Journal articles: 'Receptors, GABA-Benzodiazepine'

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WAMSLEY, JAMES K. "GABA-Benzodiazepine Receptors." American Journal of Psychiatry 149, no. 4 (April 1992): 582—a—582. http://dx.doi.org/10.1176/ajp.149.4.582-a.

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Lingford-Hughes, Anne R., P. Acton, S. Gacinovic, J. Suckling, G. F. Busatto, S. J. A. Boddington, E. Bullmore, et al. "Reduced levels of GABA-benzodiazepine receptor in alcohol dependency in the absence of grey matter atrophy." British Journal of Psychiatry 173, no. 2 (August 1998): 116–22. http://dx.doi.org/10.1192/bjp.173.2.116.

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BackgroundWe tested the hypothesis that reduced levels of the GABA-benzodiazepine receptor occur in alcohol dependency using single photon emission tomography (SPET) and the specific GABA-benzodiazepine ligand, 123l-iomazenil.MethodNeurologically and cognitively unimpaired abstinent alcohol-dependent (n=12) and non-alcohol-dependent male subjects (n=14) underwent a 123l–iomazenil SPET scan. SPET and magnetic resonance images were co-registered and voxel-based statistical tests performed. Subjects' clinical and alcohol history were obtained with standard questionnaires. The relationships between clinical and alcohol variables and the regional level of GABA-benzodiazepine receptors were investigated using multiple regression analysis.ResultsAbstinent alcohol-dependent subjects had decreased levels of GABA-benzodiazepine receptor compared with non-alcohol-dependent subjects within the frontal, parietal and temporal cortices, including regions in which grey matter atrophy was absent.ConclusionsAlcohol dependency is associated with reduced GABA-benzodiazepine receptor levels in the absence of grey matter atrophy in some cortical regions, such as within the parietal lobe. Regional variability of reduction in GABA-benzodiazepine receptors demonstrates that alcohol does not have a global, toxic effect on the brain.

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Guttman, Mark. "Receptors in the Basal Ganglia." Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques 14, S3 (August 1987): 395–401. http://dx.doi.org/10.1017/s0317167100037793.

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ABSTRACT:The study of neurotransmitter receptors aids in the understanding of the normal anatomy, pharmacology, therapeutics and pathophysiology of disease processes involving the basal ganglia. Receptors may be studied in vitro by homogenate binding experiments, enzyme analysis or quantitative autoradiography and in vivo with positron emission tomography. In the substantia nigra (SN), receptors have been identified for somatostatin, neurotensin, substance P, glycine, benzodiazepine and GABA, opiates, dopamine, angiotensin converting enzyme (ACE) and serotonin. The striatum has receptors for dopamine, GABA and benzodiazepines, acetylcholine, opiates, substance P, glutamate and cholecystokinin. GABA and benzodiazepine receptors are also located in the globus pallidus. In Parkinson's disease, striatal dopamine D-2 receptors are elevated in patients that have not received L-DOPA therapy. This supersensitivity is reversed with agonist therapy. Muscarinic binding to cholinergic receptors seems to correlate with dopamine receptors. Delta opiate receptors are increased in the caudate and mu binding is reduced in the striatum. In the SN of patients with Parkinson's disease, there is reduced binding of somatostatin, neurotensin, mu and kappa opiates, benzodiazepine and GABA and glycine. In Huntington's disease, there is reduced binding of GABA and benzodiazepines, dopamine, acetylcholine, glutamate and CCK. There is increased binding of GABA in both the SN and globus pallidus. Glycine binding is increased in the substantia nigra and ACE is reduced.

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Schnee, M., J. Rauh, S. D. Buckingham, and D. B. Sattelle. "Pharmacology of skeletal muscle GABA-gated chloride channels in the cockroach Periplaneta americana." Journal of Experimental Biology 200, no. 23 (December 1, 1997): 2947–55. http://dx.doi.org/10.1242/jeb.200.23.2947.

