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Cited by 227Neuroscience and Neuropharmacology ResearchNicotinic Acetylcholine Receptors StudyNeurotransmitter Receptor Influence on Behavior

An emerging circuit pharmacology of GABAA receptors

Open access
Engin, Elif, Benham, Rebecca S., Rudolph, Uwe·2018·Trends in Pharmacological Sciences
DOI 10.1016/j.tips.2018.04.003PMC PMC6056379
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Abstract

In the last 20 years, we have learned a great deal about GABAA receptor (GABAAR) subtypes, and which behaviors are regulated or which drug effects are mediated by each subtype. However, the question of where in the brain the GABAARs involved in specific drug effects or behaviors are remains largely unanswered. Here we review recent studies taking a circuit pharmacology approach to investigate the functions of GABAAR subtypes in specific brain circuits controlling fear, anxiety, learning, memory, reward, addiction and stress related behaviors. The findings of the studies highlight the complexity of brain inhibitory systems and the importance of taking a subtype-, circuit-and neuronal population-specific approach to develop future therapeutic strategies using cell type-specific drug delivery.

AI snapshot

Written from the paper’s full text.

TL;DR

This review argues that GABA_A receptor subtypes regulate fear, anxiety, learning, memory, reward, addiction, and stress-related behaviors in a subtype-, circuit-, and neuronal-population-specific manner. It concludes that circuit pharmacology of GABA_A receptors is emerging but still fragmentary, with findings often limited by contradictory results and incomplete anatomical specificity.

Key findings

  • In anxiety and fear circuits, α2GABAARs in dentate gyrus or CA3 principal neurons are required for diazepam-induced anxiolysis, whereas α2GABAARs in CA1 mediate diazepam-induced fear reduction; deletion in CA1 did not affect anxiolysis, and CA3/DG deletion did not affect fear reduction.
  • In learning and memory, α5GABAAR knockdown in CA3 or DG improved contextual fear memory, while DG granule-cell α5GABAAR knockdown impaired high-interference tasks such as context discrimination, reversal learning in a Morris water maze, and extinction of conditioned fear.
  • In reward and addiction, α2GABAARs in the nucleus accumbens are necessary to maintain midazolam preference in a two-bottle choice test, and α4GABAAR knockdown in the nucleus accumbens shell abolished ethanol self-administration in rats.
  • In stress and depression, global γ2 or α2 knockdown leads to anxiety- and despair-like behavior, δ subunit decreases in postpartum mice increase anxious- and depressive-like behavior and maternal neglect, and both positive and negative allosteric modulation of α5GABAARs can produce rapid antidepressant-like effects in chronically stressed rodents.

Methods

  • Narrative review of recent studies using a circuit pharmacology approach to investigate GABAAR subtypes in brain circuits controlling fear, anxiety, learning, memory, reward, addiction, and stress-related behaviors.
  • Synthesizes findings from gene-targeted mice, conditional knockout/knockdown, pharmacological manipulations, microinfusion, electrophysiology, and behavioral tasks; no primary experimental data are reported.
  • Main analysis is qualitative, organized by behavioral domain and brain circuit, with emphasis on subtype-, circuit-, and neuronal-population-specific effects.

Limitations

  • The paper states that knowledge of GABAAR subtype function within any behaviorally relevant circuit is “very fragmentary” and that the number of studies investigating anxiety- and fear-related behaviors through GABAAR subtypes in specific circuits or cell populations is “rather limited.”
  • The paper notes contradictory findings, such as for α3GABAARs in anxiety and for α2 subunits at the axon initial segment, and states that some evidence is confounded by technical limitations including compound selectivity or insufficient knockdowns.
  • Evident from the text: this is not a systematic review or meta-analysis, and it does not describe a formal search strategy, inclusion criteria, or quantitative synthesis.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/j.tips.2018.04.003

Cites

156 of 156 references verified0 citation errors · 0 not checkable

Statistics

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Claims the paper makes

0 of 222 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    The anxiolytic and fear-reducing actions of benzodiazepines are mediated mostly by α2GABAARs.

    “Later work employing gene-targeted mice demonstrated the anxiolytic and fear-reducing actions of benzodiazepines to be mediated mostly by the α2GABAARs [8-10].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [8] Low K 2000 Molecular and neuronal substrate for the selective attenuation of anxiety Science 290 131 134 11021797 source

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    • cites [9] Vollenweider I 2011 Antidepressant-like properties of alpha2-containing GABA(A) receptors Behav Brain Res 217 77 80 20965216 PMC3023881 source

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    • cites [10] Smith KS 2012 Benzodiazepine-induced anxiolysis and reduction of conditioned fear are mediated by distinct GABAA receptor subtypes in mice Neuropharmacol 63 250 258 PMC3372637 22465203 source

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  • Interpretationnone given

    GABAARs modulate behaviors in a subtype-, circuit- and neuronal population-specific manner.

    “In summary, while studies using systemic manipulations have implicated certain GABAAR subtypes in specific behaviors, GABAARs modulate these behaviors in a subtype-, circuit- and neuronal population-specific manner, and a full understanding of their roles in brain function is possible only if the study of GABAARs is approached with matching complexity.”
    Quote in the paperSubstantial claim
  • Premisecitation

    Selective knockdown of α5GABAARs in the small CeA PKC-delta+ population leads to increased anxiety-like responses by increasing spontaneous activity of these neurons.

    “One group reported that selective knockdown of α5GABAARs in this small CeA population leads to increased anxiety-like responses by increasing the spontaneous activity of these neurons [4].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [4] Botta P 2015 Regulating anxiety with extrasynaptic inhibition Nat Neurosci 18 1493 1500 26322928 PMC4607767 source

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  • Premisecitation

    α1GABAARs of the BLA do not seem important for anxiety-related behaviors in the elevated plus maze.

    “While playing such a substantial role in the acquisition and expression of conditioned fear, α1GABAARs of the BLA do not seem to be important for anxiety-related behaviors in the elevated plus maze (see Box 5) [25]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [25] Heldt SA Ressler KJ 2010 Amygdala-specific reduction of alpha1-GABAA receptors disrupts the anticonvulsant, locomotor, and sedative, but not anxiolytic, effects of benzodiazepines in mice J Neurosci 30 7139 7151 20505082 PMC2905594 source

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  • Premisecitation

    α5GABAARs have been implicated in anxiety, fear and/or response to chronic stress.

