction and prefrontal cortical circuit alterations in schizophrenia: developmental trajectories. Biol Psychiatry. 2022;92:450–9.

    Article  PubMed  PubMed Central  Google Scholar 

  117. McCutcheon R, Beck K, Jauhar S, Howes OD. Defining the locus of dopaminergic dysfunction in schizophrenia: a meta-analysis and test of the mesolimbic hypothesis. Schizophr Bull. 2018;44:1301–11.

    Article  PubMed  Google Scholar 

  118. Beck K, Hindley G, Borgan F, Ginestet C, McCutcheon R, Brugger S, et al. Association of ketamine with psychiatric symptoms and implications for its therapeutic use and for understanding schizophrenia: a systematic review and meta-analysis. JAMA Netw Open. 2020;3:e204693.

    Article  PubMed  PubMed Central  Google Scholar 

  119. Powers AR 3rd, Gancsos MG, Finn ES, Morgan PT, Corlett PR. Ketamine-induced hallucinations. Psychopathology. 2015;48:376–85.

    Article  PubMed  Google Scholar 

  120. Widman AJ, McMahon LL. Disinhibition of CA1 pyramidal cells by low-dose ketamine and other antagonists with rapid antidepressant efficacy. Proc Natl Acad Sci USA. 2018;115:E3007–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Nugent AC, Ballard ED, Gould TD, Park LT, Moaddel R, Brutsche NE, et al. Ketamine has distinct electrophysiological and behavioral effects in depressed and healthy subjects. Mol Psychiatry. 2019;24:1040–52.

    Article  CAS  PubMed  Google Scholar 

  122. McNally JM, McCarley RW. Gamma band oscillations: a key to understanding schizophrenia symptoms and neural circuit abnormalities. Curr Opin Psychiatry. 2016;29:202–10.

    Article  PubMed  PubMed Central  Google Scholar 

  123. Baradits M, Kakuszi B, Bálint S, Fullajtár M, Mód L, Bitter I, et al. Alterations in resting-state gamma activity in patients with schizophrenia: a high-density EEG study. Eur Arch Psychiatry Clin Neurosci. 2019;269:429–37.

    Article  PubMed  Google Scholar 

  124. Yadav S, Haque Nizamie S, Das B, Das J, Tikka SK. Resting state quantitative electroencephalogram gamma power spectra in patients with first episode psychosis: An observational study. Asian J Psychiatr. 2021;57:102550.

    Article  PubMed  Google Scholar 

  125. Ahnaou A, Huysmans H, Van de Casteele T, Drinkenburg WHIM. Cortical high gamma network oscillations and connectivity: a translational index for antipsychotics to normalize aberrant neurophysiological activity. Transl Psychiatry. 2017;7:1285.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Kegeles LS, Abi-Dargham A, Zea-Ponce Y, Rodenhiser-Hill J, Mann JJ, Van Heertum RL, et al. Modulation of amphetamine-induced striatal dopamine release by ketamine in humans: implications for schizophrenia. Biol Psychiatry. 2000;48:627–40.

    Article  CAS  PubMed  Google Scholar 

  127. Kokkinou M, Irvine EE, Bonsall DR, Natesan S, Wells LA, Smith M, et al. Reproducing the dopamine pathophysiology of schizophrenia and approaches to ameliorate it: a translational imaging study with ketamine. Mol Psychiatry. 2021;26:2562–76.

    Article  CAS  PubMed  Google Scholar 

  128. Howes OD, Shatalina E. Integrating the Neurodevelopmental and Dopamine Hypotheses of Schizophrenia and the Role of Cortical Excitation-Inhibition Balance. Biol Psychiatry. 2022;92:501–13.

    Article  PubMed  Google Scholar 

  129. Abi-Dargham A, Laruelle M, Krystal J, D’Souza C, Zoghbi S, Baldwin RM, et al. No evidence of altered in vivo benzodiazepine receptor binding in schizophrenia. Neuropsychopharmacology. 1999;20:650–61.

    Article  CAS  PubMed  Google Scholar 

  130. Egerton A, Modinos G, Ferrera D, McGuire P. Neuroimaging studies of GABA in schizophrenia: a systematic review with meta-analysis. Transl Psychiatry. 2017;7:e1147.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Thompson M, Weickert CS, Wyatt E, Webster MJ. Decreased glutamic acid decarboxylase67 mRNA expression in multiple brain areas of patients with schizophrenia and mood disorders. J Psychiatr Res. 2009;43:970–7.

