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1.
Life Sci ; 239: 117033, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31697950

RESUMO

AIMS: Benzodiazepines (BZDs) produce various pharmacological actions by binding to and allosterically regulating GABAA receptors. Several in vitro studies have demonstrated diazepam, the prototypic BZD, produces a high-dose action that cannot be countered with the classical BZD-binding site antagonist flumazenil. Here, we investigate the existence and behavioral relevance of non-classical BZD binding sites in zebrafish larvae. MAIN METHODS: Zebrafish larvae were treated with a series of BZDs alone or combined with flumazenil, bicuculline (a non-selective GABAA receptor antagonist), or RO 15-4513 (a general BZD antagonist and a proposed antagonist interacting with α+/ß- interfaces in α4/6/ß3δ receptors), and their locomotor activities and behavioral phenotypes were recorded. KEY FINDINGS: Diazepam-induced hypolocomotion (sedation-like state) at low doses (10 and 20 mg L-1) was effectively antagonized by flumazenil or bicuculline, while diazepam-induced immobility (anesthesia-like state) at higher dose (30 mg L-1) was prevented by bicuculline (3 mg L-1) but not flumazenil, even at doses up to 150 mg L-1. Ro 15-4513 also failed to efficiently antagonize diazepam-induced immobility. Immobility induced by high dose of another 1,4-BZD, clonazepam, was also resistant to flumazenil. SIGNIFICANCE: These results provide direct in vivo evidence for non-classical BZD-binding sites, which may be located at the second transmembrane domain of GABAA receptors and contribute to BZD-induced anesthesia.


Assuntos
Benzodiazepinas/metabolismo , Benzodiazepinas/farmacologia , Flumazenil/farmacologia , Moduladores GABAérgicos/farmacologia , Atividade Motora/efeitos dos fármacos , Receptores de GABA-A/efeitos dos fármacos , Animais , Azidas/farmacologia , Benzodiazepinas/toxicidade , Bicuculina/farmacologia , Sítios de Ligação/efeitos dos fármacos , Clonazepam/farmacologia , Relação Dose-Resposta a Droga , Feminino , Flumazenil/toxicidade , Antagonistas GABAérgicos/farmacologia , Moduladores GABAérgicos/toxicidade , Larva , Masculino , Peixe-Zebra
2.
BMC Pharmacol Toxicol ; 20(1): 48, 2019 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-31383012

RESUMO

BACKGROUND: Cushing's syndrome is an endocrine disorder characterized by the overproduction of adrenocortical steroids. Steroidogenesis enzyme inhibitors are the mainstays of pharmacological treatment. Unfortunately, they produce significant side effects. Among the most potent inhibitors is the general anesthetic etomidate whose GABAA receptor-mediated sedative-hypnotic actions restrict use. In this study, we defined the sedative-hypnotic and steroidogenesis inhibiting actions of etomidate and four phenyl-ring substituted etomidate analogs (dimethoxy-etomidate, isopropoxy-etomidate, naphthalene-etomidate, and naphthalene (2)-etomidate) that possess negligible GABAA receptor modulatory activities. METHODS: In the first set of experiments, male Sprague-Dawley rats were assessed for loss of righting reflexes (LoRR) after receiving intravenous boluses of either etomidate (1 mg/kg) or an etomidate analog (40 mg/kg). In the second set of experiments, rats were assessed for LoRR and their abilities to produce adrenocortical and androgenic steroids after receiving 2-h infusions (0.5 mg kg- 1 min- 1) of either etomidate or an etomidate analog. RESULTS: All rats that received etomidate boluses or infusions had LoRR that persisted for minutes or hours, respectively. In contrast, no rat that received an etomidate analog had LoRR. Compared to rats in the vehicle control group, rats that received etomidate analog infusions had plasma corticosterone and aldosterone concentrations that were reduced by 80-84% and 68-94%, respectively. Rats that received etomidate infusions had plasma corticosterone and aldosterone concentrations that were also significantly reduced (by 92 and 96%, respectively). Rats that received etomidate or isopropoxy-etomidate had significant reductions (90 and 57%, respectively) in plasma testosterone concentrations whereas those that received naphthalene-etomidate had significant increases (1400%) in plasma dehydroepiandrosterone concentrations. Neither etomidate nor any etomidate analog significantly affected plasma androstenedione and dihydrotestosterone concentrations. CONCLUSIONS: Our studies demonstrate that the four phenyl-ring substituted etomidate analogs form a novel class of compounds that are devoid of sedative-hypnotic activities and suppress plasma concentrations of adrenocortical steroids but vary in their effects on plasma concentrations of androgenic steroids.


