The γ-aminobutyric acid (GABA) system plays a pivotal role in orchestrating the synchronicity of local networks and the functional coupling of different brain regions. Here we review the impact of ...the GABAA receptor subtypes on cognitive and emotional behavior, paying particular attention to five disease states: cognitive dysfunction and Down syndrome, anxiety disorders, depression, schizophrenia, and autism. Through the bidirectional modulation of tonic inhibition, α5-subunit-containing GABAA receptors permit the bidirectional modulation of cognitive processes, and a partial inverse agonist acting at the α5-subunit-containing GABAA receptor is in a clinical trial in individuals with Down syndrome. With regard to anxiety disorders, the viability of nonsedative anxiolytics based on the modulation of α2- and α3-subunit-containing GABAA receptors has been established in clinical proof-of-concept trials. Regarding the remaining three disease states, the GABA hypothesis of depression offers new options for antidepressant drug development; cognitive symptoms in schizophrenia are attributed to a cortical GABAergic deficit, and dysfunctional GABAergic inhibition is increasingly understood to contribute to the pathophysiology of autism spectrum disorders.
GABAA receptors are molecular substrates for the regulation of vigilance, anxiety, muscle tension, epileptogenic activity, and memory functions, and the enhancement of GABAA receptor-mediated fast ...synaptic inhibition is the basis for the pharmacotherapy of various neurological and psychiatric disorders. Two kinds of GABAA receptor-targeted mutant mice have been generated: (a) knockout mice that lack individual GABAA receptor subunits (alpha1, alpha5, alpha6, beta2, beta3, gamma2, delta, and rho1) and (b) knockin mice that carry point mutations affecting the action of modulatory drugs alpha1(H101R), alpha2(H101R), alpha3(H126R), alpha5(H105R), and beta3(N265M). Whereas the knockout mice have provided information primarily with respect to the regulation of subunit gene transcription, receptor assembly, and some physiological functions of individual receptor subtypes, the point-mutated knockin mice in which specific GABAA receptor subtypes are insensitive to diazepam or some general anesthetics have revealed the specific contribution of individual receptor subtypes to the pharmacological spectrum of diazepam and general anesthetics.
Although general anaesthesia has been of tremendous importance for the development of surgery, the underlying mechanisms by which this state is achieved are only just beginning to be understood in ...detail. In this review, we describe the neuronal systems that are thought to be involved in mediating clinically relevant actions of general anaesthetics, and we go on to discuss how the function of individual drug targets, in particular GABA(A)-receptor subtypes, can be revealed by genetic studies in vivo.
GABA
A
receptors have important physiological functions, as revealed by pharmacological studies and experiments involving gene-targeted mouse models, and are the target of widely used drugs such as ...the benzodiazepines. In this review, we are summarizing current knowledge about the function of α2-containing GABA
A
receptors, a receptor subtype representing approximately 15–20% of all GABA
A
receptors. This receptor subtype mediates anxiolytic-like, reward-enhancing, and antihyperalgesic actions of diazepam, and has antidepressant-like properties. Secondary insufficiency of α2-containing GABA
A
receptors has been postulated to play a role in the pathogenesis of schizophrenia, and may be involved in cognitive impairment in other disorders. Moreover, polymorphisms in the
GABRA2
gene encoding the GABA
A
receptor α2 subunit have been found to be linked to chronic alcohol dependence and to polydrug abuse. Thus, α2-containing GABA
A
receptors are involved in the regulation and/or modulation of emotional behaviors and of chronic pain, and appear to be a valid target for novel therapeutic approaches for the treatment of anxiety, depression, schizophrenia and chronic pain.
Learning and memory are dependent on interactive excitatory and inhibitory mechanisms. In this review, we discuss a mechanism called disinhibition, which is the release of an inhibitory constraint ...that effectively results in an increased activity in the target neurons (for example, principal or projection neurons). We focus on discussing the role of disinhibition in learning and memory at a basic level and in disease models with cognitive deficits and highlight a strategy to reverse cognitive deficits caused by excess inhibition, through disinhibition of α5-containing GABA
A receptors mediating tonic inhibition in the hippocampus, based on subtype-selective negative allosteric modulators as a novel class of drugs.
The benzodiazepine midazolam is widely used in critical care medicine. Midazolam has a clinically active metabolite, 1-hydroxymidazolam. The contribution of 1-hydroxymidazolam to the effects of ...midazolam is controversial. The aim of the current study was to compare the actions of midazolam and 1-hydroxymidazolam on network activity of cortical neurons. Midazolam depressed neuronal activity at a low concentration of 5 nM. When midazolam concentration was increased, it depressed neuronal discharge rates in a biphasic manner. In comparison, 1-hydroxymidazolam did not depress the cortical network activity at low nanomolar concentrations. Higher concentrations of 1-hydroxymidazolam consistently inhibited neuronal activity. Moreover, midazolam shortened cortical up states at low, but not at high concentrations, while the opposite effect was observed with 1-hydroxymidazolam. The network depressant action of midazolam at low concentrations was absent in slices from GABA
receptor α
(H101R)mutant mice. The α
(H101R)mutation renders α
-subunit containing GABA
receptors insensitive towards benzodiazepines. This GABA
receptor subtype is thought to mediate sedation. As midazolam is more potent than its metabolite 1-hydroxymidazolam, the major clinical effects are thus likely caused by midazolam itself. However, 1-hydroxymidazolam could add to the effects of midazolam, especially after the application of high doses of midazolam, and in case of impaired drug metabolism.