    Article  PubMed  Google Scholar 

  132. Lewis DA, Curley AA, Glausier JR, Volk DW. Cortical parvalbumin interneurons and cognitive dysfunction in schizophrenia. Trends Neurosci. 2012;35:57–67.

    Article  CAS  PubMed  Google Scholar 

  133. Glausier JR, Lewis DA. GABA and schizophrenia: Where we stand and where we need to go. Schizophr Res. 2017;181:2–3.

    Article  PubMed  PubMed Central  Google Scholar 

  134. Petryshen TL, Middleton FA, Tahl AR, Rockwell GN, Purcell S, Aldinger KA, et al. Genetic investigation of chromosome 5q GABAA receptor subunit genes in schizophrenia. Mol Psychiatry. 2005;10:1074–88.

    Article  CAS  PubMed  Google Scholar 

  135. Mirnics K, Middleton FA, Lewis DA, Levitt P. Analysis of complex brain disorders with gene expression microarrays: schizophrenia as a disease of the synapse. Trends Neurosci. 2001;24:479–86.

    Article  CAS  PubMed  Google Scholar 

  136. Hashimoto T, Arion D, Unger T, MaldonadoAvilés JG, Morris HM, Volk DW, et al. Alterations in GABA-related transcriptome in the dorsolateral prefrontal cortex of subjects with schizophrenia. Mol Psychiatry. 2008a;13:147–61.

    Article  CAS  PubMed  Google Scholar 

  137. Hashimoto T, Bazmi HH, Mirnics K, Wu Q, Sampson AR, Lewis DA. Conserved regional patterns of GABA-related transcript expression in the neocortex of subjects with schizophrenia. Am J Psychiatry. 2008b;165:479–89.

    Article  PubMed  PubMed Central  Google Scholar 

  138. Mueller TM, Remedies CE, Haroutunian V, Meador-Woodruff JH. Abnormal subcellular localization of GABAA receptor subunits in schizophrenia brain. Transl Psychiatry. 2015;5:e612.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Beneyto M, Abbott A, Hashimoto T, Lewis DA. Lamina-specific alterations in cortical GABA(A) receptor subunit expression in schizophrenia. Cereb Cortex. 2011;21:999–1011.

    Article  PubMed  Google Scholar 

  140. Rogasch NC, Daskalakis ZJ, Fitzgerald PB. Cortical inhibition, excitation, and connectivity in schizophrenia: a review of insights from transcranial magnetic stimulation. Schizophr Bull. 2014;40:685–96.

    Article  PubMed  Google Scholar 

  141. Noda Y, Barr MS, Zomorrodi R, Cash RFH, Farzan F, Rajji TK, et al. Evaluation of short interval cortical inhibition and intracortical facilitation from the dorsolateral prefrontal cortex in patients with schizophrenia. Sci Rep. 2017;7:17106.

    Article  PubMed  PubMed Central  Google Scholar 

  142. Li X, Honda S, Nakajima S, Wada M, Yoshida K, Daskalakis ZJ, et al. TMS-EEG research to elucidate the pathophysiological neural bases in patients with schizophrenia: a systematic review. J Pers Med. 2021;11:388.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Stimmel GL. Benzodiazepines in schizophrenia. Pharmacotherapy. 1996;16:148S–151S.

    Article  CAS  PubMed  Google Scholar 

  144. Enwright JF, Sanapala S, Foglio A, Berry R, Fish KN, Lewis DA. Reduced labeling of parvalbumin neurons and perineuronal nets in the dorsolateral prefrontal cortex of subjects with schizophrenia. Neuropsychopharmacology. 2016;41:2206–14.

    Article  PubMed  PubMed Central  Google Scholar 

  145. Dienel SJ, Lewis DA. Alterations in cortical interneurons and cognitive function in schizophrenia. Neurobiol Dis. 2019;131:104208.

    Article  PubMed  Google Scholar 

  146. Dienel SJ, Fish KN, Lewis DA. The nature of prefrontal cortical GABA neuron alterations in schizophrenia: markedly lower somatostatin and parvalbumin gene expression without missing neurons. Am J Psychiatry. 2023;180:495–507.

    Article  PubMed  PubMed Central  Google Scholar 

  147. Chung DW, Geramita MA, Lewis DA. Synaptic variability and cortical gamma oscillation power in schizophrenia. Am J Psychiatry. 2022;179:277–87.