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The pharmacology of -aminobutyric acid (GABA)-gated chloride channels of the coxal levator (182c,d) muscle of the cockroach Periplaneta americana has been investigated and the data compared with similar findings for the cell body of the cockroach fast coxal depressor motor neurone (Df). Muscle GABA receptors resembled those of the motor neurone cell body in their sensitivity to picrotoxinin and insensitivity to bicuculline. However, muscle GABA receptors were insensitive to the neuronal GABA receptor agonists isoguvacine (10(-4) mol l-1) and 3-aminopropane sulphonic acid (10(-3 )mol l-1). The benzodiazepine flunitrazepam, which at 10(-6 )mol l-1 greatly enhances the amplitude of the motor neurone GABA-induced responses, failed to affect muscle responses to GABA when tested at the same and at a higher (10(-4 )mol l-1) concentration. The convulsant t-butylbicyclophosphorothionate was a weak antagonist of cockroach muscle GABA receptors, whereas several cyclodienes were much more effective antagonists. Thus, studies using a benzodiazepine and several convulsant antagonists reveal differences in the pharmacology of muscle and neuronal GABA receptors of the cockroach Periplaneta americana.

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Meldrum, B. "Classification of GABA and benzodiazepine receptors." Journal of Psychopharmacology 1, no. 1 (January 1987): 1–5. http://dx.doi.org/10.1177/026988118700100102.

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Weizman, Abraham, and Moshe Gavish. "Gonadal hormones, GABA and benzodiazepine receptors." European Neuropsychopharmacology 6 (June 1996): 97. http://dx.doi.org/10.1016/0924-977x(96)87749-2.

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Li, Ping, Megan M. Eaton, Joe Henry Steinbach, and Gustav Akk. "The Benzodiazepine Diazepam Potentiates Responses of α1β2γ2L γ-Aminobutyric Acid Type A Receptors Activated by either γ-Aminobutyric Acid or Allosteric Agonists." Anesthesiology 118, no. 6 (June 1, 2013): 1417–25. http://dx.doi.org/10.1097/aln.0b013e318289bcd3.

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Abstract Background: The γ-aminobutyric acid (GABA) type A receptor is a target for several anesthetics, anticonvulsants, anxiolytics, and sedatives. Neurosteroids, barbiturates, and etomidate both potentiate responses to GABA and allosterically activate the receptor. We examined the ability of a benzodiazepine, diazepam, to potentiate responses to allosteric agonists. Methods: The GABA type A receptors were expressed in human embryonic kidney 293 cells and studied using whole-cell and single-channel patch clamp. The receptors were activated by the orthosteric agonist GABA and allosteric agonists pentobarbital, etomidate, and alfaxalone. Results: Diazepam is equally potent at enhancing responses to orthosteric and allosteric agonists. Diazepam EC50s were 25 ± 4, 26 ± 6, 33 ± 6, and 26 ± 3 nm for receptors activated by GABA, pentobarbital, etomidate, and alfaxalone, respectively (mean ± SD, 5–6 cells at each condition). Mutations to the benzodiazepine-binding site (α1(H101C), γ2(R144C), γ2(R197C)) reduced or removed potentiation for all agonists, and an inverse agonist at the benzodiazepine site reduced responses to all agonists. Single-channel data elicited by GABA demonstrate that in the presence of 1 μm diazepam the prevalence of the longest open-time component is increased from 13 ± 7 (mean ± SD, n = 5 patches) to 27 ± 8% (n = 3 patches) and the rate of channel closing is decreased from 129 ± 28 s−1 to 47 ± 6 s−1 (mean±SD) Conclusions: We conclude that benzodiazepines do not act by enhancing affinity of the orthosteric site for GABA but rather by increasing channel gating efficacy. The results also demonstrate the presence of interactions between allosteric activators and potentiators, raising a possibility of effects on dosage requirements or changes in side effects.

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Teuber, L., F. Watjen, and L. H. Jensen. "Ligands for the Benzodiazepine Binding Site - a Survey." Current Pharmaceutical Design 5, no. 5 (May 1999): 317–43. http://dx.doi.org/10.2174/138161280505230110100242.

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Abstract: y-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the mammalian Central Nervous System (CNS). GABA participates in the 1·egulation of neuronal excitability through interaction with specific membrane proteins (the GABAA receptors). The binding of GABA to these postsynaptic receptors, results in an opening of a chloride channel integrated in the receptor which allows the entry of c1- and consequently leads to hyperpolarization of the recipient cell. The action of GABA is allosterically modulated by a wide variety of chemical entities which interact with distinct binding sites at the GABAA receptor complex. One of the most thoroughly investigated rnodulatory site is the benzodiazepin binding site. The benzodiazepines constitute a well-known class of therapeutics displaying hypnotic, anxiolytic and anticonvulsant effects. Their usefulness, however, is limited by a broad range of side effects comprising sedation, ataxia, amnesia, alcohol and barbiturate potentiation, tolerance development and abuse potential. Consequently, there has been an intensive search for modulatory agents with an improved profile, and a diversity of chemical entities distinct from the benzodiazepines. but with GABA modulatory effects have been identified. The existence of endogenous ligands for the GABAA receptor complex beside GABA has often been described, but their role in the regulation of GABA action is still a matter of controversy. The progress of molecular biology during the last decade has contributed enormously to the understanding of benzodiazepine receptor pharmacology. A total of 14 GABAA receptor subunits have been cloned from mammalian brain and have been expressed/co-expressed in stable cell lines. These transfected cells constitute an important tool in the characterization of subtype selective ligands. In spite of the rapidly expanding knowledge of the molecular and pharmacological mechanisms involved in GABA/benzodiazepine related CNS disorders. the identification of clinically selective acting drugs is still to come.

