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https://www.readbyqxmd.com/read/28816653/assembly-rules-for-gabaa-receptor-complexes-in-the-brain
#1
James S Martenson, Tokiwa Yamasaki, Nashid H Chaudhury, David Albrecht, Susumu Tomita
GABAA receptor (GABAAR) pentamers are assembled from a pool of 19 subunits, and variety in subunit combinations diversifies GABAAR functions to tune brain activity. Pentamers with distinct subunit compositions localize differentially at synaptic and non-synaptic sites to mediate phasic and tonic inhibition, respectively. Despite multitudes of theoretical permutations, limited subunit combinations have been identified in the brain. Currently, no molecular model exists for combinatorial GABAAR assembly in vivo...
August 17, 2017: ELife
https://www.readbyqxmd.com/read/28815604/chronic-morphine-reduces-the-readily-releasable-pool-of-gaba-a-presynaptic-mechanism-of-opioid-tolerance
#2
Adrianne R Wilson-Poe, Hyo-Jin Jeong, Christopher W Vaughan
The midbrain periaqueductal grey (PAG) plays a critical role in tolerance to the analgesic actions of opioids such as morphine. While numerous studies have identified the postsynaptic adaptations induced by chronic morphine treatment in this and other brain regions, the presence of presynaptic adaptations remains uncertain. We examined GABAergic synaptic transmission within rat PAG brain slices from animals which underwent a low dose morphine treatment protocol which produces tolerance, but not withdrawal. Evoked GABAergic IPSCs (inhibitory postsynaptic currents) were less in morphine compared to control saline treated animals...
August 16, 2017: Journal of Physiology
https://www.readbyqxmd.com/read/28810599/effects-of-niflumic-acid-on-%C3%AE-aminobutyric-acid-induced-currents-in-isolated-dorsal-root-ganglion-neurons-of-neuropathic-pain-rats
#3
Li-Jie Wang, Yang Wang, Meng-Jie Chen, Zhen-Pu Tian, Bi-Han Lu, Ke-Tao Mao, Liang Zhang, Lei Zhao, Li-Ya Shan, Li Li, Jun-Qiang Si
Niflumic acid (NFA) is a type of non-steroidal anti-inflammatory drug. Neuropathic pain is caused by a decrease in presynaptic inhibition mediated by γ-aminobutyric acid (GABA). In the present study, a whole-cell patch-clamp technique and intracellular recording were used to assess the effect of NFA on GABA-induced inward current in dorsal root ganglion (DRG) neurons of a chronic constriction injury (CCI) model. It was observed that 1-1,000 µmol/l GABA induced a concentration-dependent inward current in DRG neurons...
August 2017: Experimental and Therapeutic Medicine
https://www.readbyqxmd.com/read/28807671/selective-inhibition-of-extra-synaptic-%C3%AE-5-gabaa-receptors-by-s44819-a-new-therapeutic-agent
#4
Lori-An Etherington, Balázs Mihalik, Adrienn Pálvölgyi, István Ling, Katalin Pallagi, Szabolcs Kertész, Péter Varga, Ben G Gunn, Adam R Brown, Matthew R Livesey, Olivia Monteiro, Delia Belelli, József Barkóczy, Michael Spedding, István Gacsályi, Ferenc A Antoni, Jeremy J Lambert
In the mammalian central nervous system (CNS) GABAA receptors (GABAARs) mediate neuronal inhibition and are important therapeutic targets. GABAARs are composed of 5 subunits, drawn from 19 proteins, underpinning expression of 20-30 GABAAR subtypes. In the CNS these isoforms are heterogeneously expressed and exhibit distinct physiological and pharmacological properties. We report the discovery of S44819, a novel tricyclic oxazolo-2,3-benzodiazepine-derivative, that selectively inhibits α5-subunit-containing GABAARs (α5-GABAARs)...
August 11, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28805971/anticonvulsive-evaluation-of-thip-in-the-murine-pentylenetetrazole-kindling-model-lack-of-anticonvulsive-effect-of-thip-despite-functional-%C3%AE-subunit-containing-gabaa-receptors-in-dentate-gyrus-granule-cells
#5
Charlotte Simonsen, Kim Boddum, Nadia L von Schoubye, Alissa Kloppenburg, Kasper Sønderskov, Suzanne L Hansen, Uffe Kristiansen
THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol) is a GABAA receptor agonist with varying potencies and efficacies at γ-subunit-containing receptors. More importantly, THIP acts as a selective superagonist at δ-subunit-containing receptors (δ-GABAA Rs) at clinically relevant concentrations. Evaluation of THIP as a potential anticonvulsant has given contradictory results in different animal models and for this reason, we reevaluated the anticonvulsive properties of THIP in the murine pentylenetetrazole (PTZ) kindling model...