    Article  PubMed  PubMed Central  Google Scholar 

  148. Buzsáki G, Wang XJ. Mechanisms of gamma oscillations. Annu Rev Neurosci. 2012;35:203–25.

    Article  PubMed  PubMed Central  Google Scholar 

  149. Asai Y, Takano A, Ito H, Okubo Y, Matsuura M, Otsuka A, et al. GABAA/Benzodiazepine receptor binding in patients with schizophrenia using [11C]Ro15-4513, a radioligand with relatively high affinity for alpha5 subunit. Schizophr Res. 2008;99:333–40.

    Article  PubMed  Google Scholar 

  150. Marques TR, Ashok AH, Angelescu I, Borgan F, Myers J, Lingford-Hughes A, et al. GABAA receptor differences in schizophrenia: a positron emission tomography study using [11C]Ro154513. Mol Psychiatry. 2021;26:2616–25.

    Article  CAS  PubMed  Google Scholar 

  151. Gill KM, Lodge DJ, Cook JM, Aras S, Grace AA. A novel α5GABA(A)R-positive allosteric modulator reverses hyperactivation of the dopamine system in the MAM model of schizophrenia. Neuropsychopharmacology. 2011;36:1903–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Perez SM, McCoy AM, Prevot TD, Mian MY, Carreno FR, Frazer A, et al. Hippocampal α5-GABAA receptors modulate dopamine neuron activity in the rat ventral tegmental area. Biol Psychiatry Glob Open Sci. 2022;3:78–86.

    Article  PubMed  PubMed Central  Google Scholar 

  153. Richetto J, Labouesse MA, Poe MM, Cook JM, Grace AA, Riva MA, et al. Behavioral effects of the benzodiazepine-positive allosteric modulator SH-053-2’F-S-CH3 in an immune-mediated neurodevelopmental disruption model. Int J Neuropsychopharmacol. 2015;18:pyu055.

    Article  PubMed  PubMed Central  Google Scholar 

  154. Puia G, Santi MR, Vicini S, Pritchett DB, Seeburg PH, Costa E. Differences in the negative allosteric modulation of γ-aminobutyric acid receptors elicited by 4’-chlorodiazepam and by a β-carboline-3-carboxylate ester: a study with natural and reconstituted receptors. Proc Natl Acad Sci USA. 1989;86:7275–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Venault P, Chapouthier G. From the behavioral pharmacology of β-carbolines to seizures, anxiety, and memory. Sci World J. 2007;7:204–23.

    Article  CAS  Google Scholar 

  156. Lingford-Hughes A, Hume SP, Feeney A, Hirani E, Osman S, Cunningham VJ, et al. Imaging the GABA-benzodiazepine receptor subtype containing the alpha 5-subunit in vivo with [11C]Ro15 4513 positron emission tomography. J Cereb Blood Flow Metab. 2002;22:878–89.

    Article  CAS  PubMed  Google Scholar 

  157. Myers JF, Comley RA, Gunn RN. Quantification of [11C]Ro15-4513 GABAAα5 specific binding and regional selectivity in humans. J Cereb Blood Flow Metab. 2017;37:2137–48.

    Article  CAS  PubMed  Google Scholar 

  158. Stefanits H, Milenkovic I, Mahr N, Pataraia E, Hainfellner JA, Kovacs GG, et al. GABAA receptor subunits in the human amygdala and hippocampus: Immunohistochemical distribution of 7 subunits. J Comp Neurol. 2018;526:324–48.

    Article  CAS  PubMed  Google Scholar 

  159. McGinnity CJ, Riaño Barros DA, Hinz R, Myers JF, Yaakub SN, Thyssen C, et al. Αlpha 5 subunit-containing GABAA receptors in temporal lobe epilepsy with normal MRI. Brain Commun. 2021;3:fcaa190.

    Article  PubMed  PubMed Central  Google Scholar 

  160. Sur C, Fresu L, Howell O, McKernan RM, Atack JR. Autoradiographic localization of alpha5 subunit-containing GABAA receptors in rat brain. Brain Res. 1999;822:265–70.

    Article  CAS  PubMed  Google Scholar 

  161. Fritschy JM, Panzanelli P. GABAA receptors and plasticity of inhibitory neurotransmission in the central nervous system. Eur J Neurosci. 2014;39:1845–65.

