In the regulation of behavior, the role of GABA neurons has been extensively studied in the circuit of fear, where GABA interneurons play key parts in the acquisition, storage and extinction of fear. ...Therapeutically, modulators of α2/α3 GABAA receptors, such as TPA023, have shown clinical proof of concept as novel anxiolytics, which are superior to classical benzodiazepines by their lack of sedation and much reduced or absent dependence liability. In view of the finding that anxiety disorders and major depression share a GABAergic deficit as a common pathophysiology, the GABA hypothesis of depression has found increasing support. It holds that α2/α3 GABAA receptor modulators may serve as novel antidepressants. Initial clinical evidence for this view comes from the significantly enhanced antidepressant therapeutic response when eszopicole, an anxiolytic/hypnotic acting preferentially on α2/α3 and α1 GABAA receptors, was coadministered with an antidepressant. This effect persisted even when sleep items were not considered. These initial results warrant efforts to profile selective α2/α3 GABAA receptor modulators, such as TPA023, as novel antidepressants. In addition, GABAB receptor antagonists may serve as potential antidepressants.
This article is part of a Special Issue entitled ‘Anxiety and Depression’.
► A GABA deficit is a hallmark of anxiety disorders and major depression. ► Modulators of α2, α3 GABAA receptors are effective, non-sedative anxiolytics. ► Modulators of α2, α3 GABAA receptors are proposed as novel antidepressants. ► Eszopiclone co-therapy supports the novel concept of GABAergic antidepressants.
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.
The study of the psychopharmacology of benzodiazepines continues to provide new insights into diverse brain functions related to vigilance, anxiety, mood, epileptiform activity, schizophrenia, ...cognitive performance, and autism-related social behavior. In this endeavor, the discovery of the benzodiazepine receptor was a key event, as it supplied the primary benzodiazepine drug-target site, provided the molecular link to the allosteric modulation of GABAA receptors and, following the recognition of GABAA receptor subtypes, furnished the platform for future, more selective drug actions. This review has two parts. In a retrospective first part, it acknowledges the contributions to the field made by my collaborators over the years, initially at Hoffmann-La Roche in Basle and later, in academia, at the University and the ETH of Zurich. In the second part, the new frontier of GABA pharmacology, targeting GABAA receptor subtypes, is reviewed with special focus on nonsedative anxiolytics, antidepressants, analgesics, as well as enhancers of cognition in Down syndrome and attenuators of symptoms of autism spectrum disorders. It is encouraging that a clinical trial has been initiated with a partial inverse agonist acting on α5 GABAA receptors in an attempt to alleviate the cognitive deficits in Down syndrome.
Complex brains have developed specialized mechanisms for the grouping of principal cells into temporal coalitions of local or distant networks: the inhibitory interneuron 'clocking' networks. They ...consist of GABAergic (where GABA is gamma-aminobutyric acid) interneurons of a rich diversity. In cortical circuits, these neurons control spike timing of the principal cells, sculpt neuronal rhythms, select cell assemblies and implement brain states. On the basis of these considerations, the deficits in cognition, emotion and perception in psychiatric disorders such as anxiety, depression or schizophrenia are considered to manifest themselves through a dysregulation of the inhibitory interneuron 'clocking' network as a final common denominator, irrespective of the diverse underlying disease pathologies. The diversity of GABAergic interneurons is paralleled by a corresponding diversity of GABA(A) receptors in network regulation. The region-, cell- and domain-specific location of these receptor subtypes offers the possibility to gain functional insights into the role of behaviourally relevant neuronal circuits. Using genetic manipulation, the regulation of anxiety behaviour was attributed to neuronal circuits characterized by the expression of alpha(2)-GABA(A) receptors. Neurons expressing alpha(3)-GABA(A) receptors, located mainly in aminergic and basal forebrain cholinergic neurons, were related to a hyperdopaminergic phenotype, typical of schizophrenic symptoms. Temporal and spatial memory were selectively modulated by extrasynaptic alpha(5)-GABA(A) receptors. Chronic pathological pain was under the regulation of spinal and cortical alpha(2)- (and alpha(3)-) GABA(A) receptors. Thus the relevance of the diversity of inhibitory GABA(A) receptor subtypes for the regulation of cognition, emotion and memory is increasingly being recognized. The clinical proof-of-concept of a subtype-specific pharmacology is most advanced for the alleviation of cognitive dysfunctions in schizophrenia, based on the treatment of patients with an alpha(2)/alpha(3)-GABA(A) receptor ligand.
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.
The GABAergic deficit hypothesis of depression states that a deficit of GABAergic transmission in defined neural circuits is causal for depression. Conversely, an enhancement of GABA transmission, ...including that triggered by selective serotonin reuptake inhibitors or ketamine, has antidepressant effects. Brexanolone, an intravenous formulation of the endogenous neurosteroid allopregnanolone, showed clinically significant antidepressant activity in postpartum depression. By allosterically enhancing GABA
A receptor function, the antidepressant activity of allopregnanolone is attributed to an increase in GABAergic inhibition. In addition, allopregnanolone may stabilize normal mood by decreasing the activity of stress-responsive dentate granule cells and thereby sustain resilience behavior. Therefore, allopregnanolone may augment and extend its antidepressant activity by fostering resilience. The recent structural resolution of the neurosteroid binding domain of GABA
A receptors will expedite the development of more selective ligands as a potential new class of central nervous system drugs.
Animal studies of several single-gene disorders demonstrate that reversing the molecular signaling deficits can result in substantial symptomatic improvements in function. Focusing on the ratio of ...excitation to inhibition as a potential pathophysiological hallmark, seven single-gene developmental CNS disorders are reviewed which are characterized by a striking dysregulation of neuronal inhibition. Deficits in inhibition and excessive inhibition are found. The examples of developmental disorders encompass Neurofibromatosis type 1, Fragile X syndrome, Rett syndrome, Dravet syndrome including autism-like behavior, NONO-mutation-induced intellectual disability, Succinic semialdehyde dehydrogenase deficiency and Congenital nystagmus due to FRMD7 mutations. The phenotype/genotype correlations observed in animal models point to potential treatment options and will continue to inspire clinical research. Three drugs are presently in clinical trials: acamprosate and ganoxolon for Fragile X syndrome and SGS-742 for SSADH deficiency.
This article is part of the “Special Issue Dedicated to Norman G. Bowery”.
•Single-gene developmental CNS disorders with GABAergic dysregulations are discussed.•Animal models point to neuronal impairments and circuit deficiencies.•Reversing signaling deficits pharmacologically can result in symptomatic Improvements.•Drugs are presently in clinical trials for fragile X syndrome and SSADH deficiency.
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.
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.
Brain function is based on an exquisite balance between excitatory and inhibitory neurotransmission. GABAergic neurons provide the major inhibitory control. By controlling spike timing and sculpting ...neuronal rhythms they play a key role in regulating behavior. GABAergic neurons are highly diverse and operate with a corresponding diversity of GABAA receptor subtypes. In this article, the contribution of GABAA receptor deficits to central nervous system disorders, in particular anxiety disorders, epilepsy, schizophrenia and insomnia, is reviewed.
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