Because of its control of spike-timing and oscillatory network activity, γ-aminobutyric acid (GABA)-ergic inhibition is a key element in the central regulation of somatic and mental functions. The ...recognition of GABAA receptor diversity has provided molecular tags for the analysis of distinct neuronal networks in the control of specific pharmacological and physiological brain functions. Neurons expressing α₁GABAA receptors have been found to mediate sedation, whereas those expressing α₂GABAA receptors mediate anxiolysis. Furthermore, associative temporal and spatial memory can be regulated by modulating the activity of hippocampal pyramidal cells via extrasynaptic α₅GABAA receptors. In addition, neurons expressing α₃GABAA receptors are instrumental in the processing of sensory motor information related to a schizophrenia endophenotype. Finally, during the postnatal development of the brain, the maturation of GABAergic interneurons seems to provide the trigger for the experience-dependent plasticity of neurons in the visual cortex, with α₁GABAA receptors setting the time of onset of a critical period of plasticity. Thus, particular neuronal networks defined by respective GABAA receptor subtypes can now be linked to the regulation of various clearly defined behavioural patterns. These achievements are of obvious relevance for the pharmacotherapy of certain brain disorders, in particular sleep dysfunctions, anxiety disorders, schizophrenia and diseases associated with memory deficits.
Because of its control of spike-timing and oscillatory network activity, gamma-aminobutyric acid (GABA)-ergic inhibition is a key element in the central regulation of somatic and mental functions. ...The recognition of GABA(A) receptor diversity has provided molecular tags for the analysis of distinct neuronal networks in the control of specific pharmacological and physiological brain functions. Neurons expressing alpha(1)GABA(A) receptors have been found to mediate sedation, whereas those expressing alpha(2)GABA(A) receptors mediate anxiolysis. Furthermore, associative temporal and spatial memory can be regulated by modulating the activity of hippocampal pyramidal cells via extrasynaptic alpha(5)GABA(A) receptors. In addition, neurons expressing alpha(3)GABA(A) receptors are instrumental in the processing of sensory motor information related to a schizophrenia endophenotype. Finally, during the postnatal development of the brain, the maturation of GABAergic interneurons seems to provide the trigger for the experience-dependent plasticity of neurons in the visual cortex, with alpha(1)GABA(A) receptors setting the time of onset of a critical period of plasticity. Thus, particular neuronal networks defined by respective GABA(A) receptor subtypes can now be linked to the regulation of various clearly defined behavioural patterns. These achievements are of obvious relevance for the pharmacotherapy of certain brain disorders, in particular sleep dysfunctions, anxiety disorders, schizophrenia and diseases associated with memory deficits.
A new benzodiazepine pharmacology Möhler, H; Fritschy, J M; Rudolph, U
The Journal of pharmacology and experimental therapeutics
300, Številka:
1
Journal Article
Recenzirano
Classical benzodiazepine drugs are in wide clinical use as anxiolytics, hypnotics, anticonvulsants, and muscle relaxants. They act by enhancing the gamma-aminobutyric acid(A) (GABA(A)) receptor ...function in the central nervous system. The pharmacological relevance of the multitude of structurally diverse GABA(A) receptor subtypes has only recently been identified. Based on an in vivo point mutation strategy, alpha(1)-GABA(A) receptors were found to mediate sedation, anterograde amnesia, and part of the seizure protection, whereas alpha(2)-GABA(A) receptors, but not alpha(3)-receptors, mediate anxiolysis. Rational drug targeting to specific receptor subtypes has now become possible. Only restricted neuronal networks will be modulated by the new subtype-selective drugs. Promising new anxiolytics have already been developed. A new pharmacology of the benzodiazepine site is on the horizon.
Benzodiazepine tranquilizers are used in the treatment of anxiety disorders. To identify the molecular and neuronal target mediating the anxiolytic action of benzodiazepines, we generated and ...analyzed two mouse lines in which the α2 or α3 GABAA(γ-aminobutyric acid type A) receptors, respectively, were rendered insensitive to diazepam by a knock-in point mutation. The anxiolytic action of diazepam was absent in mice with the α2(H101R) point mutation but present in mice with the α3(H126R) point mutation. These findings indicate that the anxiolytic effect of benzodiazepine drugs is mediated by α2 GABAAreceptors, which are largely expressed in the limbic system, but not by α3 GABAAreceptors, which predominate in the reticular activating system.
The enhancement of GABA-mediated synaptic transmission underlies the pharmacotherapy of various neurological and psychiatric disorders. GABA
A receptors are pluripotent drug targets that display an ...extraordinary structural heterogeneity: they are assembled from a repertoire of at least 18 subunits (α1–6, β1–3, γ1–3, δ, ε, θ, ρ1–3). However, differentiating defined GABA
A receptor subtypes on the basis of function has had to await recent progress in the genetic dissection of receptor subtypes
in vivo. Evidence that the various actions of allosteric modulators of GABA
A receptors, in particular the benzodiazepines, can be attributed to specific GABA
A receptor subtypes will be discussed. Such discoveries could open up new avenues for drug development.
