Beyond classical benzodiazepines: novel therapeutic potential of GABAA receptor subtypes

Rudolph, Uwe; Knoflach, Frédéric

doi:10.1038/nrd3502

Cited by 745Neuroscience and Neuropharmacology ResearchNicotinic Acetylcholine Receptors StudyEpilepsy research and treatment

Beyond classical benzodiazepines: novel therapeutic potential of GABAA receptor subtypes

Open access

Rudolph, Uwe, Knoflach, Frédéric·2011·Nature Reviews Drug Discovery

DOI 10.1038/nrd3502PMC PMC3375401

Open this paper in CoChat — free account

Abstract

GABAA (γ-aminobutyric acid, type A) receptors are a family of ligand-gated ion channels that are essential for the regulation of central nervous system function. Benzodiazepines — which non-selectively target GABAA receptors containing the α1, α2, α3 or α5 subunits — have been in clinical use for decades and are still among the most widely prescribed drugs for the treatment of insomnia and anxiety disorders. However, their use is limited by side effects and the risk of drug dependence. In the past decade, the identification of separable key functions of GABAA receptor subtypes suggests that receptor subtype-selective compounds could overcome the limitations of classical benzodiazepines; furthermore, they might be valuable for novel indications such as chronic pain, depression, schizophrenia, cognitive enhancement and stroke.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

Integrity signals

Registry

Crossref · 10.1038/nrd3502

Cites

111 of 112 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Benzodiazepines enhance the effect of GABA on GABAA receptors.
“Since benzodiazepines enhance the effect of GABA on GABAA receptors 72 ,”
From Developmental timing and critical windows for the treatment of psychiatric disorders (2016) · cites this paper as [72]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