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Shilov, Georgii N., Oleg N. Bubel, and Petr D. Shabanov. "A new approach to understanding structure, functions and classificasion of GABA-benzodiazepine receptor complex, a molecular target for creation of new anticonvulsants on the base of inhibitory amino acids." Reviews on Clinical Pharmacology and Drug Therapy 14, no. 3 (September 15, 2016): 34–45. http://dx.doi.org/10.17816/rcf14334-45.

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The GABA molecule was shown to the methods of quantum mechanic characteristics and molecular geometry has three conformational states: linear (GABA-1 conformer), cyclic (GABA-2 comformer) and bucket-like (GABA-3 conformer). The play different functions in the brain neurons: cyclic and bucket-like conformers play role of endogenous transmitters, and linear conformer participates in neuronal metabolism. The theoretical conformational analysis shows there are two types of GABA receptors in the CNS neurons: GABA-2 receptors, agonists of which are cyclic conformer of GABA, glycine and β-alanine and antagonists are bemegride, pentilentetrazol and strychnine; and GABA-3 receptors, agonists of which is bucket-like conformer of GABA and antagonists are picrotoxin and bicuculline. Anticonvulsive and other behavioral effects of derivatives of barbituric acid, benzazepine, benzodiazepine, gidantoine, succinimide and oxasolidindione are realized probably via GABA-2 receptors to switch on them the following functional centers of their structure are nessesary: α, γ and [δ-ε] for barbitirates; β, [δ-ε] and γ for carbamazepine; β and [δ-ε] for benzodiazepine derivatives, gabapentine and vigabatrine; α, β, γ and [δ-ε] for gidantoine and oxasolidindione derivatives; α, β, γ for succinimide derivatives. The power of any behavioral effect of anticonvulsants and inhibitory amino acids depends on power, location and numbers of hydrogen bounds developed between active centers of pharmacophore of anticonvulsant or inhibitory amino acids and active centers of functional skeleton of GABA-2 receptor complex, these properties determine absense of nootropic activity in anticonvulsive drugs and presense of them in inhibitory amino acids. It is concluded there are perspectives of synthesis of conpounds, pharmacophore of which should be like as cyclic conformer of GABA, glycine and β-alanine on their quantum mechanic characteristics and molecular geometry

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Dietl, M. M., R. Cortés, and J. M. Palacios. "Neurotransmitter receptors in the avian brain. III. GABA-benzodiazepine receptors." Brain Research 439, no. 1-2 (January 1988): 366–71. http://dx.doi.org/10.1016/0006-8993(88)91496-5.

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Kohno, Tatsuro, Eiichi Kumamoto, Hiroshi Baba, Toyofumi Ataka, Manabu Okamoto, Koki Shimoji, and Megumu Yoshimura. "Actions of Midazolam on GABAergic Transmission in Substantia Gelatinosa Neurons of Adult Rat Spinal Cord Slices." Anesthesiology 92, no. 2 (February 1, 2000): 507. http://dx.doi.org/10.1097/00000542-200002000-00034.

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Background Although intrathecal administration of midazolam has been found to produce analgesia, how midazolam exerts this effect is not understood fully at the neuronal level in the spinal cord. Methods The effects of midazolam on either electrically evoked or spontaneous inhibitory transmission and on a response to exogenous gamma-aminobutyric acid (GABA), a GABA(A)-receptor agonist, muscimol, or glycine were evaluated in substantia gelatinosa neurons of adult rat spinal cord slices by using the whole-cell patch-clamp technique. Results Bath-applied midazolam (1 microM) prolonged the decay phase of evoked and miniature inhibitory postsynaptic currents (IPSCs), mediated by GABA(A) receptors, without a change in amplitudes, while not affecting glycine receptor-mediated miniature inhibitory postsynaptic currents in both the decay phase and the amplitude. Either GABA- or muscimol-induced currents were enhanced in amplitude by midazolam (0.1 microM) in a manner sensitive to a benzodiazepine receptor antagonist, flumazenil (1 microM); glycine currents were, however, unaltered by midazolam. Conclusions Midazolam augmented both the duration of GABA-mediated synaptic current and the amplitude of GABA-induced current by acting on the GABA(A)-benzodiazepine receptor in substantia gelatinosa neurons; this would increase the inhibitory GABAergic transmission. This may be a possible mechanism for antinociception by midazolam.