Assuntos
Etomidato/análogos & derivados , Hipnóticos e Sedativos/farmacologia , Inibidores da Síntese de Esteroides/farmacologia , Animais , Etomidato/química , Etomidato/farmacologia , Hipnóticos e Sedativos/química , Masculino , Ratos , Ratos Sprague-Dawley , Receptores de GABA-A/efeitos dos fármacos , Reflexo/efeitos dos fármacos , Inibidores da Síntese de Esteroides/química , Esteroides/sangue
3.
Life Sci ; 231: 116584, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31220527

RESUMO

Taurine is a key functional amino acid with many functions in the nervous system. The effects of taurine on cognitive function have aroused increasing attention. First, the fluctuations of taurine and its transporters are associated with cognitive impairments in physiology and pathology. This may help diagnose and treat cognitive impairment though mechanisms are not fully uncovered in existing studies. Then, taurine supplements in cognitive impairment of different physiologies, pathologies and toxicologies have been demonstrated to significantly improve and restore cognition in most cases. However, elevated taurine level in cerebrospinal fluid (CSF) by exogenous administration causes cognition retardations only in physiologically sensitive period between the perinatal to early postnatal period. In this review, taurine levels are summarized in different types of cognitive impairments. Subsequently, the effects of taurine supplements on cognitions in physiology, different pathologies and toxication of cognitive impairments (e.g. aging, Alzheimer' disease, streptozotocin (STZ)-induced brain damage, ischemia model, mental disorder, genetic diseases and cognitive injuries of pharmaceuticals and toxins) are analyzed. These data suggest that taurine can improve cognition function through multiple potential mechanisms (e.g. restoring functions of taurine transporters and γ-aminobutyric acid (GABA) A receptors subunit; mitigating neuroinflammation; up-regulating Nrf2 expression and antioxidant capacities; activating Akt/CREB/PGC1α pathway, and further enhancing mitochondria biogenesis, synaptic function and reducing oxidative stress; increasing neurogenesis and synaptic function by pERK; activating PKA pathway). However, more mechanisms still need explorations.


Assuntos
Cognição/efeitos dos fármacos , Taurina/metabolismo , Taurina/farmacologia , Doença de Alzheimer/fisiopatologia , Animais , Antioxidantes/farmacologia , Cognição/fisiologia , Disfunção Cognitiva/fisiopatologia , Suplementos Nutricionais , Feminino , Humanos , Masculino , Fator 2 Relacionado a NF-E2/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Gravidez , Receptores de GABA , Receptores de GABA-A/efeitos dos fármacos , Estreptozocina/farmacologia , Taurina/fisiologia
4.
Vis Neurosci ; 36: E005, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-31199212

RESUMO

At the first retinal synapse, horizontal cells (HCs) contact both photoreceptor terminals and bipolar cell dendrites, modulating information transfer between these two cell types to enhance spatial contrast and mediate color opponency. The synaptic mechanisms through which these modulations occur are still debated. The initial hypothesis of a GABAergic feedback from HCs to cones has been challenged by pharmacological inconsistencies. Surround antagonism has been demonstrated to occur via a modulation of cone calcium channels through ephaptic signaling and pH changes in the synaptic cleft. GABAergic transmission between HCs and cones has been reported in some lower vertebrates, like the turtle and tiger salamander. In these reports, it was revealed that GABA is released from HCs through reverse transport and target GABA receptors are located at the cone terminals. In mammalian retinas, there is growing evidence that HCs can release GABA through conventional vesicular transmission, acting both on autaptic GABA receptors and on receptors expressed at the dendritic tips of the bipolar cells. The presence of GABA receptors on mammalian cone terminals remains equivocal. Here, we looked specifically for functional GABA receptors in mouse photoreceptors by recording in the whole-cell or amphotericin/gramicidin-perforated patch clamp configurations. Cones could be differentiated from rods through morphological criteria. Local GABA applications evoked a Cl- current in cones but not in rods. It was blocked by the GABAA receptor antagonist bicuculline methiodide and unaffected by the GABAC receptor antagonist TPMPA [(1,2,5,6-tetrahydropyridin-4-yl)methylphosphinic acid]. The voltage dependency of the current amplitude was as expected from a direct action of GABA on cone pedicles but not from an indirect modulation of cone currents following the activation of the GABA receptors of HCs. This supports a direct role of GABA released from HCs in the control of cone activity in the mouse retina.


Assuntos
Receptores de GABA-A/metabolismo , Receptores de GABA/metabolismo , Células Fotorreceptoras Retinianas Cones/fisiologia , Células Horizontais da Retina/metabolismo , Ácido gama-Aminobutírico/metabolismo , Animais , Antagonistas GABAérgicos/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Técnicas de Patch-Clamp , Receptores de GABA/efeitos dos fármacos , Receptores de GABA-A/efeitos dos fármacos , Células Fotorreceptoras Retinianas Cones/metabolismo
6.
eNeuro ; 6(1)2019.
Artigo em Inglês | MEDLINE | ID: mdl-31058209