International Union of Pharmacology: Approaches to the Nomenclature of Voltage-Gated Ion Channels
Catterall, W. A., Chandy, K. G., Clapham, D. E., Gutman, G. A., Hofmann, F., Harmar, A. J., Abernethy, D. R., & Spedding, M. (2003) · Pharmacological Reviews · doi:10.1124/pr.55.4.5 · Cited by 7,126 · see citing works
Cortical inhibitory neurons and schizophrenia
Lewis, D. A., Hashimoto, T., & Volk, D. W. (2005) · Nature Reviews Neuroscience · doi:10.1038/nrn1648 · Cited by 2,297 · cited 1× · see citing works
“In post-mortem brain from patients with schizophrenia, there is an upregulation of the α2 subunit in the axon initial segments of these pyramidal neuron”
Background
Benzodiazepine Receptor: Demonstration in the Central Nervous System
Möhler, H., & Okada, T. (1977) · Science · doi:10.1126/science.918669 · Cited by 1,709 · cited 1× · see citing works
“Benzodiazepines have been shown to bind to specific sites in the central nervous syste”
Background
New approaches to antidepressant drug discovery: beyond monoamines
Berton, O., & Nestler, E. J. (2006) · Nature Reviews Neuroscience · doi:10.1038/nrn1846 · Cited by 1,589 · cited 1× · see citing works
“Although there is tremendous interest in developing antidepressant agents that utilize different mechanisms of action, the development of such agents has not yet been successfu”
Background
Benzodiazepine receptors in rat brain
Squires, R. F., & Bræstrup, C. (1977) · Nature · doi:10.1038/266732a0 · Cited by 1,453 · see citing works
GABAA receptors: immunocytochemical distribution of 13 subunits in the adult rat brain
Pirker, S., Schwarzer, C., Wieselthaler, A., Sieghart, W., & Sperk, G. (2000) · Neuroscience · doi:10.1016/s0306-4522(00)00442-5 · Cited by 1,344 · see citing works
GABA A ‐receptor heterogeneity in the adult rat brain: Differential regional and cellular distribution of seven major subunits
Fritschy, J., & Mohler, H. (1995) · Journal of Comparative Neurology · doi:10.1002/cne.903590111 · Cited by 1,244 · see citing works
Benzodiazepine actions mediated by specific γ-aminobutyric acidA receptor subtypes
Rudolph, U., Crestani, F., Benke, D., Brünig, I., Benson, J. A., Fritschy, J.-M., Martin, J. R., Bluethmann, H., & Möhler, H. (1999) · Nature · doi:10.1038/44579 · Cited by 1,172 · see citing works
Self-citation
International Union of Pharmacology. LXX. Subtypes of γ-Aminobutyric AcidA Receptors: Classification on the Basis of Subunit Composition, Pharmacology, and Function. Update
Olsen, R. W., & Sieghart, W. (2008) · Pharmacological Reviews · doi:10.1124/pr.108.00505 · Cited by 1,064 · see citing works
Regulation of firing of dopaminergic neurons and control of goal-directed behaviors
Grace, A. A., Floresco, S. B., Goto, Y., & Lodge, D. J. (2007) · Trends in Neurosciences · doi:10.1016/j.tins.2007.03.003 · Cited by 1,034 · cited 1× · see citing works
“, activates tonic firing of dopaminergic neurons in the midbrain; this circuit involves glutamatergic neurons in the hippocampus, GABAergic neurons in the nucleus accumbens and GABAergic neurons in the ventral pallidu”
Background
Circuit-based framework for understanding neurotransmitter and risk gene interactions in schizophrenia
Lisman, J. E., Coyle, J. T., Green, R. W., Javitt, D. C., Benes, F. M., Heckers, S., & Grace, A. A. (2008) · Trends in Neurosciences · doi:10.1016/j.tins.2008.02.005 · Cited by 1,010 · cited 1× · see citing works
“, activates tonic firing of dopaminergic neurons in the midbrain; this circuit involves glutamatergic neurons in the hippocampus, GABAergic neurons in the nucleus accumbens and GABAergic neurons in the ventral pallidu”
Background
GABAA receptors: Subtypes provide diversity of function and pharmacology
Olsen, R. W., & Sieghart, W. (2008) · Neuropharmacology · doi:10.1016/j.neuropharm.2008.07.045 · Cited by 986 · see citing works
Molecular and neuronal substrate for the selective attenuation of anxiety
Löw, K., Crestani, F., Keist, R., Benke, D., Brünig, I., Benson, J. A., Fritschy, J.-M., Rülicke, T., Bluethmann, H., Möhler, H., et al. (2000) · Science · doi:10.1126/science.290.5489.131 · Cited by 946 · cited 1× · see citing works
“Histidine-to-arginine point mutations at a conserved residue in the α1, α2, α3 or α5 subunit abolish binding of diazepam, whereas the action of the physiological neurotransmitter GABA is preserve”
BackgroundSelf-citation
Sedative but not anxiolytic properties of benzodiazepines are mediated by the GABAA receptor α1 subtype
McKernan, R. M., Rosahl, T. W., Reynolds, D. S., Sur, C., Wafford, K. A., Atack, J. R., Farrar, S., Myers, J., Cook, G., Ferris, P., et al. (2000) · Nature Neuroscience · doi:10.1038/75761 · Cited by 944 · see citing works
The GABAergic deficit hypothesis of major depressive disorder
Luscher, B., Shen, Q., & Sahir, N. (2011) · Molecular Psychiatry · doi:10.1038/mp.2010.120 · Cited by 934 · see citing works
Reducing excessive GABA-mediated tonic inhibition promotes functional recovery after stroke
Clarkson, A. N., Huang, B. S., MacIsaac, S. E., Mody, I., & Carmichael, S. T. (2010) · Nature · doi:10.1038/nature09511 · Cited by 869 · see citing works
Molecular and neuronal substrates for general anaesthetics
Rudolph, U., & Antkowiak, B. (2004) · Nature reviews. Neuroscience · doi:10.1038/nrn1496 · Cited by 771 · see citing works
Self-citation
A new benzodiazepine pharmacology
Möhler, H., Fritschy, J. M., & Rudolph, U. (2002) · The Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.300.1.2 · Cited by 716 · see citing works
Self-citation
Variations in GABRA2, Encoding the α2 Subunit of the GABAA Receptor, Are Associated with Alcohol Dependence and with Brain Oscillations
Edenberg, H. J., Dick, D. M., Xuei, X., Tian, H., Almasy, L., Bauer, L. O., Crowe, R. R., Goate, A., Hesselbrock, V., Jones, K., et al. (2004) · The American Journal of Human Genetics · doi:10.1086/383283 · Cited by 655 · see citing works
The ‘ABC’ of GABA receptors
Bormann, J. (2000) · Trends in Pharmacological Sciences · doi:10.1016/s0165-6147(99)01413-3 · Cited by 629 · see citing works
Enhanced Learning and Memory and Altered GABAergic Synaptic Transmission in Mice Lacking the α5 Subunit of the GABA A Receptor
Collinson, N., Kuenzi, F. M., Jarolimek, W., Maubach, K. A., Cothliff, R., Sur, C., Smith, A., Otu, F. M., Howell, O., Atack, J. R., et al. (2002) · The Journal of Neuroscience · doi:10.1523/jneurosci.22-13-05572.2002 · Cited by 628 · see citing works
SEVERE ANXIETY INDUCED BY FG 7142, A β-CARBOLINE LIGAND FOR BENZODIAZEPINE RECEPTORS
Dorow, R., Horowski, R., Paschelke, G., Amin, M., & Bræstrup, C. (1983) · The Lancet · doi:10.1016/s0140-6736(83)90076-4 · Cited by 580 · cited 1× · see citing works
“Importantly, none of these α5-containing receptor selective drugs displays the convulsant and anxiogenic activities of the non-selective GABA A receptor inverse agonists FG-7142, DMCM (methyl-6,7-dimethoxy-4-ethyl-β-carboline-3-carboxylate) or β-CCM (methyl β-carboline-3-carboxylate), which are not used therapeuticall”
Background
General anesthetic actions in vivo strongly attenuated by a point mutation in the GABA A receptor β3 subunit
Jurd, R., Arrasa, M., Lambert, S., Drexler, B., Siegwart, R., Crestani, F., Zaugg, M., Vogt, K. E., Ledermann, B., Antkowiak, B., et al. (2003) · The FASEB Journal · doi:10.1096/fj.02-0611fje · Cited by 558 · see citing works
Self-citation
Decreased GABAA-receptor clustering results in enhanced anxiety and a bias for threat cues
Crestani, F., Lorez, M., Baer, K., Essrich, C., Benke, D., Laurent, J. P., Belzung, C., Fritschy, J.-M., Lüscher, B., & Mohler, H. (1999) · Nature Neuroscience · doi:10.1038/12207 · Cited by 550 · cited 1× · see citing works
“In addition, heterozygous γ2 ( Gabrg2 ) knockout mice display an anxiety-like phenotype in tests of unconditioned anxiet”
Background
Interaction of Convulsive Ligands with Benzodiazepine Receptors
Bræstrup, C., Schmiechen, R., Neef, G., et al. (1982) · Science · doi:10.1126/science.6281892 · Cited by 547 · cited 1× · see citing works
“Benzodiazepines have been shown to bind to specific sites in the central nervous syste”
Background
Trace fear conditioning involves hippocampal α 5 GABA A receptors
Crestani, F., Keist, R., Fritschy, J.-M., Benke, D., Vogt, K., Prut, L., Blüthmann, H., Möhler, H., & Rudolph, U. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.142288699 · Cited by 528 · cited 1× · see citing works
“Histidine-to-arginine point mutations at a conserved residue in the α1, α2, α3 or α5 subunit abolish binding of diazepam, whereas the action of the physiological neurotransmitter GABA is preserve”
BackgroundSelf-citation
γ‐Aminobutyric AcidA Receptor α5‐Subunit Creates Novel Type II Benzodiazepine Receptor Pharmacology
Pritchett, D. B., & Seeburg, P. H. (1990) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.1990.tb01237.x · Cited by 503 · cited 1× · see citing works
“Zolpidem, which is an imidazopyridine, has a high affinity for α1-containing GABA A receptors, a 20-fold lower affinity for α2-containing GABA A receptors and α3-containing GABA A receptors, and no affinity for α5-containing GABA A receptor”
Background
GABAA receptor subtypes: dissecting their pharmacological functions
Rudolph, U., Crestani, F., & Möhler, H. (2001) · Trends in Pharmacological Sciences · doi:10.1016/s0165-6147(00)01646-1 · Cited by 472 · see citing works
Self-citation
Specific GABA A Circuits for Visual Cortical Plasticity
Fagiolini, M., Fritschy, J.-M., Löw, K., Möhler, H., Rudolph, U., & Hensch, T. K. (2004) · Science · doi:10.1126/science.1091032 · Cited by 471 · see citing works
Self-citation
Reversal of pathological pain through specific spinal GABAA receptor subtypes
Knabl, J., Witschi, R., Hösl, K., Reinold, H., Zeilhofer, U. B., Ahmadi, S., Brockhaus, J., Sergejeva, M., Hess, A., Brune, K., et al. (2008) · Nature · doi:10.1038/nature06493 · Cited by 438 · cited 1× · see citing works
“When diazepam is administered intrathecally in α2(H101R) and α3(H126R) mice, its antihyperalgesic action is significantly reduced in models of inflammatory pain and of neuropathic pain, demonstrating that spinal α2- and α3-containing GABA A receptors are mediating the antihyperalgesic actions of intrathecal diazepa”
BackgroundSelf-citation
Stuck in a rut: rethinking depression and its treatment
Holtzheimer, P. E., & Mayberg, H. S. (2010) · Trends in Neurosciences · doi:10.1016/j.tins.2010.10.004 · Cited by 431 · cited 1× · see citing works
“Currently available antidepressant medications act on the serotonergic and/or noradrenergic systems, but the response rate (defined as >50% decrease in depression severity from baseline) is only approximately 60”
Background
Neural bases for addictive properties of benzodiazepines
Tan, K. R., Brown, M., Labouèbe, G., Yvon, C., Creton, C., Fritschy, J.-M., Rudolph, U., & Lüscher, C. (2010) · Nature · doi:10.1038/nature08758 · Cited by 397 · cited 1× · see citing works
“, and their addictive properties have been linked to α1-containing GABA A receptor”
BackgroundSelf-citation
Hooked on benzodiazepines: GABAA receptor subtypes and addiction
Tan, K. R., Rudolph, U., & Lüscher, C. (2011) · Trends in Neurosciences · doi:10.1016/j.tins.2011.01.004 · Cited by 363 · see citing works
Self-citation
Co-localization of GABAA receptors and benzodiazepine receptors in the brain shown by monoclonal antibodies
Schoch, P., Richards, J. G., Häring, P., et al. (1985) · Nature · doi:10.1038/314168a0 · Cited by 316 · see citing works
GABA A receptor α4 subunits mediate extrasynaptic inhibition in thalamus and dentate gyrus and the action of gaboxadol
Chandra, D., Jia, F., Liang, J., Peng, Z., Suryanarayanan, A., Werner, D. F., Spigelman, I., Houser, C. R., Olsen, R. W., Harrison, N. L., et al. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0604304103 · Cited by 315 · cited 1× · see citing works
“In mice, it induces sedation largely via α4-containing GABA A receptor”
Background
Cognitive and sedative effects of benzodiazepine use
Buffett-Jerrott, S., & Stewart, S. (2002) · Current Pharmaceutical Design · doi:10.2174/1381612023396654 · Cited by 312 · cited 1× · see citing works
“Several studies in animals and humans have suggested that classical benzodiazepines can impair learning and memor”
Background
Mechanism of action of the hypnotic zolpidem in vivo
Crestani, F., Martin, J. R., Möhler, H., & Rudolph, U. (2000) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0703717 · Cited by 307 · cited 1× · see citing works
“Indeed, in α1(H101R) mice the motor sedative action of zolpidem was abolished, which demonstrates that the sedative action of zolpidem is mediated by α1-containing GABA A receptor”
BackgroundSelf-citation
The Role of GABA in the Mediation and Perception of Pain
Enna, S. J., & McCarson, K. E. (2006) · Advances in pharmacology · doi:10.1016/s1054-3589(06)54001-3 · Cited by 288 · cited 1× · see citing works
“Benzodiazepines are generally not considered to be analgesic agents as they lack clear efficacy when given systemically in human”
Background
Subunit-Selective Modulation of GABA Type A Receptor Neurotransmission and Cognition in Schizophrenia
Lewis, D. A., Cho, R. Y., Carter, C. S., Eklund, K. E., Förster, S., Kelly, M. A., & Montrose, D. M. (2008) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2008.08030395 · Cited by 286 · cited 1× · see citing works
“Some cognitive functions were improved with TPA023 treatmen”