    “In addition, γ2GABAARs [11], α1GABAARs [10, 12], α3GABAARs [13] (but see [14-16] for contradictory findings), and more recently, α5GABAARs [16-18, 4] have been implicated in anxiety, fear and/or response to chronic stress.”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [16] Behlke LM 2016 A pharmacogenetic ‘restriction-of-function’ approach reveals evidence for anxiolytic-like actions mediated by alpha5-containing GABAA receptors in mice Neuropsychopharmacol 41 2492 2501 PMC4987847 27067130 source

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    • cites [17] Fischell J 2015 Rapid antidepressant action and restoration of excitatory synaptic strength after chronic stress by negative modulators of alpha5-containing GABAA receptors Neuropsychopharmacol 40 2499 2509 PMC4569955 25900119 source

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    • cites [18] Piantadosi SC 2016 Sex-dependent anti-stress effect of an α5 subunit containing GABAA receptor positive allosteric modulator Front Pharmacol 7 446 27920723 PMC5118774 source

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    • cites [4] Botta P 2015 Regulating anxiety with extrasynaptic inhibition Nat Neurosci 18 1493 1500 26322928 PMC4607767 source

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  • Classified as probably not a substantial claim. 8
  • May combine two claims. 47

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Benzodiazepine anxiolytics act by allosteric modulation of GABAA receptors.

    “The role of GABAARs in the regulation of anxiety and fear responses has been known since allosteric modulation of GABAA receptors was recognized as the mechanism of action for benzodiazepine anxiolytics in the 1970's [7].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [7] Haefely W 1975 Possible involvement of GABA in the central actions of benzodiazepines Psychopharmacol Bull 11 58 59 720

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  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    A full understanding of GABAAR roles in brain function is possible only if the study of GABAARs is approached with matching complexity.

    “In summary, while studies using systemic manipulations have implicated certain GABAAR subtypes in specific behaviors, GABAARs modulate these behaviors in a subtype-, circuit- and neuronal population-specific manner, and a full understanding of their roles in brain function is possible only if the study of GABAARs is approached with matching complexity.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    γ2GABAARs have been implicated in anxiety, fear and/or response to chronic stress.

    “In addition, γ2GABAARs [11], α1GABAARs [10, 12], α3GABAARs [13] (but see [14-16] for contradictory findings), and more recently, α5GABAARs [16-18, 4] have been implicated in anxiety, fear and/or response to chronic stress.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [11] Crestani F 1999 Decreased GABAA-receptor clustering results in enhanced anxiety and a bias for threat cues Nat Neurosci 2 833 839 10461223

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  • May combine two claims.

    Premisecitation

    Intercalated cell masses express α2 and α3GABAARs synaptically, which mediates reciprocal inhibition between the two medial cell masses.

    “The intercalated cell masses also express α2 and α3GABAARs synaptically, which mediates reciprocal inhibition between the two medial cell masses [29].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [29] Geracitano R 2012 Functional expression of the GABA(A) receptor alpha2 and alpha3 subunits at synapses between intercalated medial paracapsular neurons of mouse amygdala Front Neural Circuits 6 32 22666188 PMC3364593

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    Premisecitation

    PV+ interneurons form an inhibitory microcircuit with local SST+ interneurons, the modulation of which is necessary for learning of associative fear.

    “A recent study shows that the PV+ interneurons also form an inhibitory microcircuit with the local SST+ interneurons, the modulation of which is necessary for the learning of associative fear [30].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [30] Wolff SB 2014 Amygdala interneuron subtypes control fear learning through disinhibition Nature 509 453 458 24814341

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    Premisecitation

    A population of GABAergic neurons in CeL expressing PKC-delta increase spontaneous activity following fear conditioning and are involved in fear generalization and anxiety.

    “For instance, a population of GABAergic neurons in the CeL which express protein kinase C-delta (PKC-delta+ neurons) increase their spontaneous activity following fear conditioning [34], and are involved in fear generalization and anxiety (Fig. 1D) [4].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [34] Haubensak W 2010 Genetic dissection of an amygdala microcircuit that gates conditioned fear Nature 468 270 276 21068836 PMC3597095 source

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    • cites [4] Botta P 2015 Regulating anxiety with extrasynaptic inhibition Nat Neurosci 18 1493 1500 26322928 PMC4607767

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  • May combine two claims.

    Interpretationreasoning

    δ activation increases excitatory input into the CeA via both disinhibition of BLA principal neurons and suppression of feedforward inhibition via intercalated cells.

    “Thus, δ activation increases excitatory input into the CeA via both the disinhibition of the BLA principal neurons and the suppression of feedforward inhibition via the intercalated cells.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    α1GABAARs are preferentially expressed in a CeM population of GABAergic neurons expressing CRF1 receptors, mediating tonic inhibition.

    “Similarly, α1GABAARs, which are expressed at very low levels in the CeA (where fast synaptic inhibition is predominantly mediated via α2GABAARs), were found to be preferentially expressed in a CeM population of GABAergic neurons that expresses the corticotrophin releasing factor 1 receptors (CRF1+), mediating tonic inhibition [37].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [37] Herman MA 2013 Novel subunit-specific tonic GABA currents and differential effects of ethanol in the central amygdala of CRF receptor-1 reporter mice J Neurosci 33 3284 3298 23426657 PMC3711798

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    Premisecitation

    α1GABAARs on CRF+ neurons may play important roles in anxiety-related behaviors and extinction of conditioned fear.

    “There is already some evidence from studies using a knockdown of α1GABAARs in CRF+ neurons globally showing that α1GABAARs on CRF+ neurons may play important roles in anxiety-related behaviors and extinction of conditioned fear [39]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [39] Gafford GM 2012 Cell-type specific deletion of GABA(A)alpha1 in corticotropin-releasing factor-containing neurons enhances anxiety and disrupts fear extinction Proc Natl Acad Sci USA 109 16330 16335 22992651 PMC3479581

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    Premisecitation

    δ-containing GABAARs are expressed strongly and exert tonic inhibitory control on intercalated cell masses.

    “In addition to PV+ interneurons, δ-containing GABAARs are also expressed strongly and exert tonic inhibitory control on intercalated cell masses (Fig. 1C [28]).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [28] Marowsky A Vogt KE 2014 Delta-subunit-containing GABAA-receptors mediate tonic inhibition in paracapsular cells of the mouse amygdala Front Neural Circuits 8 27 24723854 PMC3971179

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    Premisecitation

    PV+ interneurons mediating feedback inhibition onto BLA pyramidal neurons form synapses in perisomatic locations and proximal dendrites, where α2GABAARs and α3GABAARs are expressed.