RESUMO

Hyperthermia-induced febrile seizures (FSs) are the most common seizures during childhood, and prolonged complex FSs can result in the development of epilepsy. Currently, GABAA receptor modulators such as benzodiazepines and barbiturates are used as medications for FSs with the aim of enhancing GABA-mediated inhibition of neuronal activity. However, it is still up for debate whether these enhancers of GABAergic neurotransmission could depolarize immature neurons with relatively higher levels of the intracellular Cl- in the developing brain during FSs. Here, we performed simultaneous video-local field potential monitoring to determine whether benzodiazepines and barbiturates affect the phenotypes of FSs in postnatal day (P)11 and P14 mice. We found that low-dose administration of diazepam decreased the incidence of clonic seizures at P11. We also found that high-dose administration of diazepam and pentobarbital exacerbated the behavioral and electrophysiological phenotypes of the induction phase of experimental FSs at P11 but not at P14. We further found that the deteriorated phenotypes at P11 were suppressed when Na+K+2Cl- cotransporter isoform 1 (NKCC1), which mediates Cl- influx, was blocked by treatment with the diuretic bumetanide. Though our findings do not exclude the involvement of sedation effect of high-dose GABAA receptor modulators in worsening experimental FSs at P11, pharmacological enhancement of GABAergic signaling could aggravate seizure activity in the early phase of FSs.


Assuntos
Bumetanida/farmacologia , Hipocampo/efeitos dos fármacos , Receptores de GABA-A/efeitos dos fármacos , Convulsões/tratamento farmacológico , Animais , Modelos Animais de Doenças , Feminino , Masculino , Camundongos Endogâmicos C57BL , Neurônios/efeitos dos fármacos , Convulsões/induzido quimicamente
7.
Planta Med ; 85(11-12): 925-933, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31127604

RESUMO

A fluorometric imaging plate reader (FLIPR) assay utilizing Chinese hamster ovary (CHO) cells stably transfected with GABAA receptors of α 1 ß 2 γ 2 subunit composition was evaluated and validated for rapid screening of plant extract libraries and efficient localization of active compounds in extracts. Validation was performed with pure compounds and extracts known to contain allosteric GABAA receptor modulators. Plants extracts that had been previously reported as active in an assay using Xenopus laevis oocytes transiently expressing GABAA receptors of α 1 ß 2 γ 2 subunit composition were also active in the FLIPR assay. A protocol for HPLC-based activity profiling was developed, whereby separations of 0.4 - 1.2 mg of extracts on an analytical HPLC column were found to be sufficient for the sensitivity of the bioassay. The protocol successfully localized the activity of known GABAergic natural products, such as magnolol in Magnolia officinalis, valerenic acid in Valeriana officinalis, and piperine in Piper nigrum extract. EC50 values of compounds (magnolol: 4.81 ± 1.0 µM, valerenic acid: 12.56 ± 1.2 µM, and piperine: 5.76 ± 0.7 µM) were found to be comparable or lower than those reported using Xenopus oocyte assays.


Assuntos
Fluorometria/métodos , Extratos Vegetais/farmacologia , Receptores de GABA-A/efeitos dos fármacos , Alcaloides/farmacologia , Animais , Benzodioxóis/farmacologia , Bioensaio/métodos , Compostos de Bifenilo/farmacologia , Células CHO , Cromatografia Líquida de Alta Pressão , Cricetulus , Indenos/farmacologia , Lignanas/farmacologia , Magnolia/química , Oócitos/metabolismo , Piper nigrum/química , Piperidinas/farmacologia , Alcamidas Poli-Insaturadas/farmacologia , Sesquiterpenos/farmacologia , Valeriana/química , Xenopus laevis
8.
Neurol Res ; 41(6): 528-535, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30890034

RESUMO

OBJECTIVE: Harmaline and other beta-carbolines act as an inverse agonist for GABA-A receptors and cause central nervous system stimulation and anxiety; thus, it may act hypothetically as a potential seizure augmenter. To examine the hypothesis, the effect of harmaline during the seizures induced by amygdala kindling is investigated here. METHODS: Seven groups of male rats were kindled by daily electrical stimulation of the amygdala. After being kindled, Groups I-III, respectively, received 5, 15 and 50 mg/kg harmaline through intraperitoneal injection. The rats in Groups IV and V received vehicle daily (1 ml/kg) and harmaline (5 mg/kg) daily through intraperitoneal injection. Groups VI and VII received artificial cerebrospinal fluid and harmaline (50 mM) through intraventricular injection, respectively. RESULTS: In addition to significant increase of some seizure parameters in the fully kindled groups, harmaline significantly increased cumulative afterdischarge duration (P < 0.05) and decreased stage 1 latency (P < 0.01) in the acquisition groups (Groups V and VII). In Group VII, seizure duration showed a significant increase (P < 0.01) while stage 1 latency and stage 4 latency decreased significantly (P < 0.01). DISCUSSION: According to the results, it is suggested that harmaline may increase neuronal activity and the production of high-frequency action potentials by stimulating NMDA receptors and inhibiting GABA receptors. Overall, drugs and plants containing harmaline may be harmful to epileptic-susceptible people during some traditionally and costume treatments, so these should be avoided.