Background
Allelic and haplotypic association of GABRA2 with alcohol dependence
Covault, J., Gelernter, J., Hesselbrock, V., Nellissery, M., & Kranzler, H. R. (2004) · American Journal of Medical Genetics Part B Neuropsychiatric Genetics · doi:10.1002/ajmg.b.30091 · Cited by 273 · see citing works
Mutations in GABAAreceptor subunits associated with genetic epilepsies
Macdonald, R. L., Kang, J., & Gallagher, M. J. (2010) · The Journal of Physiology · doi:10.1113/jphysiol.2010.186999 · Cited by 263 · see citing works
GABAergic dysfunction in schizophrenia: new treatment strategies on the horizon
Guidotti, A., Auta, J., Davis, J. M., Dong, E., Grayson, D. R., Veldic, M., Zhang, X., & Costa, E. (2005) · Psychopharmacology · doi:10.1007/s00213-005-2212-8 · Cited by 262 · see citing works
DOG BITES IN CHILDREN
Lillington, A. W., & Ross, M. (1976) · The Lancet · doi:10.1016/s0140-6736(76)92316-3 · Cited by 261 · see citing works
The Mechanistic Classification of Addictive Drugs
Lüscher, C., & Ungless, M. A. (2006) · PLoS Medicine · doi:10.1371/journal.pmed.0030437 · Cited by 255 · cited 1× · see citing works
“All addictive drugs increase dopamine levels in the mesolimbic dopamine syste”
Background
Evidence for a Significant Role of α3-Containing GABAAReceptors in Mediating the Anxiolytic Effects of Benzodiazepines
Dias, R., Sheppard, W. F. A., Fradley, R. L., Garrett, E. M., Stanley, J. L., Tye, S. J., Goodacre, S., Lincoln, R. J., Cook, S. M., Conley, R., et al. (2005) · The Journal of Neuroscience · doi:10.1523/jneurosci.1166-05.2005 · Cited by 247 · cited 1× · see citing works
“2a ), which has been described to have a selective efficacy at recombinant α3-containing GABA A receptors in vitro , is anxiolytic in the elevated plus maze test in rat”
Background
Molecular Targets for the Myorelaxant Action of Diazepam
Crestani, F., Löw, K., Keist, R., Mandelli, M.-J., Möhler, H., & Rudolph, U. (2001) · Molecular Pharmacology · doi:10.1124/mol.59.3.442 · Cited by 239 · cited 1× · see citing works
“In α2(H101R) mice, the anxiolytic-like action of diazepam was absent and its myorelaxant action (which is observed at higher doses than the anxiolytic-like action) was reduced, whereas the sedative action was presen”
BackgroundSelf-citation
Diazepam-induced changes in sleep: Role of the α1 GABA A receptor subtype
Tobler, I., Kopp, C., Deboer, T., & Rudolph, U. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.111055398 · Cited by 230 · see citing works
Self-citation
Different GABA A receptor subtypes mediate the anxiolytic, abuse-related, and motor effects of benzodiazepine-like drugs in primates
Rowlett, J. K., Platt, D. M., Lelas, S., Atack, J. R., & Dawson, G. R. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0405621102 · Cited by 212 · see citing works
GABAergic Control of Adult Hippocampal Neurogenesis in Relation to Behavior Indicative of Trait Anxiety and Depression States
Earnheart, J. C., Schweizer, C., Crestani, F., Iwasato, T., Itohara, S., Mohler, H., & Lüscher, B. (2007) · The Journal of Neuroscience · doi:10.1523/jneurosci.3609-06.2007 · Cited by 203 · cited 1× · see citing works
“and a depressive-like phenotype in conflict- and despair-based test”
Background
GABAB receptors: synaptic functions and mechanisms of diversity
Ulrich, D., & Bettler, B. (2007) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2007.04.001 · Cited by 201 · see citing works
A schizophrenia-related sensorimotor deficit links α3-containing GABA A receptors to a dopamine hyperfunction
Yee, B. K., Keist, R., von Boehmer, L., Studer, R., Benke, D., Hagenbuch, N., Dong, Y., Malenka, R. C., Fritschy, J.-M., Bluethmann, H., et al. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0508752102 · Cited by 201 · cited 1× · see citing works
“α3 knockout mice and α5(H105R) partial knockout mice with a reduced expression of the α5 subunit display deficits in sensorimotor gating, as determined by prepulse inhibition of acoustic startle, supporting a potential involvement of α3- and α5-containing GABA A receptors in the pathophysiology of schizophreni”
BackgroundSelf-citation
Construct Validity of the Animal Latent Inhibition Model of Selective Attention Deficits in Schizophrenia
Lubow, R. E. (2005) · Schizophrenia Bulletin · doi:10.1093/schbul/sbi005 · Cited by 191 · cited 1× · see citing works
“Deficits in this form of learning have also been described in schizophreni”
Background
Association of GABRA2 with drug dependence in the collaborative study of the genetics of alcoholism sample
Agrawal, A., Edenberg, H. J., Foroud, T., Bierut, L. J., Dunne, G., Hinrichs, A. L., Nurnberger, J. I., Crowe, R., Kuperman, S., Schuckit, M. A., et al. (2006) · Behavior Genetics · doi:10.1007/s10519-006-9069-4 · Cited by 189 · see citing works
TPA023 [7-(1,1-Dimethylethyl)-6-(2-ethyl-2 H-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
Atack, J. R., Wafford, K. A., Tye, S. J., Cook, S. M., Sohal, B., Pike, A., Sur, C., Melillo, D., Bristow, L., Bromidge, F., et al. (2006) · The Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.105.089920 · Cited by 188 · see citing works
L-655,708 enhances cognition in rats but is not proconvulsant at a dose selective for α5-containing GABAA receptors
Atack, J. R., Bayley, P. J., Seabrook, G. R., Wafford, K. A., McKernan, R. M., & Dawson, G. R. (2006) · Neuropharmacology · doi:10.1016/j.neuropharm.2006.04.018 · Cited by 175 · cited 1× · see citing works
“L-655708 also enhanced performance in the Morris water maze during acquisition and in a probe tria”
Background
A randomized clinical trial of MK-0777 for the treatment of cognitive impairments in people with schizophrenia
Buchanan, R. W., Keefe, R. S. E., Lieberman, J. A., Barch, D. M., Csernansky, J. G., Goff, D. C., Gold, J. M., Green, M. F., Jarskog, L. F., Javitt, D. C., et al. (2011) · Biological Psychiatry · doi:10.1016/j.biopsych.2010.09.052 · Cited by 172 · cited 1× · see citing works
“However, a follow-up study including 60 patients, with some of the same tests, did not confirm these result”
Result
A Novel α5GABAAR-Positive Allosteric Modulator Reverses Hyperactivation of the Dopamine System in the MAM Model of Schizophrenia
Gill, K., Lodge, D., Cook, J., Aras, S., & Grace, A. (2011) · Neuropsychopharmacology · doi:10.1038/npp.2011.76 · Cited by 170 · see citing works
Specific Subtypes of GABA A Receptors Mediate Phasic and Tonic Forms of Inhibition in Hippocampal Pyramidal Neurons
Prenosil, G., Gasser, E. M. S., Rudolph, U., Keist, R., Fritschy, J., & Vogt, K. E. (2006) · Journal of Neurophysiology · doi:10.1152/jn.01199.2005 · Cited by 169 · cited 1× · see citing works
“(and are therefore extrasynaptic (see also Box 1 )) and mediate both tonic and slow phasic inhibitio”
BackgroundSelf-citation
RO4938581, a novel cognitive enhancer acting at GABAA α5 subunit-containing receptors
Ballard, T. M., Knoflach, F., Prinssen, E. P. M., Borroni, E., Vivian, J. A., Basile, J., Gasser, R., Moreau, J., Wettstein, J. G., Buettelmann, B., et al. (2008) · Psychopharmacology · doi:10.1007/s00213-008-1357-7 · Cited by 156 · cited 1× · see citing works
“Prototypes for drugs with binding selectivity are RO4938581 (Ref”
BackgroundSelf-citation
Requirement of α5-GABAAReceptors for the Development of Tolerance to the Sedative Action of Diazepam in Mice
van Rijnsoever, C., Täuber, M., Choulli, M. K., Keist, R., Rudolph, U., Mohler, H., Fritschy, J. M., & Crestani, F. (2004) · The Journal of Neuroscience · doi:10.1523/jneurosci.1067-04.2004 · Cited by 144 · cited 1× · see citing works
“Moreover, the development of tolerance to the sedative action of benzodiazepines has been linked to α5-containing GABA A receptor”
BackgroundSelf-citation
Benzodiazepines on trial: a research strategy for their rehabilitation
Costa, E., & Guidetti, A. (1996) · Trends in Pharmacological Sciences · doi:10.1016/0165-6147(96)10015-8 · Cited by 143 · see citing works
Benzodiazepines as antidepressants: Does GABA play a role in depression?
Petty, F., Trivedi, M. H., Fulton, M., & Rush, A. J. (1995) · Biological Psychiatry · doi:10.1016/0006-3223(95)00049-7 · Cited by 143 · cited 1× · see citing works
“Moreover, clinical studies have revealed that the benzodiazepines alprazolam and adinazolam elicit antidepressant responses that are similar to those elicited by widely prescribed antidepressants in patients with major depressive disorde”
Background
γ-Aminobutyric Acid-Type A Receptor Deficits Cause Hypothalamic-Pituitary-Adrenal Axis Hyperactivity and Antidepressant Drug Sensitivity Reminiscent of Melancholic Forms of Depression
Shen, Q., Lal, R., Luellen, B. A., Earnheart, J. C., Andrews, A. M., & Luscher, B. (2010) · Biological Psychiatry · doi:10.1016/j.biopsych.2010.04.024 · Cited by 139 · cited 1× · see citing works
“These mice also have elevated baseline cortico-sterone concentration”
Background
Strong genetic evidence for a selective influence of GABAA receptors on a component of the bipolar disorder phenotype
Craddock, N. J., Jones, L. A., Jones, I. R., Kirov, G., Green, E., Grozeva, D., Moskvina, V., Nikolov, I., Hamshere, M. L., Vukcevic, D., et al. (2008) · Molecular Psychiatry · doi:10.1038/mp.2008.66 · Cited by 134 · see citing works
Benzodiazepine Prescribing to the Swiss Adult Population: Results from a National Survey of Community Pharmacies
Petitjean, S., Ladewig, D., Meier, C. R., Amrein, R., & Wiesbeck, G. A. (2007) · International Clinical Psychopharmacology · doi:10.1097/yic.0b013e328105e0f2 · Cited by 132 · see citing works
GABAA receptors containing the α5 subunit mediate the trace effect in aversive and appetitive conditioning and extinction of conditioned fear
Yee, B. K., Hauser, J., Dolgov, V. V., Keist, R., Möhler, H., Rudolph, U., & Feldon, J. (2004) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2004.03642.x · Cited by 132 · see citing works
Self-citation
Genetic investigation of chromosome 5q GABAA receptor subunit genes in schizophrenia
Petryshen, T. L., Middleton, F. A., Tahl, A. R., Rockwell, G. N., Purcell, S., Aldinger, K. A., Kirby, A. W., Morley, C. P., McGann, L., Gentile, K. L., et al. (2005) · Molecular Psychiatry · doi:10.1038/sj.mp.4001739 · Cited by 131 · see citing works
Effects of benzodiazepine microinjection into the amygdala or periaqueductal gray on the expression of conditioned fear and hypoalgesia in rats.
Harris, J. A., & Westbrook, R. F. (1995) · Behavioral Neuroscience · doi:10.1037//0735-7044.109.2.295 · Cited by 126 · cited 1× · see citing works
“Central GABA A receptors, such as those in the periaqueductal grey (PAG), an area known to be involved in the regulation of descending antinociceptive tracts, are pro-nociceptive at supraspinal site”
Background
Selective anxiolysis produced by ocinaplon, a GABA A receptor modulator
LIPPA, A. S., Czobor, P., Stark, J., Beer, B., Kostakis, E., Gravielle, M. C., Bandyopadhyay, S., Russek, S. J., Gibbs, T. T., Farb, D. H., et al. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0502579102 · Cited by 125 · see citing works
Positioning of the α-subunit isoforms confers a functional signature to γ-aminobutyric acid type A receptors
Minier, F., & Sigel, E. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0400220101 · Cited by 116 · see citing works
GABAergic analgesia: new insights from mutant mice and subtype-selective agonists
Zeilhofer, H. U., Möhler, H., & Lio, A. D. (2009) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2009.05.007 · Cited by 116 · see citing works
Preclinical and clinical pharmacology of the GABAA receptor α5 subtype-selective inverse agonist α5IA
Atack, J. R. (2009) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2009.09.001 · Cited by 116 · see citing works
The Missing P in Psychiatric Training
Elman, I., Zubieta, J.-K., & Borsook, D. (2011) · Archives of General Psychiatry · doi:10.1001/archgenpsychiatry.2010.174 · Cited by 115 · see citing works
The rise of a new GABA pharmacology
Möhler, H. (2010) · Neuropharmacology · doi:10.1016/j.neuropharm.2010.10.020 · Cited by 111 · cited 1× · see citing works
“In vitro and in vivo properties of 3-tert-butyl-7-(5-methylisoxazol-3-yl)-2-(1-methyl-1H-1, 2,4-triazol-5-ylme thoxy)-pyrazolo[1,5-d]-[1,2,4] triazine (MRK-016), a GABAA receptor α5 subtypeselective inverse agonist.”
Background
Hippocampal α5 subunit-containing GABAA receptors modulate the expression of prepulse inhibition
Hauser, J., Rudolph, U., Keist, R., Möhler, H., Feldon, J., & Yee, B. K. (2004) · Molecular Psychiatry · doi:10.1038/sj.mp.4001554 · Cited by 109 · see citing works
Self-citation
Blockade of alcohol's amnestic activity in humans by an α5 subtype benzodiazepine receptor inverse agonist
Nutt, D., Besson, M. J., Wilson, S. J., Dawson, G. R., & Lingford-Hughes, A. R. (2007) · Neuropharmacology · doi:10.1016/j.neuropharm.2007.08.008 · Cited by 109 · cited 1× · see citing works
“2b ), a functionally selective compound, was able to reverse memory deficits induced by alcohol consumption in a small study involving human volunteer”
Background
Linkage and linkage disequilibrium mapping of ERP and EEG phenotypes
Bernice Porjesz, A., Begleiter, H., Wang, K., Almasy, L. A., Chorlian, D. B., Stimus, A. T., Samuel Kuperman, C., O’Connor, S., Rohrbaugh, J., Bauer, L. O., et al. (2002) · Biological Psychology · doi:10.1016/s0301-0511(02)00060-1 · Cited by 109 · see citing works