August 2017: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/28803659/seizing-control-of-kcc2-a-new-therapeutic-target-for-epilepsy
#6
REVIEW
Yvonne E Moore, Matt R Kelley, Nicholas J Brandon, Tarek Z Deeb, Stephen J Moss
Deficits in GABAergic inhibition result in the abnormal neuronal activation and synchronization that underlies seizures. However, the molecular mechanisms responsible for transforming a normal brain into an epileptic one remain largely unknown. Hyperpolarizing inhibition mediated by type A GABA (GABAA) receptors is dependent on chloride extrusion by the neuron-specific type 2K(+)-Cl(-) cotransporter (KCC2). Loss-of-function mutations in KCC2 are a known cause of infantile epilepsy in humans and KCC2 dysfunction is present in patients with both idiopathic and acquired epilepsy...
August 10, 2017: Trends in Neurosciences
https://www.readbyqxmd.com/read/28799512/modulation-of-gabaa-receptors-in-the-treatment-of-epilepsy
#7
Eleonora Palma, Gabriele Ruffolo, Pierangelo Cifelli, Cristina Roseti, Erwin A van Vliet, Eleonora Aronica
BACKGROUND: A variety of evidence suggested that an imbalance in excitatory and inhibitory neurotransmission could be one of the pathophysiological mechanisms underlying the occurrence and progression of seizures. Understanding the causes of this imbalance may provide essential insight into the basic mechanisms of epilepsy and may uncover novel targets for future drug therapies. Accordingly, GABA is the most important inhibitory neurotransmitter in the CNS and its receptors (e.g., GABAARs) can still be relevant targets of new antiepileptic drugs (AEDs)...
August 9, 2017: Current Pharmaceutical Design
https://www.readbyqxmd.com/read/28798394/orthosteric-versus-allosteric-dependent-activation-of-the-gabaa-receptor-requires-numerically-distinct-subunit-level-rearrangements
#8
Jahanshah Amin, Meena S Subbarayan
Anaesthetic molecules act on synaptic transmission via the allosteric modulation of ligand-gated chloride channels, such as hetero-oligomeric α1β2γ2 GABAA receptors. To elucidate the overall activation paradigm via allosteric versus orthosteric sites, we used highly homologous, but homo-oligomeric, ρ1 receptors that are contrastingly insensitive to anaesthetics and respond partially to several full GABA α1β2γ2 receptor agonists. Here, we coexpressed varying ratios of RNAs encoding the wild-type and the mutated ρ1 subunits, which are anaesthetic-sensitive and respond with full efficacy to partial GABA agonists, to generate distinct ensembles of receptors containing five, four, three, two, one, or zero mutated subunits...
August 10, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28798030/ethanol-exposure-regulates-gabra1-expression-via-histone-deacetylation-at-the-promoter-in-cultured-cortical-neurons
#9
John Peyton Bohnsack, Vraj K Patel, A Leslie Morrow
GABAA-Rs mediate the majority of inhibitory neurotransmission in the adult brain. α1-containing GABAA-Rs are the most prominent subtype in the adult brain, and are important in both homeostatic function and several disease pathologies including alcohol dependence, epilepsy, and stress. Ethanol exposure causes a decrease of α1 transcription and peptide expression both in vivo and in vitro, but the mechanism that controls the transcriptional regulation is unknown. Since ethanol is known to activate epigenetic regulation of gene expression, we tested the hypothesis that ethanol regulates α1 expression through histone modifications in cerebral cortical cultured neurons...
August 10, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28795438/a-specific-gabaergic-synapse-onto-oligodendrocyte-precursors-does-not-regulate-cortical-oligodendrogenesis
#10
Maddalena Balia, Najate Benamer, María Cecilia Angulo
In the brain, neurons establish bona fide synapses onto oligodendrocyte precursor cells (OPCs), but the function of these neuron-glia synapses remains unresolved. A leading hypothesis suggests that these synapses regulate OPC proliferation and differentiation. However, a causal link between synaptic activity and OPC cellular dynamics is still missing. In the developing somatosensory cortex, OPCs receive a major type of synapse from GABAergic interneurons that is mediated by postsynaptic γ2-containing GABAA receptors...
August 10, 2017: Glia
https://www.readbyqxmd.com/read/28795276/topiramate-via-nmda-ampa-kainate-gabaa-and-alpha2-receptors-and-by-modulation-of-creb-bdnf-and-akt-gsk3-signaling-pathway-exerts-neuroprotective-effects-against-methylphenidate-induced-neurotoxicity-in-rats
#11
Majid Motaghinejad, Manijeh Motevalian, Sulail Fatima, Tabassom Beiranvand, Shiva Mozaffari
Chronic abuse of methylphenidate (MPH) often causes neuronal cell death. Topiramate (TPM) carries neuroprotective effects, but its exact mechanism of action remains unclear. In the present study, the role of various doses of TPM and its possible mechanisms, receptors and signaling pathways involved against MPH-induced hippocampal neurodegeneration were evaluated in vivo. Thus, domoic acid (DOM) was used as AMPA/kainate receptor agonist, bicuculline (BIC) as GABAA receptor antagonist, ketamine (KET) as NMDA receptor antagonist, yohimbine (YOH) as α2 adrenergic receptor antagonist and haloperidol (HAL) was used as dopamine D2 receptor antagonist...