Assuntos
Tonsila do Cerebelo/efeitos dos fármacos , Harmalina/farmacologia , Excitação Neurológica/efeitos dos fármacos , Convulsões/tratamento farmacológico , Potenciais de Ação/efeitos dos fármacos , Tonsila do Cerebelo/fisiologia , Animais , Estimulação Elétrica/métodos , Epilepsia/tratamento farmacológico , Epilepsia/fisiopatologia , Excitação Neurológica/fisiologia , Ratos , Receptores de GABA-A/efeitos dos fármacos , Convulsões/etiologia
9.
Nutrients ; 11(3)2019 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-30845636

RESUMO

In our previous studies, a standardized phlorotannin (brown seaweed polyphenol) supplement (PS) exhibited sleep-promoting effects via type A γ-aminobutyric acid-benzodiazepine receptors in mice. In addition, in human clinical trials, it decreased wake after sleep onset in adults with sleep disturbance. In this follow-up study, we investigated whether PS attenuates caffeine-induced sleep disruption in mice. The effects of PS were evaluated in a caffeine model by analyzing sleep architecture based on electroencephalogram and electromyogram findings, and were compared with the effects of a well-known sedative-hypnotic drug zolpidem (ZPD). As expected, oral administration of caffeine (25 mg/kg) significantly increased sleep latency and decreased the amount of non-rapid eye movement sleep (NREMS). In the caffeine + PS and caffeine + ZPD groups, PS (500 mg/kg) attenuated caffeine-induced sleep disruption, and its effects were comparable with those of ZPD (10 mg/kg). In particular, PS inhibited the arousal effects of caffeine without change in delta activity during NREMS, whereas ZPD produced a decrease in the delta activity. Considering global trends in coffee and energy drink consumption, our finding suggest that PS may be useful to relieve transitory insomnia symptoms caused by caffeine consumption, unlike the prescription drug ZPD.


Assuntos
Hipnóticos e Sedativos/farmacologia , Fitoterapia , Preparações de Plantas/farmacologia , Polifenóis/uso terapêutico , Alga Marinha/química , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Animais , Cafeína , Eletroencefalografia , Eletromiografia , Seguimentos , Camundongos , Receptores de GABA-A/efeitos dos fármacos , Sono/efeitos dos fármacos , Medicamentos Indutores do Sono/farmacologia , Distúrbios do Início e da Manutenção do Sono/induzido quimicamente , Zolpidem/farmacologia
10.
Behav Pharmacol ; 30(2 and 3-Spec Issue): 272-281, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30724801

RESUMO

Early-life stress (ELS) is known to exert long-term effects on brain function, with resulting deleterious consequences for several aspects of mental health, including the development of addiction to drugs of abuse. One potential mechanism in humans is suggested by findings that ELS interacts with polymorphisms of the GABRA2 gene, encoding α2 subunits of GABAA receptors, to increase the risk for both post-traumatic stress disorder and vulnerability to cocaine addiction. We used a mouse model, in which the amount of material for nest building was reduced during early postnatal life, to study interactions between ELS and expression of α2-containing GABAA receptors in influencing cocaine-related behaviour. Breeding of parents heterozygous for a deletion of α2 resulted in litters containing homozygous knockout (α2), heterozygous knockout (α2) and wild-type (α2) offspring. Following the ELS procedure, the mice were allowed to develop to adulthood before being tested for the acute effect of cocaine on locomotor stimulation, behavioural sensitization to repeated cocaine and to cocaine-conditioned activity. Exposure to ELS resulted in increased acute locomotor stimulant effects of cocaine across all genotypes, with the most marked effects in α2 mice (which also showed increased activity following vehicle). Repeated cocaine administration to nonstressed mice resulted in sensitization in α2 and α2 mice, but, in keeping with previous findings, not in α2 mice. Previous exposure to ELS reduced sensitization in α2 mice, albeit not significantly, and abolished sensitization in α2 mice. Conditioned activity was elevated following ELS in all animals, independently of genotype. Thus, while the enhanced acute effects of cocaine following ELS being most marked in α2 mice suggests a function of α2-containing GABAA receptors in protecting against stress, the interaction between ELS and genotype in influencing sensitization may be more in keeping with ELS reducing expression of α2-containing GABAA receptors. The ability of ELS to increase cocaine-conditioned locomotor activity appears to be independent of α2-containing GABAA receptors.


Assuntos
Cocaína/farmacologia , Receptores de GABA-A/efeitos dos fármacos , Estresse Psicológico/fisiopatologia , Animais , Transtornos Relacionados ao Uso de Cocaína/fisiopatologia , Aprendizagem/efeitos dos fármacos , Locomoção/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de GABA-A/metabolismo
11.
Am J Physiol Lung Cell Mol Physiol ; 316(2): L385-L390, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30489155

RESUMO

Airway smooth muscle (ASM) cells express GABA A receptors (GABAARs), and previous reports have demonstrated that GABAAR activators relax ASM. However, given the activity of GABAARs in central nervous system inhibitory neurotransmission, concern exists that these activators may lead to undesirable sedation. MIDD0301 is a novel imidazobenzodiazepine and positive allosteric modulator of the GABAAR with limited brain distribution, thus eliminating the potential for sedation. Here, we demonstrate that MIDD0301 relaxes histamine-contracted guinea pig ( P < 0.05, n = 6-9) and human ( P < 0.05, n = 6-10) tracheal smooth muscle ex vivo in organ bath experiments, dilates mouse peripheral airways ex vivo in precision-cut lung-slice experiments ( P < 0.001, n = 16 airways from three mice), and alleviates bronchoconstriction in vivo in mice, as assessed by the forced-oscillation technique ( P < 0.05, n = 6 mice). Only trace concentrations of the compound were detected in the brains of mice after inhalation of nebulized 5 mM MIDD0301. Given its favorable pharmacokinetic properties and demonstrated ability to relax ASM in a number of clinically relevant experimental paradigms, MIDD0301 is a promising drug candidate for bronchoconstrictive diseases, such as asthma.