Long-lasting Modulation of Glutamatergic Transmission in VTA Dopamine Neurons after a Single Dose of Benzodiazepine Agonists
Panhelainen, A. E., Möykkynen, T. P., & Korpi, E. R. (2008) · Neuropsychopharmacology · doi:10.1038/npp.2008.89 · Cited by 108 · see citing works
GABA A Receptor α5 Subunits Contribute to GABA A,slow Synaptic Inhibition in Mouse Hippocampus
Żarnowska, E. D., Keist, R., Rudolph, U., & Pearce, R. A. (2008) · Journal of Neurophysiology · doi:10.1152/jn.91203.2008 · Cited by 104 · see citing works
Self-citation
Comparison of the Novel Subtype-Selective GABAA Receptor-Positive Allosteric Modulator NS11394 [3′-[5-(1-Hydroxy-1-methyl-ethyl)-benzoimidazol-1-yl]-biphenyl-2-carbonitrile] with Diazepam, Zolpidem, Bretazenil, and Gaboxadol in Rat Models of Inflammatory and Neuropathic Pain
Munro, G., Lopez-Garcia, J. A., Rivera‐Arconada, I., Erichsen, H. K., Nielsen, E. Ø., Larsen, J. S., Ahring, P. K., & Mirza, N. R. (2008) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.108.144568 · Cited by 103 · cited 1× · see citing works
“NS11394 is antihyperalgesic in rat models of inflammatory and neuropathic pai”
Background
Antidepressant-like properties of α2-containing GABAA receptors
Vollenweider, I., Smith, K. S., Keist, R., & Rudolph, U. (2011) · Behavioural Brain Research · doi:10.1016/j.bbr.2010.10.009 · Cited by 96 · cited 1× · see citing works
“Indeed, α2 knockout mice display increased anxiety and depression-like behaviour in the conflict-based novelty-suppressed feeding test, and increased depression-like behaviour in the despair-based forced swim and tail suspension test”
BackgroundSelf-citation
Association Between GABRA1 and Drinking Behaviors in the Collaborative Study on the Genetics of Alcoholism Sample
Dick, D. M., Plunkett, J., Wetherill, L. F., Xuei, X., Goate, A., HESSELBROCK, V. M., Schuckit, M. A., Crowe, R., Edenberg, H. J., & Foroud, T. (2006) · Alcoholism Clinical and Experimental Research · doi:10.1111/j.1530-0277.2006.00136.x · Cited by 93 · see citing works
Dynamic GABAAReceptor Subtype-Specific Modulation of the Synchrony and Duration of Thalamic Oscillations
Sohal, V. S., Keist, R., Rudolph, U., & Huguenard, J. R. (2003) · Journal of Neuroscience · doi:10.1523/jneurosci.23-09-03649.2003 · Cited by 92 · see citing works
Self-citation
Effects of benzodiazepine microinjection into the amygdala or periaqueductal gray on the expression of conditioned fear and hypoalgesia in rats.
Harris, J. A., & Westbrook, R. F. (1995) · Behavioral Neuroscience · doi:10.1037/0735-7044.109.2.295 · Cited by 92 · see citing works
An Historical Perspective on Gabaergic Drugs
Froestl, W. (2011) · Future Medicinal Chemistry · doi:10.4155/fmc.10.285 · Cited by 89 · cited 1× · see citing works
“In vitro and in vivo properties of 3-tert-butyl-7-(5-methylisoxazol-3-yl)-2-(1-methyl-1H-1, 2,4-triazol-5-ylme thoxy)-pyrazolo[1,5-d]-[1,2,4] triazine (MRK-016), a GABAA receptor α5 subtypeselective inverse agonist.”
Background
HZ166, a novel GABAA receptor subtype-selective benzodiazepine site ligand, is antihyperalgesic in mouse models of inflammatory and neuropathic pain
Lio, A. D., Benke, D., Besson, M. J., Desmeules, J. A., Daali, Y., Wang, Z., Edwankar, R. V., Cook, J. M., & Zeilhofer, H. U. (2010) · Neuropharmacology · doi:10.1016/j.neuropharm.2010.11.026 · Cited by 88 · cited 1× · see citing works
“Likewise, the compound HZ-166, a partial agonist with selectivity for α2- and α3-containing GABA A receptors, had antihyperalgesic action in mouse models of neuropathic and inflammatory pai”
Background
NS11394 [3′-[5-(1-Hydroxy-1-methyl-ethyl)-benzoimidazol-1-yl]-biphenyl-2-carbonitrile], a Unique Subtype-Selective GABAA Receptor Positive Allosteric Modulator: In Vitro Actions, Pharmacokinetic Properties and in Vivo Anxiolytic Efficacy
Mirza, N. R., Larsen, J. S., Mathiasen, C., Jacobsen, T. A., Munro, G., Erichsen, H. K., Nielsen, A. N., Troelsen, K. B., NIELSEN, E. O., & Ahring, P. K. (2008) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.108.138859 · Cited by 87 · see citing works
Relationship between benzodiazepine receptor occupancy and functional effects in vivo of four ligands of differing intrinsic efficacies.
Martin‐Facklam, M., Schoch, P., Bonetti, E. P., Jenck, F., Martin, J. R., Moreau, J., & Haefely, W. E. (1992) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(25)11126-9 · Cited by 85 · see citing works
Linkage disequilibrium, haplotype and association studies of a chromosome 4 GABA receptor gene cluster: candidate gene variants for addictions
Drgon, T., D'Addario, C., & Uhl, G. R. (2006) · American Journal of Medical Genetics Part B Neuropsychiatric Genetics · doi:10.1002/ajmg.b.30349 · Cited by 82 · see citing works
Analysis of the Presence and Abundance of GABAA Receptors Containing Two Different Types of α Subunits in Murine Brain Using Point-mutated α Subunits
Benke, D., Fakitsas, P., Roggenmoser, C., Michel, C., Rudolph, U., & Möhler, H. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m407154200 · Cited by 81 · see citing works
Self-citation
Modulation of Long-term Potentiation in CA1 Region of Mouse Hippocampal Brain Slices by GABAA Receptor Benzodiazepine Site Ligands
Seabrook, G. R., Easter, A., Dawson, G. R., & Bowery, B. J. (1997) · Neuropharmacology · doi:10.1016/s0028-3908(97)00040-3 · Cited by 75 · cited 1× · see citing works
“Several studies in animals and humans have suggested that classical benzodiazepines can impair learning and memor”
Background
In Vitro and in Vivo Properties of 3-tert-Butyl-7-(5-methylisoxazol-3-yl)-2-(1-methyl-1H-1,2,4-triazol-5-ylmethoxy)-pyrazolo[1,5-d]-[1,2,4]triazine (MRK-016), a GABAA Receptor α5 Subtype-Selective Inverse Agonist
Atack, J. R., Maubach, K. A., Wafford, K. A., O'Connor, D. V., Rodrigues, A. D., Evans, D. C., Tattersall, F. D., Chambers, M. S., MacLeod, A. M., Eng, W., et al. (2009) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.109.157636 · Cited by 72 · see citing works
GABAA Receptor α2/α3 Subtype-Selective Modulators as Potential Nonsedating Anxiolytics
Atack, J. R. (2009) · Current topics in behavioral neurosciences · doi:10.1007/7854_2009_30 · Cited by 71 · cited 1× · see citing works
“In vitro and in vivo properties of 3-tert-butyl-7-(5-methylisoxazol-3-yl)-2-(1-methyl-1H-1, 2,4-triazol-5-ylme thoxy)-pyrazolo[1,5-d]-[1,2,4] triazine (MRK-016), a GABAA receptor α5 subtypeselective inverse agonist.”
Background
Reducing Abuse Liability of GABAA/Benzodiazepine Ligands via Selective Partial Agonist Efficacy at α1 and α2/3 Subtypes
Ator, N. A., Atack, J. R., Hargreaves, R. J., Burns, H. D., & Dawson, G. R. (2010) · The Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.109.158303 · Cited by 66 · cited 1× · see citing works
“Furthermore, in self-administration experiments in baboons, a withdrawal syndrome was observed following cessation of TPA123 self-administration (this compound displays 23% efficacy at α1-containing GABA A receptors, 35% efficacy at α2-containing GABA A receptors, 43% efficacy at α3-containing GABA A receptors and 19%…”
Result
Diazepam impairs place learning in the Morris water maze
Arolfo, M. P., & Brioni, J. D. (1991) · Behavioral and Neural Biology · doi:10.1016/0163-1047(91)80133-y · Cited by 65 · see citing works
Preclinical and clinical pharmacology of TPA023B, a GABA A receptor α2/α3 subtype-selective partial agonist
Atack, J. R., Hallett, D. J., Tye, S. J., Wafford, K. A., Ryan, C. N., Bohorquez, S. M. S., Eng, W., Gibson, R., Burns, H. D., Dawson, G., et al. (2010) · Journal of Psychopharmacology · doi:10.1177/0269881109354928 · Cited by 63 · see citing works
Identification of amino acid residues responsible for the α5 subunit binding selectivity of L‐655,708, a benzodiazepine binding site ligand at the GABAA receptor
Casula, M. A., Bromidge, F. A., Pillai, G. V., et al. (2001) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2001.00289.x · Cited by 61 · see citing works
MRK-409 (MK-0343), a GABA A receptor subtype-selective partial agonist, is a non-sedating anxiolytic in preclinical species but causes sedation in humans
Atack, J. R., Wafford, K. A., Street, L. O. N. D. O. N. G., Dawson, G., Tye, S. J., Laere, K. V., Bormans, G. M., Bohorquez, S. M. S., Lepeleire, I. D., de Hoon, J., et al. (2010) · Journal of Psychopharmacology · doi:10.1177/0269881109354927 · Cited by 60 · see citing works
GABAA-receptor α-subunit is an essential prerequisite for receptor formation in vivo
Fritschy, J., Benke, D., Johnson, D. K., et al. (1997) · Neuroscience · doi:10.1016/s0306-4522(97)00244-3 · Cited by 60 · cited 1× · see citing works
“α5-containing GABA A receptors are predominantly expressed in the hippocampus (where they make up approximately 20% of all GABA A receptor”
BackgroundSelf-citation
A reduction in hippocampal GABA A receptor α5 subunits disrupts the memory for location of objects in mice
Prut, L., Prenosil, G., Willadt, S., Vogt, K., Fritschy, J. ‐., & Crestani, F. (2010) · Genes, Brain and Behavior · doi:10.1111/j.1601-183x.2010.00575.x · Cited by 53 · see citing works
A question of balance – Positive versus negative allosteric modulation of GABAA receptor subtypes as a driver of analgesic efficacy in rat models of inflammatory and neuropathic pain
Munro, G., Erichsen, H. K., Rae, M. G., & Mirza, N. R. (2011) · Neuropharmacology · doi:10.1016/j.neuropharm.2011.03.017 · Cited by 51 · see citing works
Rodent pharmacokinetics and receptor occupancy of the GABAA receptor subtype selective benzodiazepine site ligand L‐838417
Scott‐Stevens, P., Atack, J. R., Sohal, B., & Worboys, P. D. (2004) · Biopharmaceutics & Drug Disposition · doi:10.1002/bdd.423 · Cited by 50 · cited 1× · see citing works
“However, unfavourable pharmacokinetic properties have precluded further development of this compoun”
Background
β3-Containing Gamma-Aminobutyric AcidA Receptors Are Not Major Targets for the Amnesic and Immobilizing Actions of Isoflurane
Liao, M. Y., Sonner, J. M., Jurd, R., Rudolph, U., Borghese, C. M., Harris, R. A., Laster, M. J., & Eger, E. I. (2005) · Anesthesia & Analgesia · doi:10.1213/01.ane.0000154196.86587.35 · Cited by 49 · see citing works
Self-citation
The inhibitory GABA system as a therapeutic target for cognitive symptoms in schizophrenia: investigational agents in the pipeline
Vinkers, C. H., Mirza, N. R., Olivier, B., & Kahn, R. S. (2010) · Expert Opinion on Investigational Drugs · doi:10.1517/13543784.2010.513382 · Cited by 39 · see citing works
Reversal of Ketamine-Induced Working Memory Impairments by the GABAAα2/3 Agonist TPA023
Castner, S. A., Arriza, J. L., Roberts, J. C., Mrzljak, L., Christian, E. P., & Williams, G. V. (2010) · Biological Psychiatry · doi:10.1016/j.biopsych.2010.01.001 · Cited by 37 · cited 1× · see citing works
“It is interesting to note that TPA023 reversed ketamine-induced impairments in spatial working memory in rhesus monkeys but not the ketamine-induced hallucinatory-like behaviours, emphasizing the functional specificity of this approac”
Background
Efficacy of alprazolam in reducing fluoxetine-induced jitteriness in patients with major depression.
Amsterdam, J. D., Hornig, M., & Maislin, G. (1994) · PubMed · Cited by 36 · see citing works
Antipsychotic effects of bretazenil, a partial benzodiazepine agonist in acute schizophrenia—A study group report
Delini‐Stula, A., & Berdah-Tordjman, D. (1996) · Journal of Psychiatric Research · doi:10.1016/0022-3956(96)00003-9 · Cited by 35 · cited 1× · see citing works
“Before the functions of the different GABA A receptor subtypes were known, the non-selective partial agonist and anxiolytic bretazenil was shown to be efficacious as monotherapy in approximately 40% of patients with acute episodes of schizophrenia of moderate to marked severit”
Background
Isoflurane-induced surgical tolerance mediated only in part by β3-containing GABAA receptors
Lambert, S., Arras, M., Vogt, K. E., & Rudolph, U. (2005) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2005.04.030 · Cited by 35 · see citing works
Self-citation
The role of GABA-A receptor subtypes as analgesic targets
Mirza, N. R., & Munro, G. (2010) · Drug News & Perspectives · doi:10.1358/dnp.2010.23.6.1489909 · Cited by 31 · see citing works
A Multicenter, Placebo‐Controlled, Double‐Blind, Randomized Study of Efficacy and Safety of Ocinaplon (DOV 273,547) in Generalized Anxiety Disorder
Czobor, P., Skolnick, P., Beer, B., & Lippa, A. (2010) · CNS Neuroscience & Therapeutics · doi:10.1111/j.1755-5949.2009.00109.x · Cited by 29 · cited 1× · see citing works
“2a ), had anxiolytic but not sedative effects in rodents and in humans, as demonstrated in Phase I and Phase II studies with 127 and 60 patients, respectivel”
Background
Contribution of GABAA receptors containing α3 subunits to the therapeutic-related and side effects of benzodiazepine-type drugs in monkeys
Fischer, B. D., Atack, J. R., Platt, D. M., Reynolds, D. S., Dawson, G. R., & Rowlett, J. K. (2010) · Psychopharmacology · doi:10.1007/s00213-010-2142-y · Cited by 26 · see citing works
ASSESSMENT OF BENZODIAZEPINE DEPENDENCE IN ALCOHOL AND DRUG DEPENDENT OUTPATIENTS: A RESEARCH REPORT
Kan, C. C., Breteler, M., van der Ven, A., Timmermans, M. A., & Zitman, F. (2001) · Substance Use & Misuse · doi:10.1081/ja-100104491 · Cited by 21 · cited 1× · see citing works
“However, in alcohol- and drug-dependent outpatients, benzodiazepine dependence was found to be prevalen”
Background