August 9, 2017: Journal of Neural Transmission
https://www.readbyqxmd.com/read/28791154/co2-induced-ocean-acidification-does-not-affect-individual-or-group-behaviour-in-a-temperate-damselfish
#12
Garfield Tsz Kwan, Trevor James Hamilton, Martin Tresguerres
Open ocean surface CO2 levels are projected to reach approximately 800 µatm, and ocean pH to decrease by approximately 0.3 units by the year 2100 due to anthropogenic CO2 emissions and the subsequent process of ocean acidification (OA). When exposed to these CO2/pH values, several fish species display abnormal behaviour in laboratory tests, an effect proposed to be linked to altered neuronal GABAA- receptor function. Juvenile blacksmith (Chromis punctipinnis) are social fish that regularly experience CO2/pH fluctuations through kelp forest diurnal primary production and upwelling events, so we hypothesized that they might be resilient to OA...
July 2017: Royal Society Open Science
https://www.readbyqxmd.com/read/28790892/a-critical-period-for-the-rapid-modification-of-synaptic-properties-at-the-vpm-relay-synapse
#13
Libiao Pan, Junhua Yang, Qian Yang, Xiaomeng Wang, Liya Zhu, Yali Liu, Huifang Lou, Chou Xu, Ying Shen, Hao Wang
In addition to cortical areas, the thalamus also displays plasticity during a critical period in early life. Since most sensory information is transmitted to the cortex via the thalamus, it will be of significant interest to understand the precise time window and underlying mechanisms of this critical period in the thalamus. By using in vitro whole-cell patch recording in acute brain slices, we found that VPm relay synapses were only sensitive to whisker deprivation from postnatal day 11 (P11) to P14. Whisker deprivation initiated within the P11 to P14 window significantly reduced the amplitude of AMPAR-EPSCs, but not NMDAR-EPSCs when recorded 24 h after whisker removal...
2017: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/28790148/the-actions-of-drug-combinations-on-the-gabaa-receptor-manifest-as-curvilinear-isoboles-of-additivity
#14
Daniel J Shin, Allison L Germann, Joseph H Steinbach, Gustav Akk
Drug interactions are often analyzed in terms of isobolograms. In the isobologram, the line connecting the axial points corresponding to the concentrations of two different drugs that produce an effect of the same magnitude is termed an isobole of additivity. Although the isobole of additivity can be a straight line in some special cases, previous work has found that it is curvilinear when the two drugs differ in their maximal effects or Hill slopes. Modulators of transmitter-gated ion channels have a wide range of maximal effects as well as Hill slopes, suggesting that the isoboles for drug actions on ion channel function are not linear...
August 8, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28782830/altered-behavioral-responses-to-gamma-aminobutyric-acid-pharmacological-agents-in-a-mouse-model-of-huntington-s-disease
#15
Yi-Ting Hsu, Ya-Gin Chang, Ching-Pang Chang, Jian-Jing Siew, Hui-Mei Chen, Chon-Haw Tsai, Yijuang Chern
BACKGROUND: Disruptions in gamma-aminobutyric (GABA) acid signaling are believed to be involved in Huntington's disease pathogenesis, but the regulation of GABAergic signaling remains elusive. Here we evaluated GABAergic signaling by examining the function of GABAergic drugs in Huntington's disease and the expression of GABAergic molecules using mouse models and human brain tissues from Huntington's disease. METHODS: We treated wild-type and R6/2 mice (a transgenic Huntington's disease mouse model) acutely with vehicle, diazepam, or gaboxadol (drugs that selectively target synaptic or extrasynaptic GABAA receptors) and monitored their locomotor activity...
August 7, 2017: Movement Disorders: Official Journal of the Movement Disorder Society
https://www.readbyqxmd.com/read/28780872/oxazepam-dopamine-conjugates-increase-dopamine-delivery-into-striatum-of-intact-rats
#16
Tommaso Cassano, Antonio Lopalco, Modesto de Candia, Valentino Laquintana, Angela Lopedota, Annalisa Cutrignelli, Mara Perrone, Rosa M Iacobazzi, Gaurav Bedse, Massimo Franco, Nunzio Denora, Cosimo D Altomare
The neurotransmitter dopamine (DA) was covalently linked to oxazepam (OXA), a well-known positive allosteric modulator of γ-aminobutyric acid type-A (GABAA) receptor, through a carbamate linkage (4) or a succinic spacer (6). These conjugates were synthesized with the aim of improving the delivery of DA into the brain and enhancing GABAergic transmission, which may be useful for the long-term treatment of Parkinson disease (PD). Structure-based permeability properties, in vitro stability and blood-brain barrier (BBB) permeability studies led to identify the OXA-DA carbamate conjugate 4a as the compound better combining sufficient stability and ability to cross BBB...