    Article  PubMed  Google Scholar 

  162. McKernan RM, Quirk K, Prince R, Cox PA, Gillard NP, Ragan CI, et al. GABAA receptor subtypes immunopurified from rat brain with alpha subunit-specific antibodies have unique pharmacological properties. Neuron. 1991;7:667–76.

    Article  CAS  PubMed  Google Scholar 

  163. Schulz JM, Knoflach F, Hernandez MC, Bischofberger J. Dendrite-targeting interneurons control synaptic NMDA-receptor activation via nonlinear α5-GABA A receptors. Nat Commun. 2018;9:3576.

    Article  PubMed  PubMed Central  Google Scholar 

  164. Towers SK, Gloveli T, Traub RD, Driver JE, Engel D, Fradley R, et al. Alpha5 subunit-containing GABAA receptors affect the dynamic range of mouse hippocampal kainate-induced gamma frequency oscillations in vitro. J Physiol. 2004;559:721–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Zanos P, Nelson ME, Highland JN, Krimmel SR, Georgiou P, Gould TD, et al. A negative allosteric modulator for α5 subunit-containing GABA receptors exerts a rapid and persistent antidepressant-like action without the side effects of the NMDA receptor antagonist ketamine in mice. eNeuro. 2017;4:ENEURO.0285–16.2017.

    Article  PubMed  Google Scholar 

  166. Troppoli TA, Zanos P, Georgiou P, Gould TD, Rudolph U, Thompson SM. Negative allosteric modulation of gammaaminobutyric acid a receptors at α5 subunit-containing benzodiazepine sites reverses stress-induced anhedonia and weakened synaptic function in mice. Biol Psychiatry. 2022;92:216–26.

    Article  CAS  PubMed  Google Scholar 

  167. Crestani F, Keist R, Fritschy J-M, Benke D, Vogt K, Prut L, et al. Trace fear conditioning involves hippocampal α5 GABAA receptors. Proc Natl Acad Sci USA. 2002;99:8980–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Yee BK, Hauser J, Dolgov VV, Keist R, Möhler H, Rudolph U, et al. GABA receptors containing the α5 subunit mediate the trace effect in aversive and appetitive conditioning and extinction of conditioned fear. Eur J Neurosci. 2004;20:1928–36.

    Article  PubMed  Google Scholar 

  169. Collinson N, Kuenzi FM, Jarolimek W, Maubach KA, Cothliff R, Sur C, et al. Enhanced learning and memory and altered GABAergic synaptic transmission in mice lacking the α5 subunit of the GABAA receptor. J Neurosci. 2002;22:5572–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Collinson N, Atack JR, Laughton P, Dawson GR, Stephens DN. An inverse agonist selective for α5 subunit-containing GABAA receptors improves encoding and recall but not consolidation in the Morris water maze. Psychopharmacol. 2006;188:619–28.

    Article  CAS  Google Scholar 

  171. Martínez-Cué C, Delatour B, Potier MC. Treating enhanced GABAergic inhibition in Down syndrome: use of GABA α5-selective inverse agonists. Neurosci Biobehav Rev. 2014;46:218–27.

    Article  PubMed  Google Scholar 

  172. Atack JR. GABAA receptor subtype-selective modulators. II. α5-selective inverse agonists for cognition enhancement. Curr Top Med Chem. 2011;11:1203–14.

    Article  CAS  PubMed  Google Scholar 

  173. Hipp JF, Knoflach F, Comley R, Ballard TM, Honer M, Trube G, et al. Basmisanil, a highly selective GABAA-α5 negative allosteric modulator: preclinical pharmacology and demonstration of functional target engagement in man. Sci Rep. 2021;11:7700.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Goeldner C, Kishnani PS, Skotko BG, Casero JL, Hipp JF, Derks M, et al. A randomized, double-blind, placebo-controlled phase II trial to explore the effects of a GABAA-α5 NAM (basmisanil) on intellectual disability associated with Down syndrome. J Neurodev Disord. 2022;14:10.

    Article  PubMed  PubMed Central  Google Scholar 

  175. Fischell J, Van Dyke AM, Kvarta MD, LeGates TA, Thompson SM. Rapid antidepressant action and restoration of excitatory synaptic strength after chronic stress by negative modulators of α5-containing GABAA receptors. Neuropsychopharmacology. 2015;40:2499–509.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Rudolph U, Crestani F, Benke D, Brunig I, Benson JA, Fritschy J-M, et al. Benzodiazepine actions mediated by specific γ-aminobutyric acid(A) receptor subtypes. Nature. 1999;401:796–800.