    “PV+ interneurons mediating feedback inhibition onto BLA pyramidal neurons form synapses in perisomatic locations and proximal dendrites, where α2GABAARs and α3GABAARs are expressed [26].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [26] Gao Y Heldt SA 2016 Enrichment of GABAA receptor alpha-subunits on the axonal initial segment shows regional differences Front Cell Neurosci 10 39 26973458 PMC4771769

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    Interpretationcitation

    Recent experiments demonstrate a well-defined separation at the level of microcircuits between fear and anxiety, contrary to earlier unitary hippocampus view.

    “Based on earlier findings where the hippocampus was treated as a unitary structure, it would have been natural to conclude that fear and anxiety are mediated by the same circuit, while these recent experiments [43] clearly demonstrate a well-defined separation at the level of microcircuits.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [43] Engin E 2016 Modulation of anxiety and fear via distinct intrahippocampal circuits eLife 5 e14120 26971710 PMC4816644

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    Premisecitation

    Areas such as mPFC, septum, thalamus, hypothalamus, periaqueductal grey, raphe nuclei and locus coeruleus are involved in regulation of anxiety and fear, and role of GABAARs in these areas has been demonstrated through microinfusion studies using nonselective GABAergic agents.

    “There is ample evidence that areas such as the mPFC, septum, thalamus, hypothalamus, periaqueductal grey, raphe nuclei and locus coeruleus are involved in the regulation of anxiety and fear, and the role of the GABAA receptors in these areas has been demonstrated through microinfusion studies using nonselective GABAergic agents [42, 45, 51].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [42] Engin E Treit D 2007 The role of hippocampus in anxiety: intracerebral infusion studies Behav Pharmacol 18 365 374 17762507

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    • cites [45] Engin E Treit D 2007 The anxiolytic-like effects of allopregnanolone vary as a function of intracerebral microinfusion site: the amygdala, medial prefrontal cortex, or hippocampus Behav Pharmacol 18 461 470 17762514

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    • cites [51] Engin E 2008 Anxiolytic and antidepressant effects of intracerebroventricularly administered somatostatin: behavioral and neurophysiological evidence Neuroscience 157 666 676 18940236

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  • May combine two claims.

    Premisecitation

    Infusion of allopregnanolone into dorsal CA1 is anxiolytic in elevated plus maze, although not consistently.

    “For instance, the infusion of allopregnanolone, a neurosteroid that acts as a positive allosteric modulator of GABAARs, into the dorsal CA1 area was shown to be anxiolytic in an elevated plus maze [44]; although not consistently [45].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [44] Modol L 2011 Neurosteroids infusion into the CA1 hippocampal region on exploration, anxiety-like behaviour and aversive learning Behav Brain Res 222 223 229 21463656

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    • cites [45] Engin E Treit D 2007 The anxiolytic-like effects of allopregnanolone vary as a function of intracerebral microinfusion site: the amygdala, medial prefrontal cortex, or hippocampus Behav Pharmacol 18 461 470 17762514

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  • May combine two claims.

    Premisecitation

    Fear-reducing effects of diazepam in tests such as fear-potentiated startle or Vogel conflict test are completely abolished in animals with deletion of α2GABAARs in CA1, while knocking down α2GABAARs in CA3 or DG has no effect.

    “In stark contrast, the fear-reducing effects of diazepam in tests such as fear-potentiated startle or Vogel conflict test (see Box 5) were completely abolished in animals with a deletion of α2GABAARs in CA1. Knocking down α2GABAARs in CA3 or DG had no effect on diazepam-induced reduction of fear (see Figure 3A, Key Figure).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [43] Engin E 2016 Modulation of anxiety and fear via distinct intrahippocampal circuits eLife 5 e14120 26971710 PMC4816644

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    Premisecitation

    Knockout of γ2GABAARs in cerebellar Purkinje cells does not affect baseline anxiety-like behavior or anxiolytic effects of pregnanolone.

    “Another study involving a γ2GABAAR knockout focused on cerebellar Purkinje cells, providing more anatomical specificity, and found that baseline anxiety-like behavior or anxiolytic effects of the neurosteroid pregnanolone were not affected by the knockout, confirming that these cell populations are not involved in anxiety and anxiolysis [53].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [53] Leppä E 2016 Increased motor-impairing effects of the neuroactive steroid pregnanolone in mice with targeted inactivation of the GABAA receptor γ2 subunit in the cerebellum Front Pharmacol 7 403 27833556 PMC5081378

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  • May combine two claims.

    Interpretationcitation

    α2GABAARs in the intrahippocampal circuit play a pivotal role in control of anxiety; activity of diazepam in other brain anxiety nodes is not sufficient to elicit anxiolysis if DG and CA3 are not inhibited through α2GABAARs.

    “This finding suggests that the α2GABAARs in this intrahippocampal circuit play a pivotal role in the control of anxiety, as the activity of diazepam in all other important nodes in the brain anxiety circuit, such as the amygdala, the extended amygdala and the mPFC, was not sufficient to elicit an anxiolytic-like effect if DG and CA3 were not inhibited through α2GABAARs.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [43] Engin E 2016 Modulation of anxiety and fear via distinct intrahippocampal circuits eLife 5 e14120 26971710 PMC4816644

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    Premisecitation

    Ventral/temporal hippocampus is more involved in anxiety and emotional processing, while dorsal/septal portions are more involved in learning and memory.

    “with ventral/temporal portions more involved in anxiety and emotional processing, and dorsal/septal portions more involved in learning and memory [41].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [41] Fanselow MS Dong HW 2010 Are the dorsal and ventral hippocampus functionally distinct structures? Neuron 65 7 19 20152109 PMC2822727 source

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    Premisecitation

    Allopregnanolone is not selective for a single GABAAR subtype but has high efficacy on α4GABAARs.

    “While allopregnanolone is not selective for a single GABAAR subtype, it has high efficacy on α4GABAARs [46, 47].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [46] Belelli D 2002 The influence of subunit composition on the interaction of neurosteroids with GABA(A) receptors Neuropharmacol 43 651 661 12367610

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    • cites [47] Matthew CC Samba RD 2013 Neurosteroid interactions with synaptic and extrasynaptic GABA(A) receptors: regulation of subunit plasticity, phasic and tonic inhibition, and neuronal network excitability Psychopharmacol 230 151 188 PMC3832254 24071826

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    Premisecitation

    Anterograde amnestic effects of benzodiazepines have been known for a long time, suggesting a suppressive role for GABAARs in learning and memory.