August 5, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28780039/disruption-of-5-ht2a-pdz-protein-interaction-differently-affects-the-analgesic-efficacy-of-ssri-snri-and-tca-in-the-treatment-of-traumatic-neuropathic-pain-in-rats
#17
Anne-Sophie Wattiez, Amandine Dupuis, Anne-Marie Privat, Maryse Chalus, Eric Chapuy, Youssef Aissouni, Alain Eschalier, Christine Courteix
Antidepressants remain one of the first line treatments prescribed to neuropathic pain patients despite their limited efficacy and/or their numerous side effects. More and more, pharmacotherapy for neuropathic pain has evolved towards the use of therapeutic combinations. The goal of the present study was to assess the efficacy of the combination of antidepressants - selective serotonin reuptake inhibitors and serotonin-noradrenaline reuptake inhibitors-with a peptide (TAT-2ASCV) able to disrupt the interaction between serotonin type 2A (5-HT2A) receptors and associated PDZ proteins...
August 2, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28777881/early-stage-attenuation-of-phase-amplitude-coupling-in-the-hippocampus-and-medial-prefrontal-cortex-in-a-transgenic-rat-model-of-ad
#18
Paolo Bazzigaluppi, Tina L Beckett, Margaret M Koletar, Aaron Y Lai, Illsung L Joo, Mary E Brown, Peter L Carlen, JoAnne McLaurin, Bojana Stefanovic
Alzheimer's disease (AD) is pathologically characterized by amyloid-β peptide (Aβ) accumulation, neurofibrillary tangle formation, and neurodegeneration. Preclinical studies on neuronal impairments associated with progressive amyloidosis have demonstrated some Aβ-dependent neuronal dysfunction including modulation of GABAergic signalling. The present work focuses on the early stage of disease progression and uses TgF344-AD rats that recapitulate a broad repertoire of AD-like pathologies to investigate the neuronal network functioning using simultaneous intracranial recordings from the hippocampus (HPC) and the medial prefrontal cortex (mPFC), followed by pathological analyses of gamma-aminobutyric acid (GABAA ) receptors subunits α1, α5 and δ, and glutamic acid decarboxylases (GAD65 and GAD67)...
August 4, 2017: Journal of Neurochemistry
https://www.readbyqxmd.com/read/28777735/evidence-for-the-involvement-of-the-gaba-ergic-pathway-in-the-anticonvulsant-activity-of-the-roots-bark-aqueous-extract-of-anthocleista-djalonensis-a-chev-loganiaceae
#19
Germain Sotoing Taiwe, Arielle Larissa Ndieudieu Kouamou, Armelle Rosalie Mbang Ambassa, Joseph Renaud Menanga, Thierry Bang Tchoya, Paul Desire Djomeni Dzeufiet
BACKGROUND: The root bark of Anthocleista djalonensis A. Chev. (Loganiaceae) is widely used in traditional medicine in Northern Cameroon to treat epilepsy and related conditions, such as migraine, insomnia, dementia, anxiety, and mood disorders. METHODS: To investigate the anticonvulsant effects and the possible mechanisms of this plant, an aqueous extract of Anthocleista djalonensis (AEAD) was evaluated by using animal models of bicuculline-, picrotoxin-, pilocarpine-, and pentylenetetrazole-induced convulsions...
August 4, 2017: Journal of Basic and Clinical Physiology and Pharmacology
https://www.readbyqxmd.com/read/28765955/gabaergic-ventrolateral-pre%C3%A2-optic-nucleus-neurons-are-involved-in-the-mediation-of-the-anesthetic-hypnosis-induced-by-propofol
#20
Jie Yuan, Zhuxin Luo, Yu Zhang, Yi Zhang, Yuan Wang, Song Cao, Bao Fu, Hao Yang, Lin Zhang, Wenjing Zhou, Tian Yu
Intravenous anesthetics have been used clinically to induce unconsciousness for seventeen decades, however the mechanism of anesthetic‑induced unconsciousness remains to be fully elucidated. It has previously been demonstrated that anesthetics exert sedative effects by acting on endoge-nous sleep‑arousal circuits. However, few studies focus on the ventrolateral pre‑optic (VLPO) to locus coeruleus (LC) sleep‑arousal pathway. The present study aimed to investigate if VLPO is involved in unconsciousness induced by propofol...
September 2017: Molecular Medicine Reports
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