Assuntos
Asma/tratamento farmacológico , Barreira Hematoencefálica/efeitos dos fármacos , GABAérgicos/farmacologia , Receptores de GABA-A/efeitos dos fármacos , Animais , Cobaias , Humanos , Ligantes , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Masculino , Músculo Liso/efeitos dos fármacos , Músculo Liso/metabolismo , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Receptores de GABA-A/metabolismo , Traqueia/efeitos dos fármacos , Traqueia/metabolismo
12.
Neurochem Res ; 44(2): 301-311, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30387069

RESUMO

Astrocytes are the major glial cells in brain tissue and are involved, among many functions, ionic and metabolic homeostasis maintenance of synapses. These cells express receptors and transporters for neurotransmitters, including GABA. GABA signaling is reportedly able to affect astroglial response to injury, as evaluated by specific astrocyte markers such as glial fibrillary acid protein and the calcium-binding protein, S100B. Herein, we investigated the modulatory effects of the GABAA receptor on astrocyte S100B secretion in acute hippocampal slices and astrocyte cultures, using the agonist, muscimol, and the antagonists pentylenetetrazol (PTZ) and bicuculline. These effects were analyzed in the presence of tetrodotoxin (TTX), fluorocitrate (FLC), cobalt and barium. PTZ positively modify S100B secretion in hippocampal slices and astrocyte cultures; in contrast, bicuculline inhibited S100B secretion only in hippocampal slices. Muscimol, per se, did not change S100B secretion, but prevented the effects of PTZ and bicuculline. Moreover, PTZ-induced S100B secretion was prevented by TTX, FLC, cobalt and barium indicating a complex GABAA communication between astrocytes and neurons. The effects of two putative agonists of GABAA, ß-hydroxybutyrate and methylglyoxal, on S100B secretion were also evaluated. In view of the neurotrophic role of extracellular S100B under conditions of injury, our data reinforce the idea that GABAA receptors act directly on astrocytes, and indirectly on neurons, to modulate astroglial response.


Assuntos
Astrócitos/metabolismo , Hipocampo/efeitos dos fármacos , Subunidade beta da Proteína Ligante de Cálcio S100/metabolismo , Animais , Astrócitos/efeitos dos fármacos , Bicuculina/farmacologia , Células Cultivadas , Proteína Glial Fibrilar Ácida/metabolismo , Hipocampo/metabolismo , Masculino , Muscimol/farmacologia , Fatores de Crescimento Neural/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Ratos Wistar , Receptores de GABA-A/efeitos dos fármacos , Receptores de GABA-A/metabolismo
13.
Curr Neuropharmacol ; 17(9): 843-851, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30520374

RESUMO

The co-agonist concerted transition model is a simple and practical solution to analyze various aspects of GABAA receptor function. Several model-based predictions have been verified experimentally in previous reports. We review here the practical implications of the model and demonstrate how it enables simplification of the experimental procedure and data analysis to characterize the effects of mutations or properties of novel ligands. Specifically, we show that the value of EC50 and the magnitude of current response are directly affected by basal activity, and that coapplication of a background agonist acting at a distinct site or use of a gain-of-function mutation can be employed to enable studies of weak activators or mutated receptors with impaired gating. We also show that the ability of one GABAergic agent to potentiate the activity elicited by another is a computable value that depends on the level of constitutive activity of the ion channel and the ability of each agonist to directly activate the receptor. Significantly, the model accurately accounts for situations where the paired agonists interact with the same site compared to distinct sites on the receptor.


Assuntos
Agonistas de Receptores de GABA-A/farmacologia , Receptores de GABA-A/efeitos dos fármacos , Receptores de GABA-A/fisiologia , Regulação Alostérica , Mutação , Propofol/farmacologia , Receptores de GABA-A/química , Receptores de GABA-A/genética
14.
J Neurosci ; 39(6): 1058-1065, 2019 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-30541909