Flagged first, then by citations

Sorted by citations

The Link between Depression and Chronic Pain: Neural Mechanisms in the Brain
Sheng, J., Shui, L., Wang, Y., Cui, R., & Zhang, X. (2017) · Neural Plasticity · doi:10.1155/2017/9724371 · Cited by 792 · see citing works
“Because the GABAA receptors, including the α1, α2, α3, or α5 subunit, have also been found to be involved in mood regulation [82], the benzodiazepines have a potential in antidepressant therapy.”
Background
Crystal structure of a human GABAA receptor
Miller, P. S., & Aricescu, A. R. (2014) · Nature · doi:10.1038/nature13293 · Cited by 713 · see citing works
Autistic-like behaviour in Scn1a+/− mice and rescue by enhanced GABA-mediated neurotransmission
Han, S., Tai, C., Westenbroek, R. E., Yu, F. H., Cheah, C. S., Potter, G. B., Rubenstein, J. L., Scheuer, T., de la Iglesia, H. O., & Catterall, W. A. (2012) · Nature · doi:10.1038/nature11356 · Cited by 643 · see citing works
Autoantibodies to Synaptic Receptors and Neuronal Cell Surface Proteins in Autoimmune Diseases of the Central Nervous System
Dalmau, J. O., Geis, C., & Graus, F. (2017) · Physiological Reviews · doi:10.1152/physrev.00010.2016 · Cited by 631 · see citing works
Alterations in Cortical Network Oscillations and Parvalbumin Neurons in Schizophrenia
Gonzalez-Burgos, G., Cho, R. Y., & Lewis, D. A. (2015) · Biological Psychiatry · doi:10.1016/j.biopsych.2015.03.010 · Cited by 497 · see citing works
“Future pharmacologic studies could use drugs with greater potency for GABAA receptors containing an α2 subunit (147) or that target other PV cell receptor subtypes, such as α1 subunit GABAA receptors, which are also disturbed in schizophrenia (26) and possess the fast kinetics necessary for gamma oscillations.”
Background
Depression, anxiety and acute pain: links and management challenges
Michaelides, A., & Zis, P. (2019) · Postgraduate Medicine · doi:10.1080/00325481.2019.1663705 · Cited by 430 · see citing works
“Benzodiazepines have therapeutic effects in neuropathic or inflammatory pain through their effects on the GABAA receptor [56] The GABAA receptor has different subunits that have also been found to be involved in mood regulation, demonstrating the anti-depressant potential of benzodiazepines [57].”
Background
Cortical GABAergic Dysfunction in Stress and Depression: New Insights for Therapeutic Interventions
Fogaça, M. V., & Duman, R. S. (2019) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2019.00087 · Cited by 396 · see citing works
50 years of hurdles and hope in anxiolytic drug discovery
Griebel, G., & Holmes, A. (2013) · Nature Reviews Drug Discovery · doi:10.1038/nrd4075 · Cited by 414 · see citing works
GABAA receptors: structure, function, pharmacology, and related disorders
Ghit, A., Assal, D., Al‐Shami, A. S., & Hussein, D. E. (2021) · Journal of Genetic Engineering and Biotechnology · doi:10.1186/s43141-021-00224-0 · Cited by 413 · see citing works
“ceptor function usually have opposite pharmacological effects such as convulsion and anxiogenesis [78, 79].”
Background
Developmental timing and critical windows for the treatment of psychiatric disorders
Marín, O. (2016) · Nature Medicine · doi:10.1038/nm.4225 · Cited by 374 · see citing works
Rapid‐acting antidepressant ketamine, its metabolites and other candidates: A historical overview and future perspective
Hashimoto, K. (2019) · Psychiatry and Clinical Neurosciences · doi:10.1111/pcn.12902 · Cited by 335 · see citing works
“Negative modulators of α5 GABAA receptors The GABAA (γ-aminobutyric acid, type A) receptors play an important role in several psychiatric disorders, such as MDD, as the regulation of GABAA receptors reportedly influences glutamate neurotransmission.(165,166) Two negative allosteric modulators (NAM; MRK-016 and L-655,7…”
Background
GABAA receptor signalling mechanisms revealed by structural pharmacology
Masiulis, S., Desai, R., Uchański, T., Martin, I. S., Laverty, D. C., Karia, D., Malinauskas, T., Zivanov, J., Pardon, E., Kotecha, A., et al. (2018) · Nature · doi:10.1038/s41586-018-0832-5 · Cited by 559 · see citing works
GABA A Receptor Subtypes: Therapeutic Potential in Down Syndrome, Affective Disorders, Schizophrenia, and Autism
Rudolph, U., & Möhler, H. (2014) · Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-011613-135947 · Cited by 319 · see citing works
“The recognition of GABAA receptor subtypes (Table 1) provided an incentive to search for novel anxiolytics that retain the rapid and robust antianxiety actions of benzodiazepines while limiting or avoiding their side effects (62, 66, 67).”
BackgroundSelf-citation
The GABAA Receptor as a Therapeutic Target for Neurodevelopmental Disorders
Braat, S., & Kooy, R. F. (2015) · Neuron · doi:10.1016/j.neuron.2015.03.042 · Cited by 294 · see citing works
Zolpidem for insomnia
Greenblatt, D. J., & Roth, T. G. (2012) · Expert Opinion on Pharmacotherapy · doi:10.1517/14656566.2012.667074 · Cited by 284 · see citing works
“Most, but not all [13], neurochemical studies of zolpidem indicate that the drug has relatively selective affinity for the BZ-1 (omega-1) receptor subtype, corresponding to the population containing alpha-1 subunits [14-20].”
Background
GABAergic dysfunction in excitatory and inhibitory (E/I) imbalance drives the pathogenesis of Alzheimer's disease
Bi, D., Wen, L., Wu, Z., & Shen, Y. (2020) · Alzheimer's & Dementia · doi:10.1002/alz.12088 · Cited by 232 · see citing works
Neurosteroid interactions with synaptic and extrasynaptic GABAA receptors: regulation of subunit plasticity, phasic and tonic inhibition, and neuronal network excitability
Carver, C. M., & Reddy, D. S. (2013) · Psychopharmacology · doi:10.1007/s00213-013-3276-5 · Cited by 247 · see citing works
“…, ∼15–20 % have the α 2 β 3 γ 2 combination, ∼10–15 % have the α 3 β x γ 2 combination, ∼ 5 % have the α 4 β x γ or α 4 β x δ combination, less than 5 % have the α 5 β 2 γ 2 combination, and, likewise, less than 5 % have the α 6 β 2/3 γ 2 combination (Mohler et al. 2002; Rudolph and Knoflach 2011).”
The direct actions of cannabidiol and 2-arachidonoyl glycerol at GABA A receptors
Bakas, T., van Nieuwenhuijzen, P. S., Devenish, S. O., McGregor, I. S., Arnold, J. C., & Chebib, M. (2017) · Pharmacological Research · doi:10.1016/j.phrs.2017.02.022 · Cited by 246 · see citing works
Enhancement of Inhibitory Neurotransmission by GABA A Receptors Having α 2,3 -Subunits Ameliorates Behavioral Deficits in a Mouse Model of Autism
Han, S., Tai, C., Jones, C. J., Scheuer, T., & Catterall, W. A. (2014) · Neuron · doi:10.1016/j.neuron.2014.01.016 · Cited by 231 · see citing works
An emerging circuit pharmacology of GABAA receptors
Engin, E., Benham, R. S., & Rudolph, U. (2018) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2018.04.003 · Cited by 225 · see citing works
Self-citation
Neurogenetics of Aggressive Behavior: Studies in Rodents
Takahashi, A., & Miczek, K. A. (2013) · Current topics in behavioral neurosciences · doi:10.1007/7854_2013_263 · Cited by 212 · see citing works
“Mice with a point mutation in the benzodiazepine binding site of a specific a subunit and a knockout mouse for each subtype of GABAA receptor have been established (Rudolph and Knoflach 2011), and these mice will facilitate analysis of the function of each of these subunit in controlling aggression.”
Background
International Union of Basic and Clinical Pharmacology. CVI: GABAA Receptor Subtype- and Function-selective Ligands: Key Issues in Translation to Humans
Sieghart, W., & Savić, M. M. (2018) · Pharmacological Reviews · doi:10.1124/pr.117.014449 · Cited by 211 · see citing works
“…the mutations a1H101R, a3H126R, or a5H105R that are also used for demonstrating the function of the respective receptor subtypes in the brain (Rudolph and Knoflach, 2011; Rudolph and Möhler, 2014), other ligands of the benzodiazepine site, such as bretazenil or Ro15-4513, are even more…”
Background
Autism spectrum disorder causes, mechanisms, and treatments: focus on neuronal synapses
Won, H., Mah, W., & Kim, E. (2013) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2013.00019 · Cited by 204 · see citing works
Allosteric Modulation of GABAA Receptors via Multiple Drug-Binding Sites
Sieghart, W. (2014) · Advances in pharmacology · doi:10.1016/bs.apha.2014.10.002 · Cited by 198 · see citing works
“…as well as that on homologous sites in other GABAA receptor subtypes is a prerequisite for a future structure-based drug design that could dramatically accelerate the development of novel subtypeselective drugs of potential therapeutic use (Rudolph & Knoflach, 2011; Rudolph & Mohler, 2014).”
Background
Neurosteroids, stress and depression: Potential therapeutic opportunities
Zorumski, C. F., Paul, S. M., Izumi, Y., Covey, D. F., & Mennerick, S. J. (2012) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2012.10.005 · Cited by 196 · see citing works
A review on the traditional uses, phytochemistry, and pharmacological activities of clove basil (Ocimum gratissimum L.)
Ugbogu, O. C., Emmanuel, O., Agi, G. O., Ibe, C., Ekweogu, C. N., Ude, V. C., Uche, M. E., Nnanna, R. O., & Ugbogu, E. A. (2021) · Heliyon · doi:10.1016/j.heliyon.2021.e08404 · Cited by 192 · see citing works
“Benzodiazepines and other allopathic medicines that nonselectively target gamma-aminobutyric acid (GABA) receptors are commonly used to treat anxiety (Rudolph and Knoflach, 2011).”
Background
SIRT3 mediates hippocampal synaptic adaptations to intermittent fasting and ameliorates deficits in APP mutant mice
Liu, Y., Cheng, A., Li, Y.-J., Yang, Y., Kishimoto, Y., Zhang, S., Wang, Y., Wan, R., Raefsky, S. M., Lu, D., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-09897-1 · Cited by 176 · see citing works
Positive Allosteric Modulators of GluN2A-Containing NMDARs with Distinct Modes of Action and Impacts on Circuit Function
Hackos, D. H., Lupardus, P. J., Grand, T., Chen, Y., Wang, T.-M., Reynen, P. H., Gustafson, A. E., Wallweber, H. J. A., Volgraf, M., Sellers, B. D., et al. (2016) · Neuron · doi:10.1016/j.neuron.2016.01.016 · Cited by 174 · see citing works
Anxiolytic-like effect of lavender essential oil inhalation in mice: Participation of serotonergic but not GABAA/benzodiazepine neurotransmission
Chioca, L. R., Ferro, M. M., Baretta, I. P., Oliveira, S. M., Silva, C. R., Ferreira, J., Losso, E. M., & Andreatini, R. (2013) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2013.03.028 · Cited by 167 · see citing works
The interstitial duplication 15q11.2-q13 syndrome includes autism, mild facial anomalies and a characteristic EEG signature
Urraca, N., Cleary, J., Brewer, V., Pivnick, E. K., McVicar, K., Thibert, R. L., Schanen, N. C., Esmer, C., Lamport, D., & Reiter, L. T. (2013) · Autism Research · doi:10.1002/aur.1284 · Cited by 164 · see citing works
“A similar pattern is typically seen in children treated with benzodiazepines or barbiturates, both of which promote GABA(A) receptors in the brain [T.R. Browne & Penry, 1973; Rudolph et al., 1999; Rudolph & Knoflach, 2011], but none of our subjects were on these medications.”
Background
GABA Receptors: Pharmacological Potential and Pitfalls
Jembrek, M. J., & Vlainić, J. (2015) · Current Pharmaceutical Design · doi:10.2174/1381612821666150914121624 · Cited by 164 · see citing works
“This ensures propagation of neurotransmission and represents basis of neural communication [4,5].”
BackgroundInfluential
Ligand-Gated Ion Channels: New Insights into Neurological Disorders and Ligand Recognition
Lemoine, D., Jiang, R., Taly, A., Chataigneau, T., Specht, A., & Grütter, T. (2012) · Chemical Reviews · doi:10.1021/cr3000829 · Cited by 162 · see citing works
GABAergic inhibitory neurons as therapeutic targets for cognitive impairment in schizophrenia
Xu, M., & Wong, A. H. C. (2018) · Acta Pharmacologica Sinica · doi:10.1038/aps.2017.172 · Cited by 159 · see citing works
Reducing GABA A α5 Receptor-Mediated Inhibition Rescues Functional and Neuromorphological Deficits in a Mouse Model of Down Syndrome
Martínez‐Cué, C., Martinez, P. M., Rueda, N., Vidal, R., García-Cerro, S., Vidal, V., Corrales, A., Montero, J. A., Pazos, Á., Flórez, J., et al. (2013) · Journal of Neuroscience · doi:10.1523/jneurosci.1203-12.2013 · Cited by 154 · see citing works
“Among the different GABAA receptor subtypes, GABAA 5 subunit-containing receptors are preferentially localized in the hippocampus and play a key modulatory role in cognition (Collinson et al., 2002; Crestani et al., 2002; Rudolph and Knoflach, 2011).”
BackgroundSelf-citation
GABA A Receptors and the Diversity in their Structure and Pharmacology
Chua, H. C., & Chebib, M. (2017) · Advances in pharmacology · doi:10.1016/bs.apha.2017.03.003 · Cited by 154 · see citing works
Alcohol use disorders and current pharmacological therapies: the role of GABAA receptors
Liang, J., & Olsen, R. W. (2014) · Acta Pharmacologica Sinica · doi:10.1038/aps.2014.50 · Cited by 155 · see citing works
Evolutionary origin of amino acid transporter families SLC32, SLC36 and SLC38 and physiological, pathological and therapeutic aspects
Schiöth, H. B., Roshanbin, S., Hägglund, M. G. A., & Fredriksson, R. (2013) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2012.07.012 · Cited by 150 · see citing works
GABAA receptor-acting neurosteroids: a role in the development and regulation of the stress response
Gunn, B. G., Cunningham, L., Mitchell, S. G., Swinny, J. D., Lambert, J. J., & Belelli, D. (2015) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2014.06.001 · Cited by 149 · see citing works
“Sieghart, 2009; Rudolph and Knoflach, 2011; Rudolph and Mohler, 2014).”
Anxiolytic Effect of Essential Oils and Their Constituents: A Review
Zhang, N., & Yao, L. (2019) · Journal of Agricultural and Food Chemistry · doi:10.1021/acs.jafc.9b00433 · Cited by 148 · see citing works
THC and CBD: Similarities and differences between siblings
Stella, N. (2023) · Neuron · doi:10.1016/j.neuron.2022.12.022 · Cited by 149 · see citing works
Understanding the mechanism of action and clinical effects of neuroactive steroids and GABAergic compounds in major depressive disorder
Cutler, A. J., Mattingly, G. W., & Maletic, V. (2023) · Translational Psychiatry · doi:10.1038/s41398-023-02514-2 · Cited by 147 · see citing works
“Extrasynaptic GABAA receptors containing δ subunits are insensitive to benzodiazepines [32, 53, 62, 64, 78, 79, 91, 92, 167].”
Background
Dysfunctional hippocampal activity affects emotion and cognition in mood disorders
Femenía, T., Gómez-Galán, M., Lindskog, M., & Magara, S. (2012) · Brain Research · doi:10.1016/j.brainres.2012.03.053 · Cited by 143 · see citing works
Seizing Control of KCC2: A New Therapeutic Target for Epilepsy
Moore, Y. E., Kelley, M. R., Brandon, N. J., Deeb, T. Z., & Moss, S. J. (2017) · Trends in Neurosciences · doi:10.1016/j.tins.2017.06.008 · Cited by 142 · see citing works
“GABAA receptors comprise five subunits selected from 19 isoforms: six a subunits, three b subunits, three g subunits, three r subunits, and one each of the e, d, u, and p subunits [1].”
Drug models of schizophrenia
Steeds, H., Carhart-Harris, R. L., & Stone, J. M. (2014) · Therapeutic Advances in Psychopharmacology · doi:10.1177/2045125314557797 · Cited by 134 · see citing works
“Although there is considerable interest in the potential for novel drugs targeting GABA neurotransmission in schizophrenia [Rudolph and Knoflach, 2011], results from existing compounds in patients have not been promising [Rudolph and Knoflach, 2011; Buchanan et al.”
BackgroundInfluential
Reciprocal control of obesity and anxiety–depressive disorder via a GABA and serotonin neural circuit
Xia, G., Han, Y., Meng, F., He, Y., Srisai, D., Farías, M., Dang, M., Palmiter, R. D., Xu, Y., & Wu, Q. (2021) · Molecular Psychiatry · doi:10.1038/s41380-021-01053-w · Cited by 133 · see citing works
Identification and Characterization of GABAA Receptor Autoantibodies in Autoimmune Encephalitis
Ohkawa, T., Satake, S., Yokoi, N., Miyazaki, Y., Ohshita, T., Sobue, G., Takashima, H., Watanabe, O., Fukata, Y., & Fukata, M. (2014) · Journal of Neuroscience · doi:10.1523/jneurosci.4415-13.2014 · Cited by 131 · see citing works
“…mediates most of the fast inhibitory synaptic transmission in the brain and is composed of heteropentameric assemblies of different subunit subtypes [ (1– 6), (1–3), (1–3), , , , , and (1–3)] to form chloride ion channels (Macdonald and Olsen, 1994; Jacob et al., 2008; Rudolph and Knoflach, 2011).”
Background
Insomnia: Pharmacologic Therapy.
Matheson, E. M., & Hainer, B. L. (2017) · PubMed · Cited by 132 · see citing works
Electrophysiology of ionotropic GABA receptors
Sallard, E., Letourneur, D., & Legendre, P. (2021) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-021-03846-2 · Cited by 132 · see citing works
“The most abundant subtype in the mammalian nervous system is α1β2γ2, possibly accounting for 60% of all GABAA receptors [65].”
Background
α2-containing GABAA receptors: A target for the development of novel treatment strategies for CNS disorders
Engin, E., Liu, J., & Rudolph, U. (2012) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2012.08.006 · Cited by 129 · see citing works
Self-citation
The brain GABA-benzodiazepine receptor alpha-5 subtype in autism spectrum disorder: A pilot [11C]Ro15-4513 positron emission tomography study
Méndez, M. A., Horder, J., Myers, J., Coghlan, S., Stokes, P. R. A., Erritzøe, D., Howes, O. D., Lingford-Hughes, A. R., Murphy, D., & Nutt, D. (2012) · Neuropharmacology · doi:10.1016/j.neuropharm.2012.04.008 · Cited by 127 · see citing works