The heterogeneity of γ-aminobutyric acid type A (GABA A ) receptors contributes to the diversity of neuronal inhibition in the regulation of information processing. Although most GABA A receptors are ...located synaptically, the small population of α 5 GABA A receptors is largely expressed extrasynaptically. To clarify the role of the α 5 GABA A receptors in the control of behavior, a histidine-to-arginine point mutation was introduced in position 105 of the murine α 5 subunit gene, which rendered the α 5 GABA A receptors diazepam-insensitive. Apart from an incomplete muscle relaxing effect, neither the sedative, anticonvulsant, nor anxiolytic-like activity of diazepam was impaired in α 5 (H105R) mice. However, in hippocampal pyramidal cells, the point mutation resulted in a selective reduction of α 5 GABA A receptors, which altered the drug-independent behavior. In line with the role of the hippocampus in certain forms of associative learning, trace fear conditioning, but not delay conditioning or contextual conditioning, was facilitated in the mutant mice. Trace fear conditioning differs from delay conditioning in that the conditioned and unconditioned stimulus are separated by a time interval. Thus, the largely extrasynaptic α 5 GABA A receptors in hippocampal pyramidal cells are implicated as control elements of the temporal association of threat cues in trace fear conditioning.
Overactivity of the dopaminergic system in the brain is considered to be a contributing factor to the development and symptomatology of schizophrenia. Therefore, the GABAergic control of dopamine ...functions was assessed by disrupting the gene encoding the α3 subunit of the GABA A receptor. α3 knockout (α3KO) mice exhibited neither an obvious developmental defect nor apparent morphological brain abnormalities, and there was no evidence for compensatory up-regulation of other major GABA A -receptor subunits. Anxiety-related behavior in the elevated-plus-maze test was undisturbed, and the anxiolytic-like effect of diazepam, which is mediated by α2-containing GABA A receptors, was preserved. As a result of the loss of α3 GABA A receptors, the GABA-induced whole-cell current recorded from midbrain dopamine neurons was significantly reduced. Spontaneous locomotor activity was slightly elevated in α3KO mice. Most notably, prepulse inhibition of the acoustic startle reflex was markedly attenuated in the α3KO mice, pointing to a deficit in sensorimotor information processing. This deficit was completely normalized by treatment with the antipsychotic D2-receptor antagonist haloperidol. The amphetamine-induced hyperlocomotion was not altered in α3KO mice compared with WT mice. These results suggest that the absence of α3-subunit-containing GABA A receptors induces a hyperdopaminergic phenotype, including a severe deficit in sensorimotor gating, a common feature among psychiatric conditions, including schizophrenia. Hence, agonists acting at α3-containing GABA A receptors may constitute an avenue for an effective treatment of sensorimotor-gating deficits in various psychiatric conditions. haloperidol sensorimotor gating
Prepulse inhibition (PPI) refers to the phenomenon in which a low-intensity prepulse stimulus attenuates the reflexive response to a succeeding startle-eliciting pulse stimulus. The hippocampus, ...among other structures, is believed to play an important role in the modulation of PPI expression. In α5(H105R) mutant mice, the expression of the α5 subunit-containing GABAA receptors in the hippocampus is reduced. Here, we report that PPI was attenuated, and spontaneous locomotor activity was increased in α5(H105R) mutant mice. These effects were apparent in both genders. Thus, α5 subunit-containing GABAA receptors, which are located extrasynaptically and are thought to mediate tonic inhibition, are important regulators of the expression of PPI and locomotor exploration. Post-mortem analyses of schizophrenia brains have consistently revealed structural abnormalities of a developmental origin in the hippocampus. There may be a possibility that such abnormalities include disturbance of α5 GABAA receptor function or distribution, given that schizophrenia patients are known to exhibit a PPI deficit. Our data further highlight that the potential use of α5-selective inverse agonists to treat hippocampal-related mnemonic dysfunction needs to be considered against the possibility that such compounds may be adversely associated with deficient sensorimotor gating.
GABAergic interneurons are highly diverse and operate with a corresponding diversity of GABA
A receptor subtypes in controlling behaviour. In this article, we review the significance of GABA
A ...receptor heterogeneity for neural circuit development and central nervous system pharmacology. GABA
A receptor subtypes were identified as selective targets for behavioural actions of benzodiazepines and of selected intravenous anesthetic agents using point mutations which render a specific receptor subtype insensitive to the action of the respective drugs and also by novel subtype-selective ligands. The pharmacological separation of anxiolysis and sedation guides the development of novel anxiolytics, while inverse agonism at extrasynaptic GABA
A receptors involved in learning and memory is currently being evaluated as a novel therapeutic principle for symptomatic memory enhancement.
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