RESUMO

Nigrostriatal dopamine (DA) is critical to action selection and learning. Axonal DA release is locally influenced by striatal neurotransmitters. Striatal neurons are principally GABAergic projection neurons and interneurons, and a small minority of other neurons are cholinergic interneurons (ChIs). ChIs strongly gate striatal DA release via nicotinic receptors (nAChRs) identified on DA axons. Striatal GABA is thought to modulate DA, but GABA receptors have not been documented conclusively on DA axons. However, ChIs express GABA receptors and are therefore candidates for potential mediators of GABA regulation of DA. We addressed whether striatal GABA and its receptors can modulate DA release directly, independently from ChI regulation, by detecting DA in striatal slices from male mice using fast-scan cyclic voltammetry in the absence of nAChR activation. DA release evoked by single electrical pulses in the presence of the nAChR antagonist dihydro-ß-erythroidine was reduced by GABA or agonists of GABAA or GABAB receptors, with effects prevented by selective GABA receptor antagonists. GABA agonists slightly modified the frequency sensitivity of DA release during short stimulus trains. GABA agonists also suppressed DA release evoked by optogenetic stimulation of DA axons. Furthermore, antagonists of GABAA and GABAB receptors together, or GABAB receptors alone, significantly enhanced DA release evoked by either optogenetic or electrical stimuli. These results indicate that striatal GABA can inhibit DA release through GABAA and GABAB receptors and that these actions are not mediated by cholinergic circuits. Furthermore, these data reveal that there is a tonic inhibition of DA release by striatal GABA operating through predominantly GABAB receptors.SIGNIFICANCE STATEMENT The principal inhibitory transmitter in the mammalian striatum, GABA, is thought to modulate striatal dopamine (DA) release, but definitive evidence for GABA receptors on DA axons is lacking. Striatal cholinergic interneurons regulate DA release via axonal nicotinic receptors (nAChRs) and also express GABA receptors, but they have not been eliminated as potentially critical mediators of DA regulation by GABA. Here, we found that GABAA and GABAB receptors inhibit DA release without requiring cholinergic interneurons. Furthermore, ambient levels of GABA inhibited DA release predominantly through GABAB receptors. These findings provide further support for direct inhibition of DA release by GABA receptors and reveal that striatal GABA operates a tonic inhibition on DA output that could critically influence striatal output.


Assuntos
Corpo Estriado/metabolismo , Dopamina/metabolismo , Receptores de GABA-A/metabolismo , Receptores de GABA-B/metabolismo , Substância Negra/metabolismo , Animais , Axônios/metabolismo , Antagonistas Colinérgicos/farmacologia , Di-Hidro-beta-Eritroidina/farmacologia , Estimulação Elétrica , Agonistas GABAérgicos/farmacologia , Antagonistas GABAérgicos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Optogenética , Sistema Nervoso Parassimpático/efeitos dos fármacos , Sistema Nervoso Parassimpático/metabolismo , Receptores de GABA-A/efeitos dos fármacos , Receptores de GABA-B/efeitos dos fármacos , Ácido gama-Aminobutírico/metabolismo
15.
Brain Struct Funct ; 224(1): 171-190, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30298290

RESUMO

Deficient prefrontal cortex (PFC) GABA function is hypothesized to play a role in schizophrenia and other psychiatric disorders. In rodents, PFC GABAA receptor antagonism produces cognitive and behavioral changes relevant to these disorders, including impaired spatial memory assessed with the traditional working/reference memory radial maze task. This aspect of spatial memory does not depend on PFC, suggesting that deficient PFC GABAergic transmission may interfere with non-PFC-dependent cognitive functions via aberrant increases in PFC output. To test this, we assessed whether PFC GABAA antagonism (50 ng bicuculline methbromide) alters neuronal activation in PFC terminal regions, including the striatum, thalamus, hippocampus, amygdala, and cortical regions, of adult male rats using the immediate early gene, c-Fos, as an activity marker. A subset of these animals were also trained and/or tested on the working/reference memory radial maze task. These treatments caused widespread increases in neuronal activation in animals under baseline conditions, with notable exception of the hippocampus. Furthermore, PFC GABAA antagonism impaired task performance. In most instances, training and/or testing on the radial maze had no additional effects on neuronal activation. However, in both the hippocampus and rhomboid thalamic nucleus, PFC GABAA antagonism caused a selective increase in neuronal activation in animals trained on the maze. These results indicate that deficiencies in PFC GABAergic transmission may have widespread impacts on neuronal activity that may interfere with certain PFC-independent cognitive functions. Furthermore, these alterations in activity are modulated by plasticity induced by spatial learning in the hippocampus and rhomboid thalamic nucleus.


Assuntos
Comportamento Animal , Aprendizagem em Labirinto , Plasticidade Neuronal , Córtex Pré-Frontal/metabolismo , Receptores de GABA-A/metabolismo , Transmissão Sináptica , Ácido gama-Aminobutírico/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Bicuculina/análogos & derivados , Bicuculina/farmacologia , Antagonistas de Receptores de GABA-A/farmacologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Vias Neurais/metabolismo , Plasticidade Neuronal/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos Long-Evans , Receptores de GABA-A/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos
16.
J Neurosci ; 39(6): 1077-1087, 2019 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-30509960

