An Emerging Circuit Pharmacology of GABAA Receptors

In the paper

“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].”

What the sources say

• Not checked yetcites [7] Haefely W 1975 Possible involvement of GABA in the central actions of benzodiazepines Psychopharmacol Bull 11 58 59 720

In the paper

“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.”

In the paper

“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.”

What the sources say

• Not checked yetcites [11] Crestani F 1999 Decreased GABAA-receptor clustering results in enhanced anxiety and a bias for threat cues Nat Neurosci 2 833 839 10461223

In the paper

“The intercalated cell masses also express α2 and α3GABAARs synaptically, which mediates reciprocal inhibition between the two medial cell masses [29].”

What the sources say

• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [30] Wolff SB 2014 Amygdala interneuron subtypes control fear learning through disinhibition Nature 509 453 458 24814341

In the paper

“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].”

What the sources say

• Not checked yetcites [34] Haubensak W 2010 Genetic dissection of an amygdala microcircuit that gates conditioned fear Nature 468 270 276 21068836 PMC3597095 source
• Not checked yetcites [4] Botta P 2015 Regulating anxiety with extrasynaptic inhibition Nat Neurosci 18 1493 1500 26322928 PMC4607767

In the paper

“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.”

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“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]”

What the sources say

• Not checked yetcites [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

In the paper

“In addition to PV+ interneurons, δ-containing GABAARs are also expressed strongly and exert tonic inhibitory control on intercalated cell masses (Fig. 1C [28]).”

What the sources say

• Not checked yetcites [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

In the paper

“PV+ interneurons mediating feedback inhibition onto BLA pyramidal neurons form synapses in perisomatic locations and proximal dendrites, where α2GABAARs and α3GABAARs are expressed [26].”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [43] Engin E 2016 Modulation of anxiety and fear via distinct intrahippocampal circuits eLife 5 e14120 26971710 PMC4816644

In the paper

“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].”

What the sources say

• Not checked yetcites [42] Engin E Treit D 2007 The role of hippocampus in anxiety: intracerebral infusion studies Behav Pharmacol 18 365 374 17762507
• Not checked yetcites [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
• Not checked yetcites [51] Engin E 2008 Anxiolytic and antidepressant effects of intracerebroventricularly administered somatostatin: behavioral and neurophysiological evidence Neuroscience 157 666 676 18940236

In the paper

“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].”

What the sources say

• Not checked yetcites [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
• Not checked yetcites [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

In the paper

“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).”

What the sources say

• Not checked yetcites [43] Engin E 2016 Modulation of anxiety and fear via distinct intrahippocampal circuits eLife 5 e14120 26971710 PMC4816644

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [43] Engin E 2016 Modulation of anxiety and fear via distinct intrahippocampal circuits eLife 5 e14120 26971710 PMC4816644

In the paper

“with ventral/temporal portions more involved in anxiety and emotional processing, and dorsal/septal portions more involved in learning and memory [41].”

What the sources say

• Not checked yetcites [41] Fanselow MS Dong HW 2010 Are the dorsal and ventral hippocampus functionally distinct structures? Neuron 65 7 19 20152109 PMC2822727 source

In the paper

“While allopregnanolone is not selective for a single GABAAR subtype, it has high efficacy on α4GABAARs [46, 47].”

What the sources say

• Not checked yetcites [46] Belelli D 2002 The influence of subunit composition on the interaction of neurosteroids with GABA(A) receptors Neuropharmacol 43 651 661 12367610
• Not checked yetcites [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

In the paper

“The anterograde amnestic effects of benzodiazepines have been known for a long time [55], suggesting a suppressive role for GABAARs in learning and memory.”

What the sources say

• Not checked yetcites [55] Lister RG 1985 The amnesic action of benzodiazepines in man Neurosci Biobehav Rev 9 87 94 2858084

In the paper

“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].”

What the sources say

• Not checked yetcites [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
• Not checked yetcites [70] Zarnowska ED 2009 GABAA receptor alpha5 subunits contribute to GABAA, slow synaptic inhibition in mouse hippocampus J Neurophysiol 101 1179 1191 19073796 PMC2666407

In the paper

“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.”

What the sources say

• Not checked yetcites [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
• Not checked yetcites [73] Gafford GM 2005 Effects of post-training hippocampal injections of midazolam on fear conditioning Learn Mem 12 573 578 16322359 PMC1356174
• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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
• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [71] Scimemi A 2005 Multiple and plastic receptors mediate tonic GABAA receptor currents in the hippocampus J Neurosci 25 10016 10024 16251450 PMC6725560

In the paper

“There is also evidence suggesting the involvement of α1GABAARs [62, 63], α2GABAARs [50], and α4/δGABAARs in learning and memory [64-68].”

What the sources say

• Not checked yetcites [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
• Not checked yetcites [63] Rudolph U 1999 Benzodiazepine actions mediated by specific gamma-aminobutyric acid(A) receptor subtypes Nature 401 796 800 10548105 source
• Not checked yetcites [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
• Not checked yetcites [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
• Not checked yetcites [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
• Not checked yetcites [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
• Not checked yetcites [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
• Not checked yetcites [68] Zhang WH 2017 δ Subunit-containing GABAA receptor prevents overgeneralization of fear in adult mice Learn Mem 24 381 384 28716958 PMC5516689

In the paper

“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.”

What the sources say

• Not checked yetcites [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
• Not checked yetcites [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

In the paper

“Presence and abundance of GABAA receptors with two different types of α subunits has been described previously [80].”

What the sources say

• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [6] Papatheodoropoulos C Koniaris E 2011 Alpha5GABAA receptors regulate hippocampal sharp wave-ripple activity in vitro Neuropharmacol 60 662 673 21146551
• Not checked yetcites [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

In the paper

“which may be an adaptive response to protect the recently encoded memory from interference during the memory consolidation period.”

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [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 yetcites [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 yetcites [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 yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“These findings clearly demonstrate a role for α2GABAARs in benzodiazepine reward and point to the NAc as the possible anatomical locus for this effect.”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [104] Tan KR 2010 Neural bases for addictive properties of benzodiazepines Nature 463 769 774 20148031 PMC2871668

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

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

In the paper

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

In the paper

“Moreover, infusion of diazepam into the VTA leads to increased activity of D1+ MSNs, but not D2+ MSNs [109].”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [123] Luscher B 2011 The GABAergic deficit hypothesis of major depressive disorder Mol Psychiatry 16 383 406 21079608 PMC3412149 source
• Not checked yetcites [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 yetcites [125] Mayberg HS 2005 Deep brain stimulation for treatment-resistant depression Neuron 45 651 660 15748841 source
• Not checked yetcites [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 yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [121] Mitchell SJ 2014 The effects of early life stress on nucleus accumbens GABAA receptor function and cocaine mediated behaviour Eur Neuropsychopharmacol 24 S119

In the paper

“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].”

What the sources say

• Not checked yetcites [123] Luscher B 2011 The GABAergic deficit hypothesis of major depressive disorder Mol Psychiatry 16 383 406 21079608 PMC3412149 source

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [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 yetcites [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

In the paper

“As noted earlier, PV+ and SST+ interneurons form relatively non-overlapping interneuron populations [132, 133].”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [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

In the paper

“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.”

In the paper

“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].”

What the sources say

• Not checked yetcites [143] Shields BC 2017 Deconstructing behavioral neuropharmacology with cellular specificity Science 356 10.1126/science.aaj2161 28385956

In the paper

“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.”

What the sources say

• Not checked yetcites [143] Shields BC 2017 Deconstructing behavioral neuropharmacology with cellular specificity Science 356 10.1126/science.aaj2161 28385956