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NOËL, F., D. L. MENDONÇA-SILVA, J.-P. B. THIBAUT, and D. V. S. LOPES. "Characterization of two classes of benzodiazepine binding sites in Schistosoma mansoni." Parasitology 134, no. 7 (February 22, 2007): 1003–12. http://dx.doi.org/10.1017/s0031182007002442.

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SUMMARYAs we have recently shown that GABA should be considered a putative neurotransmitter inSchistosoma mansoni, the present work aimed to search for GABAAreceptors in adult worms using [3H]-flunitrazepam to label the allosteric benzodiazepine binding site which is classically present on GABAAreceptor complexes. We detected a large population (Bmax=8·25±1·1 pmol . mg protein−1) of high affinity (Kd=33·6±1·5 nm) binding sites for flunitrazepam. These sites harboured a singular pharmacological modulation that does not fit well with a mammalian central benzodiazepine receptor, mainly due to a very high affinity for Ro5-4864 and a very low affinity for clonazepam. We also detected a second population of benzodiazepine binding sites labelled with high affinity (IC50=85 nm) by [3H]-PK11195, a selective ligand of the mammalian peripheral benzodiazepine receptor. In conclusion, this work describes the pharmacological properties of a large population of central-like benzodiazepine receptors supporting their study as putative new targets for the development of anti-parasitic agents. We also describe, for the first time, the presence of peripheral benzodiazepine receptors in this parasite.

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Feigenspan, Andreas, Stefano Gustincich, and Elio Raviola. "Pharmacology of GABAA Receptors of Retinal Dopaminergic Neurons." Journal of Neurophysiology 84, no. 4 (October 1, 2000): 1697–707. http://dx.doi.org/10.1152/jn.2000.84.4.1697.

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When the vertebrate retina is stimulated by light, a class of amacrine or interplexiform cells release dopamine, a modulator responsible for neural adaptation to light. In the intact retina, dopamine release can be pharmacologically manipulated with agonists and antagonists at GABAA receptors, and dopaminergic (DA) cells receive input from GABAergic amacrines. Because there are only 450 DA cells in each mouse retina and they cannot be distinguished in the living state from other cells on the basis of their morphology, we used transgenic technology to label DA cells with human placental alkaline phosphatase, an enzyme that resides on the outer surface of the cell membrane. We could therefore identify DA cells in vitro after dissociation of the retina and investigate their activity with whole cell voltage clamp. We describe here the pharmacological properties of the GABAA receptors of solitary DA cells. GABA application induces a large inward current carried by chloride ions. The receptors are of the GABAA type because the GABA-evoked current is blocked by bicuculline. Their affinity for GABA is very high with an EC50 value of 7.4 μM. Co-application of benzodiazepine receptor ligands causes a strong increase in the peak current induced by GABA (maximal enhancement: CL-218872 220%; flunitrazepam 214%; zolpidem 348%) proving that DA cells express a type I benzodiazepine-receptor (BZ1). GABA-evoked currents are inhibited by Zn2+ with an IC50 of 58.9 ± 8.9 μM. Furthermore, these receptors are strongly potentiated by the modulator alphaxalone with an EC50 of 340 ± 4 nM. The allosteric modulator loreclezole increases GABA receptor currents by 43% (1 μM) and by 107% (10 μM). Using outside-out patches, we measured in single-channel recordings a main conductance (29 pS) and two subconductance (20 and 9 pS) states. We have previously shown by single-cell RT-PCR and immunocytochemistry that DA cells express seven different GABAA receptor subunits (α1, α3, α4, β1, β3, γ1, γ2S, and γ2L) and by immunocytochemistry that all subunits are expressed in the intact retina. We show here that at least α1, β3 and γ2 subunits are assembled into functional receptors.

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Lutz, P. L., and S. L. Leone-Kabler. "Upregulation of the GABAA/benzodiazepine receptor during anoxia in the freshwater turtle brain." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 268, no. 5 (May 1, 1995): R1332—R1335. http://dx.doi.org/10.1152/ajpregu.1995.268.5.r1332.