    “The anterograde amnestic effects of benzodiazepines have been known for a long time [55], suggesting a suppressive role for GABAARs in learning and memory.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [55] Lister RG 1985 The amnesic action of benzodiazepines in man Neurosci Biobehav Rev 9 87 94 2858084

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    Premisecitation

    α5GABAARs are expressed in all three subregions of the hippocampus, with lower expression in the DG, and they mediate tonic, as well as slow phasic inhibition.

    “The α5GABAARs are expressed in all three subregions of the hippocampus, with lower expression in the DG, and they mediate tonic, as well as slow phasic inhibition [69, 70].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [69] Glykys J 2008 Which GABA(A) receptor subunits are necessary for tonic inhibition in the hippocampus? J Neurosci 28 1421 1426 18256262 PMC6671570 source

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    • cites [70] Zarnowska ED 2009 GABAA receptor alpha5 subunits contribute to GABAA, slow synaptic inhibition in mouse hippocampus J Neurophysiol 101 1179 1191 19073796 PMC2666407

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    Premisecitation

    Evidence for involvement of dorsal hippocampal α5GABAARs in memory encoding and consolidation has been sparse and mixed, the latter likely due to technical limitations with compound selectivity or insufficient knockdowns.

    “However, the evidence for the involvement of dorsal hippocampal α5GABAARs in memory encoding and consolidation has been sparse [72] and mixed [73, 74], the latter likely due to technical limitations with compound selectivity or insufficient knockdowns.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [72] McEown K Treit D 2013 A2 GABAA receptor subunits in the ventral hippocampus and alpha5 GABAA receptor subunits in the dorsal hippocampus mediate anxiety and fear memory Neuroscience 252 169 177 23962649

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    • cites [73] Gafford GM 2005 Effects of post-training hippocampal injections of midazolam on fear conditioning Learn Mem 12 573 578 16322359 PMC1356174

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    • cites [74] Bailey DJ 2002 Effects of hippocampal injections of a novel ligand selective for the α5β2γ2 subunits of the GABA/benzodiazepine receptor on pavlovian conditioning Neurobiol Learn Mem 78 1 10 12071663

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    Premisecitation

    α5GABAARs seem to be more densely expressed in the ventral hippocampus, and ventral hippocampal α5GABAARs play an important role in establishing a high threshold for induction of long-term potentiation.

    “α5GABAARs seem to be more densely expressed in the ventral hippocampus, and ventral hippocampal α5GABAARs play an important role in establishing a high threshold for the induction of long-term potentiation, a physiological measure of synaptic plasticity thought to underlie memory formation [75, 76].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [75] Pofantis H Papatheodoropoulos C 2014 The alpha5GABAA receptor modulates the induction of long-term potentiation at ventral but not dorsal CA1 hippocampal synapses Synapse 68 394 401 24823837

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    • cites [76] Sarantis K 2008 Differential pharmacological properties of GABAA/benzodiazepine receptor complex in dorsal compared to ventral rat hippocampus Neurochem Int 52 1019 1029 18069090

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    Premisecitation

    α5GABAARs contribute to tonic currents and control overall network excitability within hippocampus particularly when ambient GABA levels are high, while tonic inhibition through δGABAARs prevails during times of low ambient GABA.

    “α5GABAARs contribute to tonic currents, and thus the control of overall network excitability within the hippocampus, particularly when ambient GABA levels are high, as may occur during times of increased neuronal activity, while tonic inhibition through δGABAARs prevails during times of low ambient GABA [71].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [71] Scimemi A 2005 Multiple and plastic receptors mediate tonic GABAA receptor currents in the hippocampus J Neurosci 25 10016 10024 16251450 PMC6725560

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    Premisecitation

    There is evidence suggesting involvement of α1GABAARs, α2GABAARs, and α4/δGABAARs in learning and memory.

    “There is also evidence suggesting the involvement of α1GABAARs [62, 63], α2GABAARs [50], and α4/δGABAARs in learning and memory [64-68].”
    Quote in the paperNot a substantial claim0 of 8 sources checked
    • cites [62] Berry RB 2008 Mice with targeted genetic reduction of GABA(A) receptor alpha1 subunits display performance differences in Morris water maze tasks Neurobiol Learn Mem 90 580 583 18625330 PMC2581787

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    • cites [63] Rudolph U 1999 Benzodiazepine actions mediated by specific gamma-aminobutyric acid(A) receptor subtypes Nature 401 796 800 10548105 source

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    • cites [50] Engin E 2015 Tonic inhibitory control of dentate gyrus granule cells by alpha5-containing GABAA receptors reduces memory interference J Neurosci 35 13698 13712 26446222 PMC4595621

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    • cites [64] Cushman JD 2014 The role of the delta GABA(A) receptor in ovarian cycle-linked changes in hippocampus-dependent learning and memory Neurochem Res 39 1140 1146 24667980

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    • cites [65] Moore MD 2010 Trace and contextual fear conditioning is enhanced in mice lacking the alpha4 subunit of the GABA(A) receptor Neurobiol Learn Mem 93 383 387 20018248 PMC3985603

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    • cites [66] Whissell PD 2013 Acutely increasing deltaGABA(A) receptor activity impairs memory and inhibits synaptic plasticity in the hippocampus Front Neural Circuits 7 146 24062648 PMC3775149

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    • cites [67] Whissell PD 2013 gamma-aminobutyric acid type A receptors that contain the delta subunit promote memory and neurogenesis in the dentate gyrus Ann Neurol 74 611 621 23686887

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    • cites [68] Zhang WH 2017 δ Subunit-containing GABAA receptor prevents overgeneralization of fear in adult mice Learn Mem 24 381 384 28716958 PMC5516689

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    Interpretationcitation

    Extrasynaptic rather than synaptic receptors play an essential role in managing memory interference and enabling behavioral flexibility.

    “These findings suggest that extrasynaptic rather than synaptic receptors play an essential role in managing memory interference and enabling behavioral flexibility, at least providing evidence that these processes are not disrupted by any simple shift in E/I balance.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [50] Engin E 2015 Tonic inhibitory control of dentate gyrus granule cells by alpha5-containing GABAA receptors reduces memory interference J Neurosci 35 13698 13712 26446222 PMC4595621

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    • cites [81] Hausrat TJ 2015 Radixin regulates synaptic GABAA receptor density and is essential for reversal learning and short-term memory Nat Commun 6 6872 25891999 PMC4411296

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Presence and abundance of GABAA receptors with two different types of α subunits has been described previously.