Immunological GABAergic interactions and therapeutic applications in autoimmune diseases
Prud’homme, G. J., Glinka, Y., & Wang, Q. (2015) · Autoimmunity Reviews · doi:10.1016/j.autrev.2015.07.011 · Cited by 126 · see citing works
GABA abnormalities in schizophrenia: A methodological review of in vivo studies
Taylor, S. F., & Tso, I. F. (2014) · Schizophrenia Research · doi:10.1016/j.schres.2014.10.011 · Cited by 125 · see citing works
“A uthor M anuscript A uthor M anuscript A uthor M anuscript A uthor M anuscript (Rudolph and Knoflach, 2011) an imperfect test of the hypothesis that these subunit selective compounds can play a role in schizophrenia therapeutics.”
Enhanced phasic GABA inhibition during the repair phase of stroke: a novel therapeutic target
Hiu, T., Farzampour, Z., Paz, J. T., Wang, E. H.-J., Badgely, C., Olson, A., Micheva, K. D., Wang, G. X., Lemmens, R., Tran, K. C., et al. (2015) · Brain · doi:10.1093/brain/awv360 · Cited by 125 · see citing works
“Moreover, as the GABAA receptors that mediate phasic and tonic inhibition differ in their subunit composition—phasic GABAARs contain primarily 13,5 subunits whereas tonic GABAARs contain primarily 4,6 subunits (Farrant and Nusser, 2005; Glykys et al., 2008; Rudolph and Knoflach, 2011; Hines et al., 2012)— it highlight…”
Background
The GABAergic Hypothesis for Cognitive Disabilities in Down Syndrome
Contestabile, A., Magara, S., & Cancedda, L. (2017) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2017.00054 · Cited by 141 · see citing works
“…and/or expression of NKCC1 may play a role in sleep disorders in DS. Finally, the strong involvement of GABAA signaling in anxiety disorders (Rudolph and Knoflach, 2011; Möhler, 2012) and the observation that DS patients show increased anxiety (Vicari et al., 2013) may indicate that also…”
BackgroundInfluential
Brexanolone, a neurosteroid antidepressant, vindicates the GABAergic deficit hypothesis of depression and may foster resilience
Lüscher, B., & Möhler, H. (2019) · F1000Research · doi:10.12688/f1000research.18758.1 · Cited by 105 · see citing works
Cryo-Electron Microscopy: Moving Beyond X-Ray Crystal Structures for Drug Receptors and Drug Development
García‐Nafría, J., & Tate, C. G. (2019) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-010919-023545 · Cited by 116 · see citing works
Heart–brain interactions in cardiac and brain diseases: why sex matters
Rossi, A., Mikaïl, N., Bengs, S., Haider, A., Treyer, V., Buechel, R. R., Wegener, S., Rauen, K., Tawakol, A. A., Merz, C. N. B., et al. (2022) · European Heart Journal · doi:10.1093/eurheartj/ehac061 · Cited by 116 · see citing works
Dendrite-targeting interneurons control synaptic NMDA-receptor activation via nonlinear α5-GABAA receptors
Schulz, J. M., Knoflach, F., Hernandez, M., & Bischofberger, J. (2018) · Nature Communications · doi:10.1038/s41467-018-06004-8 · Cited by 115 · see citing works
Self-citation
Regulation of GABAARs by Phosphorylation
Nakamura, Y., Darnieder, L. M., Deeb, T. Z., & Moss, S. J. (2014) · Advances in pharmacology · doi:10.1016/bs.apha.2014.11.008 · Cited by 114 · see citing works
Role of Glyoxalase 1 (Glo1) and methylglyoxal (MG) in behavior: recent advances and mechanistic insights
Distler, M. G., & Palmer, A. A. (2012) · Frontiers in Genetics · doi:10.3389/fgene.2012.00250 · Cited by 112 · see citing works
Differential assembly diversifies GABAA receptor structures and signalling
Sente, A., Desai, R., Naydenova, K., Malinauskas, T., Jounaïdi, Y., Miehling, J., Zhou, X., Masiulis, S., Hardwick, S. W., Chirgadze, D. Y., et al. (2022) · Nature · doi:10.1038/s41586-022-04517-3 · Cited by 112 · see citing works
GABA ergic signalling in the immune system
Barragán, A., Weidner, J. M., Jin, Z., Korpi, E. R., & Birnir, B. (2015) · Acta Physiologica · doi:10.1111/apha.12467 · Cited by 111 · see citing works
Estrogen receptor GPR30 exerts anxiolytic effects by maintaining the balance between GABAergic and glutamatergic transmission in the basolateral amygdala of ovariectomized mice after stress
Tian, Z., Wang, Y., Zhang, N., Guo, Y., Feng, B., Liu, S., & Zhao, M. (2013) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2013.04.011 · Cited by 110 · see citing works
Benzodiazepines Modulate GABAAReceptors by Regulating the Preactivation Step after GABA Binding
Gielen, M. C., Lumb, M. J., & Smart, T. G. (2012) · Journal of Neuroscience · doi:10.1523/jneurosci.5663-11.2012 · Cited by 110 · see citing works
Analgesia and unwanted benzodiazepine effects in point-mutated mice expressing only one benzodiazepine-sensitive GABAA receptor subtype
Ralvenius, W. T., Benke, D., Acuña, M. A., Rudolph, U., & Zeilhofer, H. U. (2015) · Nature Communications · doi:10.1038/ncomms7803 · Cited by 107 · see citing works
Self-citation
Alterations in GABAA-Receptor Trafficking and Synaptic Dysfunction in Brain Disorders
Mele, M., Costa, R. O., & Duarte, C. B. (2019) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2019.00077 · Cited by 106 · see citing works
“…other receptors may be considered a mechanism for tuning inhibition in the CNS. Deficits in the functional expression of GABAAR have been implicated in the pathogenesis of several neurological and psychiatric diseases (Schwartz-Bloom and Sah, 2001; Rudolph and Knoflach, 2011; Kaila et al., 2014).”
Background
Herbal Insomnia Medications that Target GABAergic Systems: A Review of the Psychopharmacological Evidence
Shi, Y., Dong, J., Zhao, J.-H., Tang, L.-N., & Zhang, J. (2014) · Current Neuropharmacology · doi:10.2174/1570159x11666131227001243 · Cited by 107 · see citing works
“However, BZDs have addictive properties and are associated with abuse liability, physical dependence, and tolerance, limiting their long-term use [18].”
Background
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
Zanos, P., Nelson, M. E., Highland, J. N., Krimmel, S. R., Georgiou, P., Gould, T. D., & Thompson, S. M. (2017) · eNeuro · doi:10.1523/eneuro.0285-16.2017 · Cited by 106 · see citing works
“, 2009) and are under development as cognitive enhancers (Rudolph and Knoflach, 2011).”
Background
Possible alterations in GABAAreceptor signaling that underlie benzodiazepine‐resistant seizures
Deeb, T. Z., Maguire, J. L., & Moss, S. J. (2012) · Epilepsia · doi:10.1111/epi.12037 · Cited by 103 · see citing works
“…2012 doi: 10.1111/epi.12037 MOLECULAR PLASTICITY 79 the benzodiazepine-binding site is formed at the extracellular interface of a c2 and adjacent a1-3 or a5 subunit; the a4 and a6 subunits do not support benzodiazepine binding (Puia et al., 1991; Benson et al., 1998; Rudolph & Knoflach, 2011).”
BackgroundInfluential
GABAergic system in the endocrine pancreas: a new target for diabetes treatment
Wang, Q., Prud'homme, G., & Wan, Y. (2015) · Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy · doi:10.2147/dmso.s50642 · Cited by 100 · see citing works
“GABA A Rs are heteropentamers of different subunits that form fast-acting chloride channels.(22) There are 19 known”
Background
Cognitive deficits caused by prefrontal cortical and hippocampal neural disinhibition
Bast, T., Pezze, M. A., & McGarrity, S. (2017) · British Journal of Pharmacology · doi:10.1111/bph.13850 · Cited by 92 · see citing works
“, 2008; Rudolph and Knoflach, 2011), studies using intra-cerebral microinfusions of broadly acting GABA agonists and antagonists may be complemented by studies using more selective ligands, to target specific GABA receptors subtypes (Rudolph and Knoflach, 2011), and opto- and pharmacogenetic methods, to modulate GABA…”
BackgroundInfluential
Benzodiazepine-induced anxiolysis and reduction of conditioned fear are mediated by distinct GABAA receptor subtypes in mice
Smith, K. S., Engin, E., Meloni, E. G., & Rudolph, U. (2012) · Neuropharmacology · doi:10.1016/j.neuropharm.2012.03.001 · Cited by 94 · see citing works
“These receptors modulate processes as diverse as sleep, anxiety, learning and memory, seizures, depressive symptomatology, and reward (Rudolph and Knoflach, 2011).”
Self-citation
GABAA receptor subtype involvement in addictive behaviour
Stephens, D. N., King, S. L., Lambert, J. J., Belelli, D., & Duka, T. (2016) · Genes Brain & Behavior · doi:10.1111/gbb.12321 · Cited by 92 · see citing works
“…by 𝛼1-containing and 𝛼2- (and perhaps 𝛼3-) subunit containing receptors respectively, while an action at 𝛼5-containing receptors makes a significant contribution to the well-characterized amnestic effects of benzodiazepines (Collinson et al. 2006; Mohler et al. 2002; Rudolph & Knoflach 2011).”
Background
Nanostructured Lipid Carriers to Mediate Brain Delivery of Temazepam: Design and In Vivo Study
Eleraky, N. E., Omar, M. M., Mahmoud, H. A., et al. (2020) · Pharmaceutics · doi:10.3390/pharmaceutics12050451 · Cited by 91 · see citing works
Insights and progress on the biosynthesis, metabolism, and physiological functions of gamma-aminobutyric acid (GABA): a review
Zhang, Q., Zhu, L., Li, H., Chen, Q., Li, N., Li, J., Zhao, Z., Xiao, D., Tang, T., Bi, C., et al. (2024) · PeerJ · doi:10.7717/peerj.18712 · Cited by 93 · see citing works
Cognitive Enhancers (Nootropics). Part 1: Drugs Interacting with Receptors
Froestl, W., Muhs, A., & Pfeifer, A. (2012) · Journal of Alzheimer s Disease · doi:10.3233/jad-2012-121186 · Cited by 91 · see citing works
“5 2 GABAA receptors, particularly abundant in the hippocampus, display valuable cognition enhancing properties (in chronological order) [544–555].”
Social isolation induces neuroinflammation and microglia overactivation, while dihydromyricetin prevents and improves them
Omran, A. J. A., Shao, A. S., Watanabe, S., Zhang, Z., Zhang, J., Chen, X., Watanabe, J., Davies, D. L., Shao, X. M., & Liang, J. (2022) · Journal of Neuroinflammation · doi:10.1186/s12974-021-02368-9 · Cited by 91 · see citing works
The balancing act of GABAergic synapse organizers
Ko, J., Choii, G., & Um, J. W. (2015) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2015.01.004 · Cited by 86 · see citing works
GABAkines – Advances in the discovery, development, and commercialization of positive allosteric modulators of GABAA receptors
Cerne, R., LIPPA, A. S., Poe, M. M., Smith, J. L., Jin, X., Ping, X., Golani, L. K., Cook, J. M., & Witkin, J. M. (2021) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2021.108035 · Cited by 89 · see citing works
Phytochemical analysis and biological properties of Cyperus rotundus L.
Kandikattu, H. K., Razack, S., Nallamuthu, I., & Khanum, F. (2013) · Industrial Crops and Products · doi:10.1016/j.indcrop.2013.11.040 · Cited by 88 · see citing works
A developmental reduction of the excitation:inhibition ratio in association cortex during adolescence
Larsen, B., Cui, Z., Adebimpe, A., Pines, A., Alexander-Bloch, A., Bertolero, M., Calkins, M. E., Gur, R. E., Gur, R. C., Mahadevan, A. S., et al. (2022) · Science Advances · doi:10.1126/sciadv.abj8750 · Cited by 80 · see citing works
Molecular and clinical descriptions of patients with GABAA receptor gene variants ( GABRA1 , GABRB2 , GABRB3 , GABRG2 ): A cohort study, review of literature, and genotype–phenotype correlation
Maillard, P., Baer, S., Schaefer, É., Desnous, B., Villeneuve, N., Lepine, A. F., Fabre, A., Lacoste, C., Chehadeh, S. E., Piton, A., et al. (2022) · Epilepsia · doi:10.1111/epi.17336 · Cited by 84 · see citing works
“For each case, we noted the clinical phenotype according to the classification previously described: (1) epilepsy associated with fever sensibility, (2) early developmental epileptic encephalopathy, and (3) genetic generalized epilepsy.”
BackgroundMethod
Privileged Diazepine Compounds and Their Emergence as Bromodomain Inhibitors
Smith, S. G., Sánchez, R., & Zhou, M. (2014) · Chemistry & Biology · doi:10.1016/j.chembiol.2014.03.004 · Cited by 83 · see citing works
“…and through the use of BZD inhibition in the altered mice and in wild-type mice, were able to determine the activities controlled by each a subtype (Crestani et al., 2001, 2002; Löw et al., 2000; McKernan et al., 2000; van Rijnsoever et al., 2004; Rudolph et al., 1999; Rudolph and Knoflach, 2011).”
Method
Idiopathic Hypersomnia
Trotti, L. M. (2017) · Sleep Medicine Clinics · doi:10.1016/j.jsmc.2017.03.009 · Cited by 83 · see citing works
Randomised clinical trial of the effects of prolonged-release melatonin, temazepam and zolpidem on slow-wave activity during sleep in healthy people
Arbon, E. L., Knurowska, M., & Dijk, D. (2015) · Journal of Psychopharmacology · doi:10.1177/0269881115581963 · Cited by 81 · see citing works
“…options for insomnia include benzodiazepine and non-benzodiazepine hypnotics that target γ-aminobutyric acid (GABA)A receptors and other hypnotics including melatonin receptor agonists (Ebert et al., 2006; Rudolph and Knoflach, 2011), the latter of which are sometimes referred to as chronobiotics.”
Background
Long-term diazepam treatment enhances microglial spine engulfment and impairs cognitive performance via the mitochondrial 18 kDa translocator protein (TSPO)
Shi, Y., Cui, M., Ochs, K., Brendel, M., Strübing, F., Briel, N., Eckenweber, F., Zou, C., Banati, R. B., Liu, G. J., et al. (2022) · Nature Neuroscience · doi:10.1038/s41593-022-01013-9 · Cited by 85 · see citing works
Self-citation
Discovery of allosteric modulators for GABAA receptors by ligand-directed chemistry
Yamaura, K., Kiyonaka, S., Numata, T., Inoue, R., & Hamachi, I. (2016) · Nature Chemical Biology · doi:10.1038/nchembio.2150 · Cited by 80 · see citing works
Phytochemical analysis of Ocimum gratissimum by LC-ESI–MS/MS and its antioxidant and anxiolytic effects
Venuprasad, M. P., Kandikattu, H. K., Razack, S., & Khanum, F. (2014) · South African Journal of Botany · doi:10.1016/j.sajb.2014.02.010 · Cited by 78 · see citing works
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
Epperson, C. N., Rubinow, D. R., Meltzer-Brody, S. E., Deligiannidis, K. M., Riesenberg, R. A., Krystal, A. D., Bankole, K., Huang, M., Li, H., Brown, C., et al. (2022) · Journal of Affective Disorders · doi:10.1016/j.jad.2022.09.143 · Cited by 77 · see citing works
GABAA receptor subtypes and benzodiazepine use, misuse, and abuse
Engin, E. (2023) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2022.1060949 · Cited by 79 · see citing works
“BDZs have anxiolytic, sedative, hypnotic, amnestic, anticonvulsant, myorelaxant effects (9).”
Background
Activation-induced regulation of GABAA receptors: Is there a link with the molecular basis of benzodiazepine tolerance?
Gravielle, M. C. (2015) · Pharmacological Research · doi:10.1016/j.phrs.2015.12.030 · Cited by 77 · see citing works
Role of GABAA receptor subtypes in the behavioural effects of intravenous general anaesthetics
Weir, C. J., Mitchell, S. J., & Lambert, J. J. (2017) · British Journal of Anaesthesia · doi:10.1093/bja/aex369 · Cited by 78 · see citing works
“sedative action of diazepam was abolished, but the anxiolytic action was maintained.(26) In contrast, for the equivalent a2H101R mouse, the anxiolytic effect of diazepam was abolished, but the sedative effect remained intact.”
BackgroundInfluential
Molecular and Functional Diversity of GABA-A Receptors in the Enteric Nervous System of the Mouse Colon
Seifi, M., Brown, J. F., Mills, J. J., Bhandari, P., Belelli, D., Lambert, J. J., Rudolph, U., & Swinny, J. D. (2014) · Journal of Neuroscience · doi:10.1523/jneurosci.0441-14.2014 · Cited by 76 · see citing works
“, 2012) and pharmacologically (Rudolph and Knoflach, 2011) diverse receptor subtypes within distinct regions (Wisden et al.”
BackgroundInfluentialSelf-citation
The effects of chamomile extract on sleep quality among elderly people: A clinical trial
Adib‐Hajbaghery, M., & Mousavi, S. N. (2017) · Complementary Therapies in Medicine · doi:10.1016/j.ctim.2017.09.010 · Cited by 76 · see citing works
Transplantation of fecal microbiota from patients with alcoholism induces anxiety/depression behaviors and decreases brain mGluR1/PKC ε levels in mouse
Zhao, W., Hu, Y., Li, C., Li, N., Zhu, S., Tan, X., Li, M., Zhang, Y., Xu, Z., Ding, Z., et al. (2020) · BioFactors · doi:10.1002/biof.1567 · Cited by 75 · see citing works
Impaired GABAergic inhibition in the hippocampus of Fmr1 knockout mice
Sabanov, V., Braat, S., D’Andrea, L., Willemsen, R., Zeidler, S., Rooms, L., Bagni, C., Kooy, R. F., & Balschun, D. (2016) · Neuropharmacology · doi:10.1016/j.neuropharm.2016.12.010 · Cited by 75 · see citing works
GABA Pharmacology: The Search for Analgesics
McCarson, K. E., & Enna, S. J. (2014) · Neurochemical Research · doi:10.1007/s11064-014-1254-x · Cited by 74 · see citing works
Synthesis of 1,3,4-oxadiazole derivatives with anticonvulsant activity and their binding to the GABAA receptor
Wang, S., Liu, H., Wang, X., et al. (2020) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2020.112672 · Cited by 74 · see citing works
Cryo-EM: the resolution revolution and drug discovery
de Oliveira, T. M., van Beek, L., Shilliday, F., Debreczeni, J. É., & Phillips, C. (2021) · SLAS DISCOVERY · doi:10.1177/2472555220960401 · Cited by 73 · see citing works
The (Poly)Pharmacology of Cannabidiol in Neurological and Neuropsychiatric Disorders: Molecular Mechanisms and Targets
Vitale, R. M., Iannotti, F. A., & Amodeo, P. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22094876 · Cited by 74 · see citing works
“Preclinical studies with transgenic mice and/or selective ligands suggested that diverse receptor isoforms have a different role in mediating the action of drugs in specific disorders: α1 is implicated in epilepsy and in sedative/hypnotic effects, α2/α3 mediate anxiolytic and analgesic actions, α5 is involved in learn…”
Background