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The freshwater turtle brain survives anoxia by decreasing its energy expenditure. During this anoxic period there is a sustained release of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). This study investigated whether there was a corresponding change in the binding properties of the GABAA/benzodiazepine (GABA/BDZ) receptor. Turtles (Trachemys scripta) were subjected to a 100% N2 atmosphere for up to 24 h. After exposure, the cerebral cortex was dissected out, and saturation binding assays for GABA/BDZ receptors were performed using the radioligand [3H]flunitrazepam. Control turtles had a dissociation constant (Kd) of 1.97 +/- 0.54 nM and a receptor density (Bmax) of 2,404 +/- 221 fmol/mg protein. The Kd showed no significant change over 24 h of anoxia. However, significant increases were seen in Bmax after 12 h (21%, P < 0.05) and 24 h (29%, P < 0.01) of anoxia. We suggest that a long-term upregulation of GABAA receptors occurs in the anoxic turtle brain that acts to increase the inhibitory effectiveness of the released GABA and thereby contributes to anoxia survival of the turtle.

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Lüddens, Hartmut, and Esa R. Korpi. "GabaA Receptors: Pharmacology, Behavioral Roles, and Motor Disorders." Neuroscientist 2, no. 1 (January 1996): 15–23. http://dx.doi.org/10.1177/107385849600200109.

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τ-Aminobutyric acid (GABA), the most prevalent inhibitory neurotransmitter in the mammalian brain, exerts its main action through GABAA receptors. They belong to the superfamily of ligand-gated ion channels and respond to GABA by the opening of an intrinsic anion channel. Multiple GABAA receptor subtypes in the brain show differential regional and developmental expression patterns. The receptors have a pentameric structure and are formed from members of at least three different subunit families (α1–6, β1–3, and τ1–3). The regulation of functional properties by GABA and its analogs and by benzodiazepine (BZ) receptor ligands differs dramatically with the type of α variant in the receptor complex. Additional variations of GABAA receptors result from substitution of γ subunits. The role of the β subunits, which are essential for receptor assembly, is less well defined on a functional basis. Besides their involvement in anxiolysis and sedation, GABAA receptors clearly have an impact on motor coordination. However, with the possible exception of the alcohol-and BZ-sensitive alcohol non-tolerant (ANT) rat line, it is not well documented whether a genetic alteration in this receptor system is directly involved in the impairment of animal or human motor activity.

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Fukuda, Hideomi, Junichiro Oka, Kenichi Saito, and Yoshihisa Kudo. "Ontogenetic and phylogenetic development of GABA and benzodiazepine receptors." Japanese Journal of Pharmacology 43 (1987): 18. http://dx.doi.org/10.1016/s0021-5198(19)57909-4.

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Liu, Qing-Song, Peter R. Patrylo, Xiao-Bing Gao, and Anthony N. van den Pol. "Kainate Acts at Presynaptic Receptors to Increase GABA Release From Hypothalamic Neurons." Journal of Neurophysiology 82, no. 2 (August 1, 1999): 1059–62. http://dx.doi.org/10.1152/jn.1999.82.2.1059.

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Recent reports suggest that kainate acting at presynaptic receptors reduces the release of the inhibitory transmitter GABA from hippocampal neurons. In contrast, in the hypothalamus in the presence of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-d-aspartate (NMDA) receptor antagonists [1-(4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine (GYKI 52466) and d,l-2-amino-5-phosphonopentanoic acid (AP5)], kainate increased GABA release. In the presence of tetrodotoxin, the frequency, but not the amplitude, of GABA-mediated miniature inhibitory postsynaptic currents (IPSCs) was enhanced by kainate, consistent with a presynaptic site of action. Postsynaptic activation of kainate receptors on cell bodies/dendrites was also found. In contrast to the hippocampus where kainate increases excitability by reducing GABA release, in the hypothalamus where a much higher number of GABAergic cells exist, kainate-mediated activation of transmitter release from inhibitory neurons may reduce the level of neuronal activity in the postsynaptic cell.

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Clayton, Terry, Michael M. Poe, Sundari Rallapalli, Poonam Biawat, Miroslav M. Savić, James K. Rowlett, George Gallos, et al. "A Review of the Updated Pharmacophore for the Alpha 5 GABA(A) Benzodiazepine Receptor Model." International Journal of Medicinal Chemistry 2015 (November 10, 2015): 1–54. http://dx.doi.org/10.1155/2015/430248.