    “Presence and abundance of GABAA receptors with two different types of α subunits has been described previously [80].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [80] Benke D 2004 Analysis of the presence and abundance of GABAA receptors containing two different types of alpha subunits in murine brain using point-mutated alpha subunits J Biol Chem 279 43654 43660 15304513

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    Premisecitation

    Training in a spatial memory task also leads to parallel increase in α1GABAARs and colocalization of α1 and α5, suggesting formation of complexes containing both α subunits.

    “The same study also noted a parallel increase in α1GABAARs and of the colocalization of α1 and α5, suggesting the formation of complexes containing both α subunits [79].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [79] Ghafari M 2017 Formation of GABAA receptor complexes containing alpha1 and alpha5 subunits is paralleling a multiple T-maze learning task in mice Brain Struct Funct 222 549 561 27155990

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    Premisecitation

    Memory-suppressing effects of α5GABAARs have been demonstrated repeatedly and have led to development of several negative GABAAR allosteric modulators with some selectivity for α5GABAARs as potential cognitive enhancers.

    “The memory-suppressing effects of α5GABAARs have been demonstrated repeatedly and have led to the development of several negative GABAAR allosteric modulators with some selectivity for α5GABAARs with the hope that they can be used as cognitive enhancers [40].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [40] Rudolph U Mohler H 2014 GABAA receptor subtypes: Therapeutic potential in Down syndrome, affective disorders, schizophrenia, and autism Annu Rev Pharmacol Toxicol 54 483 507 24160694 PMC3997216

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Reduction of α5GABAAR activity increases gamma and ripple band power in CA3 in hippocampal slices, two oscillations involved in memory formation and consolidation which may support context learning.

    “A reduction of α5GABAAR activity increases gamma and ripple band power in CA3 in hippocampal slices, two hippocampal oscillations known to be involved in memory formation and consolidation which may support context learning [6, 77].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [6] Papatheodoropoulos C Koniaris E 2011 Alpha5GABAA receptors regulate hippocampal sharp wave-ripple activity in vitro Neuropharmacol 60 662 673 21146551

      Not checked in the free run.

    • cites [77] Towers SK 2004 Alpha 5 subunit-containing GABAA receptors affect the dynamic range of mouse hippocampal kainate-induced gamma frequency oscillations in vitro J Physiol 559 721 728 15284346 PMC1665170

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    The increase in α5GABAARs after spatial memory training may be an adaptive response to protect recently encoded memory from interference during consolidation.

    “which may be an adaptive response to protect the recently encoded memory from interference during the memory consolidation period.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In DG, a large subpopulation of PV+ interneurons express δ subunits, a small minority of SST+ interneurons express δ subunit, and none of calbindin+ or calretinin+ interneurons express δ subunit.

    “For instance, a large subpopulation of PV+ interneurons in DG express δ subunits, while only a small minority of SST+ interneurons, and none of the calbindin+ or calretinin+ interneurons express the δ subunit [91].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [91] Milenkovic I 2013 The parvalbumin-positive interneurons in the mouse dentate gyrus express GABAA receptor subunits alpha1, beta2, and delta along their extrasynaptic cell membrane Neuroscience 254 80 96 24055402 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    GABAAR genes, particularly GABRA2 and GABRA4, have been linked to illicit drug use, to dependence for drugs with non-GABA-related mechanisms of action, and to polydrug use.

    “More surprisingly, GABAAR genes (particularly GABRA2 and GABRA4) have also been linked to illicit drug use, to dependence for drugs that have non-GABA-related mechanisms of action and to polydrug use [97, 99-103].”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [97] Enoch MA 2013 A factor analysis of global GABAergic gene expression in human brain identifies specificity in response to chronic alcohol and cocaine exposure PLOS ONE 8 e64014 23717525 PMC3661725

      Not checked in the free run.

    • cites [99] Dixon CI 2010 Cocaine effects on mouse incentive-learning and human addiction are linked to alpha2 subunit-containing GABAA receptors Proc Natl Acad Sci USA 107 2289 2294 20133874 PMC2836671

      Not checked in the free run.

    • cites [100] Enoch MA 2010 The influence of GABRA2, childhood trauma, and their interaction on alcohol, heroin, and cocaine dependence Biol Psychiatry 67 20 27 19833324 PMC2964936

      Not checked in the free run.

    • cites [101] Agrawal A 2006 Association of GABRA2 with drug dependence in the collaborative study of the genetics of alcoholism sample Behav Genet 36 640 50 16622805

      Not checked in the free run.

    • cites [102] Agrawal A 2008 Gamma-aminobutyric acid receptor genes and nicotine dependence: evidence for association from a case-control study Addiction 103 1027 1038 18482426

      Not checked in the free run.

    • cites [103] Drgon T 2006 Linkage disequilibrium, haplotype and association studies of a chromosome 4 GABA receptor gene cluster: candidate gene variants for addictions Am J Med Genet Part B, Neuropsychiatric Genetics 141B 854 860 PMC3922197 16894595

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Selective knockout of γ2GABAARs on SST+ interneurons of the forebrain leads to a subtler behavioral phenotype with no observed changes in spatial learning.

    “Selective knockout of γ2GABAARs on SST+ interneurons of the forebrain, on the other hand, led to a subtler behavioral phenotype with no observed changes in spatial learning, despite increasing both spontaneous and miniature inhibitory postsynaptic currents (IPSCs) in CA1 [52].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [52] Fuchs T 2016 Disinhibition of somatostatin-positive GABAergic interneurons results in an anxiolytic and antidepressant-like brain state Mol Psychiatry 22 920 930 27821870 PMC5422144

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    α2GABAARs play a role in benzodiazepine reward, with the NAc as a possible anatomical locus for this effect.

    “These findings clearly demonstrate a role for α2GABAARs in benzodiazepine reward and point to the NAc as the possible anatomical locus for this effect.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [106] Reynolds LM 2012 Differential roles of GABAA receptor subtypes in benzodiazepine-induced enhancement of brain-stimulation reward Neuropsychopharmacol 37 2531 2540 PMC3442348 22763624

      Not checked in the free run.

    • cites [107] Engin E 2014 Neural basis of benzodiazepine reward: requirement for alpha2 containing GABAA receptors in the nucleus accumbens Neuropsychopharmacol 39 1805 1815 PMC4059902 24553732

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Activation of α1GABAARs causes hyperpolarization of GABAergic neurons, relieving inhibitory control over VTA dopamine neurons.