    Article  CAS  PubMed  Google Scholar 

  177. Cerne R, Lippa A, Poe MM, Smith JL, Jin X, Ping X, et al. GABAkines - Advances in the discovery, development, and commercialization of positive allosteric modulators of GABAA receptors. Pharmacol Ther. 2022;234:108035.

    Article  CAS  PubMed  Google Scholar 

  178. Möhler H. The rise of a new GABA pharmacology. Neuropharmacology, 2011;60:1042–9.

    Article  PubMed  Google Scholar 

  179. Atack JR. GABAA receptor subtype-selective modulators. I. α2/α3-selective agonists as non-sedating anxiolytics. Curr Top Med Chem. 2011;11:1176–202.

    Article  CAS  PubMed  Google Scholar 

  180. Engin E, Liu J, Rudolph U. α2-containing GABA(A) receptors: a target for the development of novel treatment strategies for CNS disorders. Pharmacol Ther. 2012;136:142–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Bialer M, Johannessen SI, Levy RH, Perucca E, Tomson T, White HS. Progress report on new antiepileptic drugs: a summary of the Thirteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XIII). Epilepsia 2017;58:181–221.

    Article  PubMed  Google Scholar 

  182. Atack JR. GABAA receptor α2/α3 subtype-selective modulators as potential nonsedating anxiolytics. Curr Top Behav Neurosci. 2010;2:331–60.

    Article  PubMed  Google Scholar 

  183. Lewis DA, Cho RY, Carter CS, Eklund K, Forster S, Kelly MA, et al. Subunit-selective modulation of GABA type A receptor neurotransmission and cognition in schizophrenia. Am J Psychiatry. 2008;165:1585–93.

    Article  PubMed  PubMed Central  Google Scholar 

  184. Buchanan RW, Keefe RS, Lieberman JA, Barch DM, Csernansky JG, Goff DC, et al. A randomized clinical trial of MK-0777 for the treatment of cognitive impairments in people with schizophrenia. Biol Psychiatry. 2011;69:442–9.

    Article  CAS  PubMed  Google Scholar 

  185. Atack JR, Wafford KA, Tye SJ, Cook SM, Sohal B, Pike A. et al. TPA023 [7-(1,1-dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine], an agonist selective for α2- and α3-containing GABAA receptors, is a nonsedating anxiolytic in rodents and primates. J Pharmacol Exp Ther. 2006;316:410–22.

    Article  CAS  PubMed  Google Scholar 

  186. Jensen ML, Wafford KA, Brown AR, Belelli D, Lambert JJ, Mirza NR. A study of subunit selectivity, mechanism and site of action of the delta selective compound 2 (DS2) at human recombinant and rodent native GABA(A) receptors. Br J Pharmacol. 2013;168:1118–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Genaro K, Yoshimura RF, Doan BP, Johnstone TB, Hogenkamp DJ, Gee KW. Allosteric modulators of the δ GABAA receptor subtype demonstrate a therapeutic effect in morphine-antinociceptive tolerance and withdrawal in mice. Neuropharmacology. 2022;219:109221.

    Article  CAS  PubMed  Google Scholar 

  188. Gee KW, Tran MB, Hogenkamp DJ, Johnstone TB, Bagnera RE, Yoshimura RF, et al. Limiting activity at beta1-subunit-containing GABAA receptor subtypes reduces ataxia. J Pharmacol Exp Ther. 2010;332:1040–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Zanos P, Thompson SM, Duman RS, Zarate CA Jr, Gould TD. Convergent mechanisms underlying rapid antidepressant action. CNS Drugs. 2018;32:197–227.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

I am grateful to the members of my laboratory and my collaborators who have taught me much about both GABA actions and drug development, Drs. J. Atack, R. Berman, J. Fischell, T. Gould, M. Kvarta, T. LeGates, T. Troppoli, and P. Zanos. Portions of my work with α5 NAMs have been supported by the Kahlert Foundation and the NIH (R01 MH086828).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Scott M. Thompson.

Ethics declarations

Competing interests

The University of Maryland Baltimore has patents, on which I am listed as an inventor, covering the use of α5-selective NAMs to treat psychiatric disease.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Thompson, S.M. Modulators of GABAA receptor-mediated inhibition in the treatment of neuropsychiatric disorders: past, present, and future. Neuropsychopharmacol. 49, 83–95 (2024). https://doi.org/10.1038/s41386-023-01728-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41386-023-01728-8

Search

Quick links