A new benzodiazepine pharmacology
Möhler, H., Fritschy, J. M., & Rudolph, U. (2002) · The Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.300.1.2 · Cited by 716 · see citing works
Self-citation
GABAA-receptor Subtypes: Clinical Efficacy and Selectivity of Benzodiazepine Site Ligands
Korpi, E. R., Mattila, M. J., Wisden, W., & Lüddens, H. (1997) · Annals of Medicine · doi:10.3109/07853899708999348 · Cited by 91 · see citing works
The value of genetic and pharmacological approaches to understanding the complexities of GABAA receptor subtype functions: The anxiolytic effects of benzodiazepines
Reynolds, D. S. (2008) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2008.03.015 · Cited by 37 · see citing works
S.15.03 Imaging GABA-benzodiazepine receptor subtypes in addiction
Lingford-Hughes, A. R., Myers, J. F., Watson, B. J., Stokes, P. R. A., Kalk, N. J., Rosso, L., Brooks, D. J., Turkheimer, F., Wilson, S. J., & Nutt, D. (2012) · European Neuropsychopharmacology · doi:10.1016/s0924-977x(12)70167-0
Development of Subtype Selective GABAA Modulators: A Review Article
Nagarathna, P., Vardhini, N. H., Bashir, B., Kumar, C. S., & Sreedhar, C. (2019) · Research Journal of Pharmacy and Technology · doi:10.5958/0974-360x.2019.00683.8 · Cited by 2 · see citing works