RESUMO

Humans with alcohol use disorder typically abstain because of the negative consequences associated with excessive drinking, and exposure to contexts previously associated with alcohol use can trigger relapse. We used a rat model that captures a characteristic of this human condition: namely voluntary abstinence from alcohol use because of contingent punishment. There is substantial variability in the propensity to relapse following extended periods of abstinence, and this is a critical feature preventing the successful treatment of alcohol use disorder. Here we examined relapse following acute or prolonged abstinence. In male alcohol preferring P rats, we found an increased propensity to relapse in Context B, the punishment context after prolonged abstinence. Next, we found that neither alcohol intake history nor the motivational strength of alcohol predicted the propensity to relapse. We next examined the putative circuitry of context-induced relapse to alcohol seeking following prolonged abstinence using Fos as a marker of neuronal activation. The anterior insular cortex (AI) was the only brain region examined where Fos expression correlated with alcohol seeking behavior in Context B after prolonged abstinence. Finally, we used local infusion of GABAA and GABAB receptor agonists (muscimol + baclofen) to show a causal role of the AI in context-induced relapse in Context B, the punishment context after prolonged abstinence. Our results show that there is substantial individual variability in the propensity to relapse in the punishment-associated context after prolonged abstinence, and this is mediated by activity in the AI.SIGNIFICANCE STATEMENT A key feature of alcohol use disorder is that sufferers show an enduring propensity to relapse throughout their lifetime. Relapse typically occurs despite the knowledge of adverse consequences including health complications or relationship breakdowns. Here we use a recently developed rodent model that recapitulates this behavior. After an extended period of abstinence, relapse propensity is markedly increased in the "adverse consequence" environment, akin to humans with alcohol use disorder relapsing in the face of adversity. From a circuitry perspective, we demonstrate a causal role of the anterior insular cortex in relapse to alcohol seeking after extended abstinence following punishment imposed voluntary cessation of alcohol use.


Assuntos
Abstinência de Álcool/psicologia , Consumo de Bebidas Alcoólicas/psicologia , Córtex Cerebral/fisiologia , Comportamento de Procura de Droga/fisiologia , Punição/psicologia , Animais , Depressores do Sistema Nervoso Central/farmacologia , Córtex Cerebral/efeitos dos fármacos , Comportamento de Procura de Droga/efeitos dos fármacos , Etanol/farmacologia , Agonistas GABAérgicos/farmacologia , Agonistas dos Receptores de GABA-B/farmacologia , Genes fos/genética , Masculino , Motivação , Ratos , Receptores de GABA-A/efeitos dos fármacos , Recidiva
17.
Neuropharmacology ; 148: 21-30, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30562540

RESUMO

Ketogenesis is a metabolic process wherein ketone bodies are produced from the breakdown of fatty acids. In humans, fatty acid catabolism results in the production of acetyl-CoA which can then be used to synthesize three ketone bodies: acetoacetate, acetone, and ß-hydroxybutyrate. Ketogenesis occurs at a higher rate in situations of low blood glucose, such as during fasting, heavy alcohol consumption, and in situations of low insulin, as well as in individuals who follow a 'ketogenic diet' consisting of low carbohydrate and high fat intake. This diet has various therapeutic indications, including reduction of seizure likelihood in epileptic patients and alcohol withdrawal syndrome. However, the mechanisms underlying these therapeutic benefits are still unclear, with studies suggesting various mechanisms such as a shift in energy production in the brain, effects on neurotransmitter production, or effects on various protein targets. Two-electrode voltage clamp electrophysiology in Xenopus laevis oocytes was used to investigate the actions of ketone bodies on three ionotropic receptors: GABAA, glycine, and NMDA receptors. While physiologically-relevant concentrations of acetone have little effect on inhibitory GABA or glycine receptors, ß-hydroxybutyrate inhibits the effects of agonists of these receptors at concentrations achieved in vivo. Additionally, both acetone and ß-hydroxybutyrate act as inhibitors of glutamate at the excitatory NMDA receptor. Due to the role of hyperexcitability in the pathogenesis of epilepsy and alcohol withdrawal, the inhibitory actions of acetone and ß-hydroxybutyrate at NMDA receptors may underlie the therapeutic benefit of a ketogenic diet for these disorders.


Assuntos
Ácido 3-Hidroxibutírico/farmacologia , Acetona/farmacologia , Corpos Cetônicos/metabolismo , Receptores de GABA-A/efeitos dos fármacos , Receptores da Glicina/agonistas , Receptores da Glicina/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Animais , Interações Medicamentosas , Agonistas de Receptores de GABA-A/farmacologia , Oócitos/fisiologia , Receptores de N-Metil-D-Aspartato/agonistas , Xenopus
18.
Molecules ; 23(10)2018 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-30287800

RESUMO

In traditional Asian medicinal systems, preparations of the root and stem bark of Magnolia species are widely used to treat anxiety and other nervous disturbances. The biphenyl-type neolignans honokiol and magnolol are the main constituents of Magnolia bark extracts. In the central nervous system, Magnolia bark preparations that contain honokiol are thought to primarily interact with γ-aminobutyric acid A (GABAA) receptors. However, stress responses inherently involve the noradrenergic system, which has not been investigated in the pharmacological mechanism of honokiol. We present here interactions of honokiol and other synthesized biphenyl-type neolignans and diphenylmethane analogs with the norepinephrine transporter (NET), which is responsible for the synaptic clearance of norepinephrine and the target of many anxiolytics. Of the synthesized compounds, 16 are new chemical entities, which are fully characterized. The 52 compounds tested show mild, non-potent interactions with NET (IC50 > 100 µM). It is thus likely that the observed anxiolytic effects of, e.g., Magnolia preparations, are not due to direct interaction with the noradrenergic system.