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An updated model of the GABA(A) benzodiazepine receptor pharmacophore of the α5-BzR/GABA(A) subtype has been constructed prompted by the synthesis of subtype selective ligands in light of the recent developments in both ligand synthesis, behavioral studies, and molecular modeling studies of the binding site itself. A number of BzR/GABA(A) α5 subtype selective compounds were synthesized, notably α5-subtype selective inverse agonist PWZ-029 (1) which is active in enhancing cognition in both rodents and primates. In addition, a chiral positive allosteric modulator (PAM), SH-053-2′F-R-CH3 (2), has been shown to reverse the deleterious effects in the MAM-model of schizophrenia as well as alleviate constriction in airway smooth muscle. Presented here is an updated model of the pharmacophore for α5β2γ2 Bz/GABA(A) receptors, including a rendering of PWZ-029 docked within the α5-binding pocket showing specific interactions of the molecule with the receptor. Differences in the included volume as compared to α1β2γ2, α2β2γ2, and α3β2γ2 will be illustrated for clarity. These new models enhance the ability to understand structural characteristics of ligands which act as agonists, antagonists, or inverse agonists at the Bz BS of GABA(A) receptors.

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Lingford-Hughes, Anne, Susan P. Hume, Adrian Feeney, Ella Hirani, Safiye Osman, Vincent J. Cunningham, Victor W. Pike, David J. Brooks, and David J. Nutt. "Imaging the GABA-Benzodiazepine Receptor Subtype Containing the α5-Subunit In Vivo with [11C]Ro15 4513 Positron Emission Tomography." Journal of Cerebral Blood Flow & Metabolism 22, no. 7 (July 2002): 878–89. http://dx.doi.org/10.1097/00004647-200207000-00013.

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There is evidence of marked variation in the brain distribution of specific subtypes of the GABA-benzodiazepine receptor and that particular subtypes mediate different functions. The α5-containing subtype is highly expressed in the hippocampus, and selective α5 inverse agonists (which decrease tonic GABA inhibition) are being developed as potential memory-enhancing agents. Evidence for such receptor localization and specialization in humans in vivo is lacking because the widely used probes for imaging the GABA-benzodiazepine receptors, [11C]flumazenil and [123I]iomazenil, appear to reflect binding to the α1 subtype, based on its distribution and affinity of flumazenil for this subtype. The authors characterized for positron emission tomography (PET) a radioligand from Ro15 4513, the binding of which has a marked limbic distribution in the rat and human brain in vivo. Competition studies in vivo in the rat revealed that radiolabeled Ro15 4513 uptake was reduced to nonspecific levels only by drugs that have affinity for the α5 subtype (flunitrazepam, RY80, Ro15 4513, L655,708), but not by the α1 selective agonist, zolpidem. Quantification of [11C]Ro15 4513 PET was performed in humans using a metabolite-corrected plasma input function. [11C]Ro15 4513 uptake was relatively greater in limbic areas compared with [11C]flumazenil, but lower in the occipital cortex and cerebellum. The authors conclude that [11C]Ro15 4513 PET labels in vivo the GABA-benzodiazepine receptor containing the α5 subtype in limbic structures and can be used to further explore the functional role of this subtype in humans.

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Islam, Md Shahazul, Rajib Hossain, Taukir Ahmed, Md Mizanur Rahaman, Khattab Al-Khafaji, Rasel Ahmed Khan, Chandan Sarkar, et al. "Anxiolytic-like Effect of Quercetin Possibly through GABA Receptor Interaction Pathway: In Vivo and In Silico Studies." Molecules 27, no. 21 (October 22, 2022): 7149. http://dx.doi.org/10.3390/molecules27217149.

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Scientific evidence suggests that quercetin (QUR) has anxiolytic-like effects in experimental animals. However, the mechanism of action responsible for its anxiolytic-like effects is yet to be discovered. The goal of this research is to assess QUR’s anxiolytic effects in mouse models to explicate the possible mechanism of action. After acute intraperitoneal (i.p.) treatment with QUR at a dose of 50 mg/kg (i.p.), behavioral models of open-field, hole board, swing box, and light–dark tests were performed. QUR was combined with a GABAergic agonist (diazepam) and/or antagonist (flumazenil) group. Furthermore, in silico analysis was also conducted to observe the interaction of QUR and GABA (α5), GABA (β1), and GABA (β2) receptors. In the experimental animal model, QUR had an anxiolytic-like effect. QUR, when combined with diazepam (2 mg/kg, i.p.), drastically potentiated an anxiolytic effect of diazepam. QUR is a more highly competitive ligand for the benzodiazepine recognition site that can displace flumazenil (2.5 mg/kg, i.p.). In all the test models, QUR acted similar to diazepam, with enhanced effects of the standard anxiolytic drug, which were reversed by pre-treatment with flumazenil. QUR showed the best interaction with the GABA (α5) receptor compared to the GABA (β1) and GABA (β2) receptors. In conclusion, QUR may exert an anxiolytic-like effect on mice, probably through the GABA-receptor-interacting pathway.