Authors: Rudolph, U., & Knoflach, F.
Affiliations: Harvard University (US)
F. Hoffmann-La Roche AG (CH)
Corresponding author: Rudolph, Uwe
ORCID: Rudolph, Uwe
Knoflach, Frédéric
Venue: Nature Reviews Drug Discovery
Publisher: Springer Science and Business Media LLC
Published: 2011-07-29
Volume: 10
Issue: 9
Pages: 685-697
ISSN: 1474-1776 (ISSN-L)
1474-1784
DOI: 10.1038/nrd3502
PMC: PMC3375401
OpenAlex: W2013775967
Semantic Scholar: bfb4fcd647899053b94eaf5edf1fe9e748076c6b
Cited by: 733
References: 111
Citations by year: 2026: 41 · 2025: 42 · 2024: 35 · 2023: 46 · 2022: 43 · 2021: 55 · 2020: 49 · 2019: 56 · 2018: 51 · 2017: 58 · 2016: 52 · 2015: 45 · 2014: 62 · 2013: 58 · 2012: 38
FWCI: 4.90
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springer.com/tdm (tdm)
Locations: Nature Reviews Drug Discovery (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: National Institute of Mental Health (R21MH087829, R01MH080006, R03MH085149, MH087829, MH085149, MH080006)
National Institute on Drug Abuse (DA027051, DA026578, R03DA026578, R03DA027051)
National Institute of General Medical Sciences (R01GM086448, GM086448)
Topics: Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
Keywords: GABAA receptor, benzodiazepines, GABAA receptor subtypes, ligand-gated ion channels, chronic pain, depression, schizophrenia, cognitive enhancement, stroke, drug addiction
MeSH terms: Analgesics, Animals, Anxiety Disorders, Benzodiazepines, Depressive Disorder, Humans, Hypnotics and Sedatives, Sleep Initiation and Maintenance Disorders, Mutation, Receptors, GABA-A, Schizophrenia, Nootropic Agents, GABA Modulators, Substance-Related Disorders, Stroke

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review

Beyond classical benzodiazepines: novel therapeutic potential of GABAA receptor subtypes

Abstract

Integrity signals

Claims the paper makes

Claims other papers make about this one

Self-check

Cites

Cited by

Related

Record

About these checks