Neurosteroids and benzodiazepines are modulators of the GABAA receptors, thereby causing anxiolysis. Furthermore, benzodiazepines such as midazolam are known to cause adverse side-effects on ...cognition upon administration. We previously found that midazolam at nanomolar concentrations (10 nM) blocked long-term potentiation (LTP). Here, we aim to study the effect of neurosteroids and their synthesis using XBD173, which is a synthetic compound that promotes neurosteroidogenesis by binding to the translocator protein 18 kDa (TSPO), since they might provide anxiolytic activity with a favourable side-effect profile. By means of electrophysiological measurements and the use of mice with targeted genetic mutations, we revealed that XBD173, a selective ligand of the translocator protein 18 kDa (TSPO), induced neurosteroidogenesis. In addition, the exogenous application of potentially synthesised neurosteroids (THDOC and allopregnanolone) did not depress hippocampal CA1-LTP, the cellular correlate of learning and memory. This phenomenon was observed at the same concentrations that neurosteroids conferred neuroprotection in a model of ischaemia-induced hippocampal excitotoxicity. In conclusion, our results indicate that TSPO ligands are promising candidates for post-ischaemic recovery exerting neuroprotection, in contrast to midazolam, without detrimental effects on synaptic plasticity.
GABAA receptor modulating drugs such as benzodiazepines (BZs) have been used to treat anxiety disorders for over five decades. In order to determine whether the same or different GABAA receptor ...subtypes are necessary for the anxiolytic-like action of BZs in unconditioned anxiety and conditioned fear models, we investigated the role of different GABAA receptor subtypes by challenging wild type, α1(H101R), α2(H101R) and α3(H126R) mice bred on the C57BL/6J background with diazepam or chlordiazepoxide in the elevated plus maze and the fear-potentiated startle paradigms. Both drugs significantly increased open arm exploration in the elevated plus maze in wild type, α1(H101R) and α3(H126R), but this effect was abolished in α2(H101R) mice; these were expected results based on previous published results. In contrast, while administration of diazepam and chlordiazepoxide significantly attenuated fear-potentiated startle (FPS) in wild type mice and α3(H126R) mice, the fear-reducing effects of these drugs were absent in both α1(H101R) and α2(H101R) point mutants, indicating that both α1- and α2-containing GABAA receptors are necessary for BZs to exert their effects on conditioned fear responses. Our findings illustrate both an overlap and a divergence between the GABAA receptor subtype requirements for the impact of BZs, specifically that both α1- and α2-containing GABAA receptors are necessary for BZs to reduce conditioned fear whereas only α2-containing GABAA receptors are needed for BZ-induced anxiolysis in unconditioned tests of anxiety. This raises the possibility that GABAergic pharmacological interventions for specific anxiety disorders can be differentially tailored.
► We used H–R point mutated mice to study benzodiazepine effects on anxiety and fear. ► α2-subunits are required for benzodiazepine-induced anxiolysis in elevated plus maze. ► α1- and α2-subunits are required for benzodiazepine-induced reduction of conditioned fear. ► Pharmacological interventions for specific anxiety disorders can be differentially tailored.
Inflammatory diseases and neuropathic insults are frequently accompanied by severe and debilitating pain, which can become chronic and often unresponsive to conventional analgesic treatment. A loss ...of synaptic inhibition in the spinal dorsal horn is considered to contribute significantly to this pain pathology. Facilitation of spinal gamma-aminobutyric acid (GABA)ergic neurotransmission through modulation of GABA(A) receptors should be able to compensate for this loss. With the use of GABA(A)-receptor point-mutated knock-in mice in which specific GABA(A) receptor subtypes have been selectively rendered insensitive to benzodiazepine-site ligands, we show here that pronounced analgesia can be achieved by specifically targeting spinal GABA(A) receptors containing the alpha2 and/or alpha3 subunits. We show that their selective activation by the non-sedative ('alpha1-sparing') benzodiazepine-site ligand L-838,417 (ref. 13) is highly effective against inflammatory and neuropathic pain yet devoid of unwanted sedation, motor impairment and tolerance development. L-838,417 not only diminished the nociceptive input to the brain but also reduced the activity of brain areas related to the associative-emotional components of pain, as shown by functional magnetic resonance imaging in rats. These results provide a rational basis for the development of subtype-selective GABAergic drugs for the treatment of chronic pain, which is often refractory to classical analgesics.
Abstract
Chronic itch is a highly debilitating condition affecting about 10% of the general population. The relay of itch signals is under tight control by inhibitory circuits of the spinal dorsal ...horn, which may offer a hitherto unexploited therapeutic opportunity. Here, we found that specific pharmacological targeting of inhibitory α2 and α3GABA
A
receptors reduces acute histaminergic and non-histaminergic itch in mice. Systemic treatment with an α2/α3GABA
A
receptor selective modulator alleviates also chronic itch in a mouse model of atopic dermatitis and in dogs sensitized to house dust mites, without inducing sedation, motor dysfunction, or loss of antipruritic activity after prolonged treatment. Transsynaptic circuit tracing, immunofluorescence, and electrophysiological experiments identify spinal α2 and α3GABA
A
receptors as likely molecular targets underlying the antipruritic effect. Our results indicate that drugs targeting α2 and α3GABA
A
receptors are well-suited to alleviate itch, including non-histaminergic chronic itch for which currently no approved treatment exists.
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