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Nusser, Zoltan, and Istvan Mody. "Selective Modulation of Tonic and Phasic Inhibitions in Dentate Gyrus Granule Cells." Journal of Neurophysiology 87, no. 5 (May 1, 2002): 2624–28. http://dx.doi.org/10.1152/jn.2002.87.5.2624.

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In some nerve cells, activation of GABAA receptors by GABA results in phasic and tonic conductances. Transient activation of synaptic receptors generates phasic inhibition, whereas tonic inhibition originates from GABA acting on extrasynaptic receptors, like in cerebellar granule cells, where it is thought to result from the activation of extrasynaptic GABAA receptors with a specific subunit composition (α6βxδ). Here we show that in adult rat hippocampal slices, extracellular GABA levels are sufficiently high to generate a powerful tonic inhibition in δ subunit–expressing dentate gyrus granule cells. In these cells, the mean tonic current is approximately four times larger than that produced by spontaneous synaptic currents occurring at a frequency of ∼10 Hz. Antagonizing the GABA transporter GAT-1 with NO-711 (2.5 μM) selectively enhanced tonic inhibition by 330% without affecting the phasic component. In contrast, by prolonging the decay of inhibitory postsynaptic currents (IPSCs), the benzodiazepine agonist zolpidem (0.5 μM) augmented phasic inhibition by 66%, while leaving the mean tonic conductance unchanged. These results demonstrate that a tonic GABAA receptor–mediated conductance can be recorded from dentate gyrus granule cells of adult rats in in vitro slice preparations. Furthermore, we have identified distinct pharmacological tools to selectively modify tonic and phasic inhibitions, allowing future studies to investigate their specific roles in neuronal function.

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Sigel, Erwin. "Mapping of the Benzodiazepine Recognition Site on GABA-A Receptors." Current Topics in Medicinal Chemistry 2, no. 8 (August 1, 2002): 833–39. http://dx.doi.org/10.2174/1568026023393444.

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Onodera, Hiroshi, Gen Sato, and Kyuya Kogure. "GABA and Benzodiazepine Receptors in the Gerbil Brain after Transient Ischemia: Demonstration by Quantitative Receptor Autoradiography." Journal of Cerebral Blood Flow & Metabolism 7, no. 1 (February 1987): 82–88. http://dx.doi.org/10.1038/jcbfm.1987.12.

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Quantitative receptor autoradiography was used to measure the binding of γ-aminobutyric acid (GABA) and benzodiazepine receptors after ischemia by means of transient occlusion of bilateral common carotid arteries in the gerbil. [3H]Muscimol was used to label the GABAA receptors and [3H]funitrazepam to label central type benzodiazepine receptors. In the superolateral convexities of the frontal cortices, [3H]muscimol binding was increased in 60% of the animals killed 3 days after ischemia, and decreased in 67% of the animals killed 27 days after ischemia. Twenty-seven days after ischemia, [3H]funitrazepam binding in the substantia nigra pars reticulata increased to 252% of the control, though the increase in [3H]muscimol binding was not significant. In the dorsolateral region of the caudate putamen, marked neuronal necrosis and depletion of both [3H]muscimol and [3H]funitrazepam binding sites were observed 27 days after ischemia, the ventromedial region being left intact. In spite of the depletion of pyramidal cells in the CA1 region of the hippocampus, both [3H]muscimol and [3H]funitrazepam binding sites were preserved 27 days after ischemia. Since our previous study revealed that adenosine A1 binding sites were depleted in the CA1 subfield of the hippocampus after ischemia correlating with neuronal damage, GABAA and benzodiazepine receptors may not be distributed predominantly on the pyramidal cells in the CA1 region.