    “As the α1GABAARs are expressed on GABAergic neurons that target the dopaminergic neurons in the VTA (see Fig 4B), the activation of these receptors causes hyperpolarization of the GABAergic neurons, relieving the inhibitory control over VTA dopamine neurons.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [104] Tan KR 2010 Neural bases for addictive properties of benzodiazepines Nature 463 769 774 20148031 PMC2871668

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In rhesus monkeys, under certain circumstances, compounds that do not modulate α1GABAARs are self-administered intravenously, suggesting rewarding properties.

    “However, it has been shown in rhesus monkeys that at least under certain circumstances, compounds that do not modulate α1GABAARs are self-administered intravenously, suggesting that they have rewarding properties [105].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [105] Shinday NM 2013 Reinforcing effects Of compounds lacking intrinsic efficacy at alpha 1 subunit-containing GABA(A) receptor subtypes in midazolam-but not cocaine-experienced rhesus monkeys Neuropsychopharmacol 38 1006 1014 PMC3629390 23303046

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationreasoning

    Activation of α4GABAARs in the NAc reduces activity of MSNs, which should be aversive.

    “For instance, the activation of the α4GABAARs in NAc should have the effect of reducing activity of the MSNs, which should be aversive.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationreasoning

    Activation of α4GABAARs in the mPFC reduces excitatory input into VTA dopaminergic neurons, leading to an overall aversive effect.

    “Similarly, activating α4GABAARs in mPFC should reduce the excitatory input into VTA dopaminergic neurons, again leading to an overall aversive effect.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Infusion of diazepam into the VTA leads to increased activity of D1+ MSNs, but not D2+ MSNs.

    “Moreover, infusion of diazepam into the VTA leads to increased activity of D1+ MSNs, but not D2+ MSNs [109].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [109] van der Kooij MA 2018 Diazepam actions in the VTA enhance social dominance and mitochondrial function in the nucleus accumbens by activation of dopamine D1 receptors Mol Psychiatry 23 569 578 28727688 PMC5822450

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Reduction of α1GABAARs in the VTA may increase baseline GABAergic inhibition over dopaminergic neurons and require higher ethanol concentrations for dopaminergic disinhibition.

    “For instance, long-term administration of ethanol reduces the expression of α1GABAARs in the VTA [117], possibly increasing baseline GABAergic inhibition over dopaminergic neurons and requiring higher ethanol concentrations for dopaminergic disinhibition.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [117] Charlton ME 1997 Chronic ethanol administration regulates the expression of GABAA receptor alpha 1 and alpha 5 subunits in the ventral tegmental area and hippocampus J Neurochem 68 121 127 8978717

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Antidepressant treatment or increases in cellular activation reverses disease and stress-induced changes in GABAergic signaling.

    “Conversely, antidepressant treatment or increases in cellular activation (through deep brain stimulation or optogenetic/pharmacological manipulations) reverses these disease and stress-induced changes in GABAergic signaling [123-127].”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [123] Luscher B 2011 The GABAergic deficit hypothesis of major depressive disorder Mol Psychiatry 16 383 406 21079608 PMC3412149 source

      Not checked in the free run.

    • cites [124] Bewernick BH 2010 Nucleus accumbens deep brain stimulation decreases ratings of depression and anxiety in treatment-resistant depression Biol Psychiatry 67 110 116 19914605 source

      Not checked in the free run.

    • cites [125] Mayberg HS 2005 Deep brain stimulation for treatment-resistant depression Neuron 45 651 660 15748841 source

      Not checked in the free run.

    • cites [126] Ren Z 2016 Bidirectional homeostatic regulation of a depression-related brain state by gamma-aminobutyric acidergic deficits and ketamine treatment Biol Psychiatry 80 457 468 27062563 PMC4983262 source

      Not checked in the free run.

    • cites [127] Shen Q 2010 Gamma-aminobutyric acid-type A receptor deficits cause hypothalamic-pituitary-adrenal axis hyperactivity and antidepressant drug sensitivity reminiscent of melancholic forms of depression Biol Psychiatry 68 512 520 20579975 PMC2930197

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    These findings may explain both initial sensitization and later acceleration of intake.

    “A reduction in NAc α2GABAARs accompanies cocaine sensitization through long-term administration [120], while there is some evidence that these same receptors are required for the development of behavioral sensitization to cocaine in the first place [99,121], which may explain both initial sensitization and later acceleration of intake.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [120] Chen Q 2007 Reversal of cocaine sensitization-induced behavioral sensitization normalizes GAD67 and GABAA receptor alpha2 subunit expression, and PKC zeta activity Biochem Biophys Res Commun 356 733 738 17382295 PMC1924471

      Not checked in the free run.

    • cites [99] Dixon CI 2010 Cocaine effects on mouse incentive-learning and human addiction are linked to alpha2 subunit-containing GABAA receptors Proc Natl Acad Sci USA 107 2289 2294 20133874 PMC2836671

      Not checked in the free run.

    • cites [121] Mitchell SJ 2014 The effects of early life stress on nucleus accumbens GABAA receptor function and cocaine mediated behaviour Eur Neuropsychopharmacol 24 S119

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Decreases in GABA signaling and GABAergic cell types, and alterations in receptor subtypes, are detected in depressed patients and animals exposed to stress.

    “Clinical and preclinical studies provide evidence for a GABA hypothesis in depression where decreases in GABA signaling and GABAergic cell types, as well as alterations in receptor subtypes are detected in depressed patients as well as animals exposed to stress (a factor in the development of depression), for a thorough review of these studies see [123].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [123] Luscher B 2011 The GABAergic deficit hypothesis of major depressive disorder Mol Psychiatry 16 383 406 21079608 PMC3412149 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Eszopiclone is a positive GABAAR modulator with postulated selectivity for α2/α3GABAARs.

    “There is clinical evidence for the antidepressant effects of subtype selective GABAAR compounds as eszopiclone, a positive GABAAR modulator with postulated selectivity for α2/α3GABAARs [138], has a synergistic effect when given in combination with fluoxetine in patients with depression and insomnia [139].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [138] Nutt DJ Stahl SM 2010 Searching for the perfect sleep: the continuing evolution of GABAA receptor modulators as hypnotics J Psychopharmacol 24 1601 1612 19942638 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Chronic inhibition of SST interneurons has an anxiolytic- and antidepressant-like effect.

    “Manipulation of SST firing through designer receptor exclusively activated by a designer drug (DREADD) technology, demonstrated that acute inhibition of this GABAergic cell type has an anxiogenic- and prodepressant-like effect while chronic inhibition has an anxiolytic- and antidepressant-like effect [137].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [137] Soumier A Sibille E 2014 Opposing effects of acute versus chronic blockade of frontal cortex somatostatin-positive inhibitory neurons on behavioral emotionality in mice Neuropsychopharmacol 39 2252 2262 PMC4104344 24690741 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    This manipulation has anxiolytic- and antidepressant-like effects.