Assuntos
Neurônios Adrenérgicos/efeitos dos fármacos , Ansiolíticos/farmacologia , Sistema Nervoso Central/efeitos dos fármacos , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/efeitos dos fármacos , Extratos Vegetais/farmacologia , Ansiolíticos/química , Compostos Benzidrílicos/química , Compostos Benzidrílicos/farmacologia , Compostos de Bifenilo/química , Compostos de Bifenilo/farmacologia , Sistema Nervoso Central/metabolismo , Células HEK293 , Humanos , Lignanas/química , Lignanas/farmacologia , Magnolia/química , Norepinefrina/metabolismo , Casca de Planta/química , Extratos Vegetais/química , Receptores de GABA-A/efeitos dos fármacos
19.
Stroke ; 49(10): 2495-2503, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30355106

RESUMO

Background and Purpose- Poststroke, neuronal excitability is tonically reduced in peri-infarct tissue via inhibitory influences of extrasynaptic GABAA receptors. We hypothesized that GABAA α5 blockade by the competitive antagonist S44819 enhances postischemic neurological recovery, brain remodeling, and neuroplasticity. Methods- In an explorative study followed by a confirmation study, male C57Bl6/j mice were exposed to transient intraluminal middle cerebral artery occlusion. Starting 72 hours poststroke, vehicle or S44819 (3 or 10 mg/kg, BID) was delivered orally for 28 days. Neurological recovery, perilesional tissue remodeling, and contralesional pyramidal tract plasticity were evaluated for 42 days, that is, 14 days after completion of S44819 delivery. Results- S44819, delivered at 10 but not 3 mg/kg, persistently improved motor coordination and spatial memory in both studies. Striatal atrophy was reduced by 10 mg/kg S44819 at 42 days post-treatment onset, and neuronal long-term survival in the peri-infarct striatum was increased. Delayed neuroprotection was associated with reduced peri-infarct astrogliosis, increased peri-infarct brain capillary density, and increased neural precursor cell proliferation and differentiation in proximity to the ipsilesional subventricular zone. Contralesional pyramidal tract plasticity, evaluated by anterograde tract tracing at the level of the red nucleus, was not influenced by S44819. Concentrations of neurotrophic (brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor) and angiogenic (vascular endothelial growth factor and basic fibroblast growth factor) growth factors were elevated by 10 mg/kg S44819 in peri-infarct but not contralesional brain tissue. Conclusions- Our data demonstrate that S44819 enhances neurological recovery and peri-infarct brain remodeling in the postacute stroke phase.


Assuntos
Benzodiazepinas/farmacologia , Antagonistas GABAérgicos/farmacologia , Oxazóis/farmacologia , Recuperação de Função Fisiológica/efeitos dos fármacos , Acidente Vascular Cerebral/tratamento farmacológico , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Infarto da Artéria Cerebral Média/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Plasticidade Neuronal/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neuroproteção/efeitos dos fármacos , Receptores de GABA-A/efeitos dos fármacos , Receptores de GABA-A/metabolismo , Acidente Vascular Cerebral/fisiopatologia
20.
World J Biol Psychiatry ; 19(sup1): S36-S45, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30204559

RESUMO

OBJECTIVES: Anxiety and adjustment disorders are among the most prevalent mental health conditions. This review focuses on γ-aminobutyric acid receptor type A (GABAAR)-mediated anxiolysis, describing the action of both endogenous and exogenous modulators of GABAAR. Future directions and innovative strategies to alleviate anxiety symptoms are discussed, with a particular emphasis on etifoxine. METHODS: We used available data from the recent literature to update the mode of action of anxiolytics. We focussed our search on anxiolytics acting at GABAARs, as well as on the pharmacological properties of formerly and currently prescribed anxiolytics. RESULTS: Considering the adverse effects of current treatments aimed at increasing inhibitory controls, optimisation of existing pharmacotherapies is of crucial importance. Among the alternative compounds targeting the GABAergic system, translocator protein (TSPO) ligands, such as etifoxine (EFX), which promote endogenous neurosteroidogenesis, are emerging as promising candidates for anxiety relief. In several papers comparing the efficacy of benzodiazepines and EFX, EFX showed interesting properties with limited side effects. Indeed, neurosteroids are potent GABAAR modulators with highly underrated anxiolytic properties. CONCLUSIONS: Novel therapeutic strategies have been emerging following the recognition of neurosteroids as potent anxiolytics. Featured at the top of the list for well-tolerated anxiety relief, TSPO ligands such as etifoxine appear promising.


Assuntos
Transtornos de Adaptação/tratamento farmacológico , Ansiolíticos/farmacologia , Transtornos de Ansiedade/tratamento farmacológico , Oxazinas/farmacologia , Receptores de GABA-A/efeitos dos fármacos , Humanos
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