    “More recently, conditional deletion of γ2 from SST+ interneurons in the forebrain was shown to disinhibit this interneuron population, in turn inhibiting excitatory pyramidal cells within CA1 of the hippocampus and layer 2/3 of the cingulate cortex and having anxiolytic- and antidepressant-like effects [52].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [52] Fuchs T 2016 Disinhibition of somatostatin-positive GABAergic interneurons results in an anxiolytic and antidepressant-like brain state Mol Psychiatry 22 920 930 27821870 PMC5422144

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Both positive and negative allosteric modulation of α5GABAARs produces rapid antidepressant-like effects and/or reductions in stress-related behaviors in rodents exposed to chronic stress.

    “Interestingly, both positive and negative allosteric modulation of α5GABAARs produces rapid antidepressant-like effects and/or reductions in stress-related behaviors in rodents exposed to chronic stress [17, 18, 140, 141].”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [17] Fischell J 2015 Rapid antidepressant action and restoration of excitatory synaptic strength after chronic stress by negative modulators of alpha5-containing GABAA receptors Neuropsychopharmacol 40 2499 2509 PMC4569955 25900119 source

      Not checked in the free run.

    • cites [18] Piantadosi SC 2016 Sex-dependent anti-stress effect of an α5 subunit containing GABAA receptor positive allosteric modulator Front Pharmacol 7 446 27920723 PMC5118774

      Not checked in the free run.

    • cites [140] Carreno FR 2017 Selective pharmacological augmentation of hippocampal activity produces a sustained antidepressant-like response without abuse-related or psychotomimetic effects Int J Neuropsychopharmacol 20 504 509 28339593 PMC5458335

      Not checked in the free run.

    • cites [141] Zanos P 2017 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 4 PMC5334634 28275719

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    PV+ and SST+ interneurons form relatively non-overlapping interneuron populations.

    “As noted earlier, PV+ and SST+ interneurons form relatively non-overlapping interneuron populations [132, 133].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [132] Rudy B 2011 Three groups of interneurons account for nearly 100% of neocortical GABAergic neurons Dev Neurobiol 71 45 61 21154909 PMC3556905 source

      Not checked in the free run.

    • cites [133] Xu X 2010 Immunochemical characterization of inhibitory mouse cortical neurons: three chemically distinct classes of inhibitory cells J Comp Neurol 518 389 404 19950390 PMC2804902 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Decreases in SST expression are detected in the dorsolateral prefrontal cortex and subgenual anterior cingulate cortex of depressed patients and the prefrontal cortex of mice exposed to chronic unpredictable stress.

    “Decreases in SST expression are detected in the dorsolateral prefrontal cortex and subgenual anterior cingulate cortex of depressed patients as well as the prefrontal cortex of mice exposed to chronic unpredictable stress, while changes in PV are less consistent [134-136].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [134] Sibille E 2011 GABA-related transcripts in the dorsolateral prefrontal cortex in mood disorders Int J Neuropsychopharmacol 14 721 734 21226980 PMC3388740 source

      Not checked in the free run.

    • cites [135] Guilloux JP 2012 Molecular evidence for BDNF- and GABA-related dysfunctions in the amygdala of female subjects with major depression Mol Psychiatry 17 1130 1142 21912391 PMC3237836

      Not checked in the free run.

    • cites [136] Banasr M 2017 Characterization of GABAergic marker expression in the chronic unpredictable stress model of depression Chronic Stress 1 10.1177/2470547017720459 Epub 2017 Aug 3 PMC5565173 28835932 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    α5 positive allosteric modulators may be useful to attenuate hippocampal hyperactivity in order to improve cognitive function in schizophrenia, age-related cognitive dysfunction, and mild cognitive impairment due to Alzheimer's disease.

    “e,g, α5 positive allosteric modulators may be useful to attenuate hippocampal hyperactivity in order to improve cognitive function in schizophrenia, age-related cognitive dysfunction and mild cognitive impairment due to Alzheimer's disease.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Extremely low doses of the compound which have no effect on their own in control animals are administered systemically and only on the surface of HaloTag-expressing neurons is the compound concentration high enough to elicit an effect.

    “Extremely low doses of the compound which have no effect on their own in control animals are administered systemically and only on the surface of the HaloTag-expressing neurons is the compound concentration high enough to elicit an effect [143].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [143] Shields BC 2017 Deconstructing behavioral neuropharmacology with cellular specificity Science 356 10.1126/science.aaj2161 28385956

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    HaloTag is expressed in defined neuronal cells and captures and tethers drugs to the cell surface over seconds to minutes.

    “A protein called HaloTag is expressed in defined neuronal cells (e.g. using a cell-type-specific promoter) and captures and tethers drugs to the cell surface over seconds to minutes, producing an approximately 100-fold enrichment of the drug on the surface of the HaloTag-expressing cells.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [143] Shields BC 2017 Deconstructing behavioral neuropharmacology with cellular specificity Science 356 10.1126/science.aaj2161 28385956

      Not checked in the free run.

53 of 53

  • The paper relies on this without support.

    All GABAAR subtypes except α6 are expressed in varying cell groups and subregions of the amygdala.

    “All GABAAR subtypes, with the exception of α6GABAARs, are expressed in varying cell groups and subregions of the amygdala.”

  • The paper relies on this without support.

    α3GABAARs on LA principal neurons are localized preferentially extrasynaptically and mediate tonic inhibition.

    “Despite this, the α3GABAARs on LA principal neurons are localized preferentially exrasynaptically, mediating tonic inhibition.”

  • The paper relies on this without support.

    There are no studies to date that investigate the role of specific GABAAR subtypes within the circuitry of the mPFC, septum, thalamus, hypothalamus, periaqueductal grey, raphe nuclei and locus coeruleus.

    “However, to our knowledge, there are no studies to date that investigate the role of specific GABAAR subtypes within the circuitry of these areas.”

  • The paper relies on this without support.

    α2GABAARs are expressed on dendrites, soma and axon initial segment of principal neurons in all three hippocampal subregions, receiving input from different subtypes of interneuron depending on subcellular location.

    “α2GABAARs, which have been consistently implicated in the control of fear and anxiety, are expressed on the dendrites, soma and axon initial segment of principal neurons in all three hippocampal subregions, receiving input from different subtypes of interneuron depending on subcellular location.”

  • The paper relies on this without support.

    Circuit pharmacology studies in rodents can identify GABAAR subtypes and circuits relevant to human anxiety, fear, learning, memory, reward, addiction, and stress-related behaviors.

    “The findings of the studies highlight the complexity of brain inhibitory systems and the importance of taking a subtype-, circuit-and neuronal population-specific approach to develop future therapeutic strategies using cell type-specific drug delivery.”

  • The paper relies on this without support.

    Tonic inhibition in the DG is mediated through both α5GABAARs and α4/δGABAARs.

    “Given that tonic inhibition in the DG is mediated through both α5GABAARs and α4/δGABAARs, a natural question that comes to mind is: would α4/SGABAARs of the DG also play a similar role in managing memory interference, or is the specific pharmacology and expression pattern of α5GABAARs required for this process?”

  • The paper relies on this without support.

    The γ2 subunit is found in 90% of GABAARs.

    “While these studies are much more targeted than the global gene deletion studies discussed earlier, the γ2 subunit is found in 90% of GABAARs.”

  • The paper relies on this without support.

    α subtype selective compounds lack some side effects associated with nonselective GABAergic compounds such as sedation and tolerance.

    “Additionally, pharmacological compounds with α subtype selectivity are a promising potential therapeutic tool as they lack some of the side effects associated with nonselective GABAergic compounds such as sedation and tolerance.”

  • The paper relies on this without support.

    Activation of D1+ MSNs leads to positive reinforcement and enhances the rewarding properties of addictive drugs.

    “It has been demonstrated that the activation of D1+ MSNs leads to positive reinforcement and enhances the rewarding properties of addictive drugs, while the activation of D2+ MSNs may have the opposite effect (see [108] for a contradictory viewpoint).”

  • The paper relies on this without support.

    Activation of D2+ MSNs may have the opposite effect to D1+ MSN activation.

    “It has been demonstrated that the activation of D1+ MSNs leads to positive reinforcement and enhances the rewarding properties of addictive drugs, while the activation of D2+ MSNs may have the opposite effect (see [108] for a contradictory viewpoint).”

  • The paper relies on this without support.

    α4GABAARs are expressed in both D1+ and D2+ neurons.

    “While α4GABAARs are expressed in both D1+ and D2+ neurons, and have been shown to play opposing roles in the reinforcing properties of other drugs of abuse [115], the relative abundance of the receptor in the two neuronal populations is not clear.”

  • The paper relies on this without support.

    Neurosteroids modulate the activity of GABAARs.

    “As noted earlier, neurosteroids modulate the activity of GABAARs, and thus, ethanol may induce changes in the activity of GABAARs via its effect on neurosteroids, in addition to directly binding to GABAARs.”

  • The paper relies on this without support.

    Drugs of abuse exert their addictive actions through increasing dopamine levels in target structures and inducing synaptic plasticity in the VTA.

    “Drugs of abuse exert their addictive actions through increasing dopamine levels in target structures and inducing synaptic plasticity in the VTA.”
13 of 13

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?

  • Animal and human studies have established the critical role of both GABA-A and GABA-B receptors in the processing of anxiety, as well as in the pathogenesis and pathology of anxiety disorders.

    “Animal and human studies have established the critical role of both the GABA-A and the GABA-B receptors in the processing of anxiety, as well as in the pathogenesis and pathology of anxiety disorders (Bandelow et al., 2016;Engin et al., 2018;Nuss, 2015;Pizzo, O'Leary, & Cryan, 2018).”

    From Novel pharmacological targets in drug development for the treatment of anxiety and anxiety-related disorders (2019) · cites this paper as Engin et al., 2018

  • BDZs exhibit rapid anxiolytic effects, but also have sedative, amnestic, anticonvulsant, muscle relaxant and addictive properties.

    “BDZs, which have been in clinical use for decades, not only exhibit rapid anxiolytic effects, but also have sedative, amnestic, anticonvulsant, muscle relaxant and addictive properties (Coric et al., 2005;Engin et al., 2018).”

    From Novel pharmacological targets in drug development for the treatment of anxiety and anxiety-related disorders (2019) · cites this paper as Engin et al., 2018

  • The key neuronal circuits and brain areas mediating the anxiolytic effects of BDZs are still not entirely clear, although the limbic system, and the amygdala in particular, has been revealed as a central component.

    “The key neuronal circuits and brain areas mediating the anxiolytic effects of BDZs are still not entirely clear, although the limbic system, and the amygdala in particular, has been revealed as a central component (Engin et al., 2018;Griessner et al., 2018).”

    From Novel pharmacological targets in drug development for the treatment of anxiety and anxiety-related disorders (2019) · cites this paper as Engin et al., 2018

Cites

Flagged first, then by citations

1 of the 157 references couldn’t be matched to a known paper.

Research works printed but not linked: 1

  1. Fan, 2013, GABAA receptor α2 but not α1 subunit knock down in dentate gyrus reduces inhibition activity and improves learning abilities of rats, J. Mol. Neurosci., 51, S36

Cited by

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Related

Authors
Engin, E., Benham, R. S., & Rudolph, U.
Affiliations
Harvard University (US)
Corresponding author
  • Engin, Elif
  • Rudolph, Uwe
ORCID
Venue
Trends in Pharmacological Sciences
Publisher
Elsevier BV
Published
2018-08
Volume
39
Issue
8
Pages
710-732
ISSN
0165-6147 (ISSN-L)
DOI
10.1016/j.tips.2018.04.003
PMC
PMC6056379
OpenAlex
W2807958215
Semantic Scholar
b4cb6620d5c955bc6c2bd7d41f69b28ffef813e0
Cited by
225
References
157
Citations by year
2026: 21 · 2025: 21 · 2024: 32 · 2023: 25 · 2022: 26 · 2021: 46 · 2020: 22 · 2019: 25 · 2018: 6 · 2017: 1
FWCI
3.24
Type
journal article
Language
en
Open access
Licence
Locations
  • Trends in Pharmacological Sciences (acceptedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Whitehall Foundation
  • Harvard Brain Science Initiative Bipolar Disorder Seed Grant
  • Brain and Behavior Research Foundation (19266))
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
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Keywords
GABAA receptor, GABA receptor subtypes, brain circuits, fear, anxiety, learning and memory, reward, addiction, stress behavior, inhibitory systems, treatment options
MeSH terms
Animals, Benzodiazepines, Brain, gamma-Aminobutyric Acid, Humans, Neurons, Receptors, GABA-A, GABA-A Receptor Agonists, GABA-A Receptor Antagonists

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.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

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