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24

Motohashi, Nobutaka, Kunihiko Shioe, and Tetsuhiko Kariya. "Effects of GABA Agonist, Sodium Valproate, on GABA and Benzodiazepine Receptors in Rat Brain." Psychiatry and Clinical Neurosciences 44, no. 1 (March 1990): 156–57. http://dx.doi.org/10.1111/j.1440-1819.1990.tb00465.x.

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Zhang, S. J., and M. B. Jackson. "Properties of the GABAA receptor of rat posterior pituitary nerve terminals." Journal of Neurophysiology 73, no. 3 (March 1, 1995): 1135–44. http://dx.doi.org/10.1152/jn.1995.73.3.1135.

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1. We investigated gamma-aminobutyric acid (GABA) receptors using thin slice patch-clamp techniques in the swellings along axons of posterior pituitary nerve terminals. 2. Activation of the nerve terminal GABAA receptor induced a mean conductance change of 1.5 nS. Normalizing to area gave a mean conductance density of 0.38 mS/cm2. 3. Whereas GABAA receptor-mediated responses could be seen in 91% of the nerve terminals tested, GABAB receptor-mediated responses could not be detected. The GABAB receptor agonist baclofen had no effect on holding current or on voltage-activated K+ and Ca2+ channels. It is unlikely that nerve terminals of the posterior pituitary contain GABAB receptors. 4. The channel gated by the nerve terminal GABAA receptor exhibited only a single open conductance level. Only fully open and fully closed states were observed. Subconductance states typical of other GABAA receptor channels were not seen in the GABA-gated channels of posterior pituitary nerve terminals. 5. Both open time and closed time distributions were biexponential, indicating at least two open and two closed conformations of the channel. At a higher GABA concentration, long-duration openings predominated, suggesting that long-duration openings were distinguished from short-duration openings by the occupation of a greater number of agonist binding sites. 6. Sustained application of GABA desensitized the receptor with simple exponential kinetics. The time constant for desensitization was approximately 9 s for both GABA and muscimol. 7. Zinc ions at concentrations of 100 microM reduced GABA responses by only 22%. This weak sensitivity to zinc, together with a previous observation of benzodiazepine sensitivity, suggested that the nerve terminal GABAA receptor possesses a gamma-subunit. 8. Responses mediated by the GABAA receptor persist in whole terminal recordings without Mg-ATP in the pipette solution. Thus, in contrast to many other GABAA receptors, this receptor showed no rundown in the absence of ATP. 9. The GABAA receptor channel of posterior pituitary nerve terminals has many properties in common with GABAA receptors of other preparations. A number of subtle differences between the nerve terminal receptor described here and cell body receptors described elsewhere may reflect the presence of receptor protein subunits unique to nerve terminals.

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26

SHIMAHARA, T., Y. PICHON, G. LEES, C. A. BEADLE, and D. J. BEADLE. "Gamma-Aminobutyric Acid Receptors on Cultured Cockroach Brain Neurones." Journal of Experimental Biology 131, no. 1 (September 1, 1987): 231–44. http://dx.doi.org/10.1242/jeb.131.1.231.

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Gamma-aminobutyric acid (GABA) at 10−1 moll−1 inhibited spontaneous activity and produced conductance changes in 60% of cultured cockroach neurones tested. The reversal potential for the GABA-evoked response was between −65 mV and −75 mV. Under whole-cell voltage-clamp conditions, with 114mmoll−1 potassium chloride in the electrode, the reversal potential had a similar value to that predicted for a chloride current. The response was blocked by 10−5 moll−1 picrotoxin but was not affected by 10−5 moll−1 bicuculline. In the whole-cell voltage-clamp conditions, 50 μmoll−1 GABA evoked an inward current that was accompanied by an increase in current noise. Fluctuation analysis of the noise gave a mean channel opening time of 11.8 ms for GABA and 6.5 ms for muscimol. The single-channel conductance was 18.6 pS for GABA and 15.2 pS for muscimol. When 50 μmoll−1 GABA was applied in the presence of the benzodiazepine, flunitrazepam, there was an increase in both the evoked current and the accompanying current noise. Analysis of this noise gave values of 14.3 ms for the mean channel opening time and 18.3 pS for the singlechannel conductance. The variance of the noise was increased by approximately 60% in the presence of flunitrazepam, suggesting that this drug potentiates the GABA responses of cockroach neurones by increasing the frequency of channel events. Note: Present address: Pesticide Research Department, Wellcome Research Laboratories, Berkhamsted, Herts, UK. Present address: Department of Biology, Oxford Polytechnic, Gipsy Lane, Headington, Oxford.

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Taguchi, Jun-Ichi, Kinya Kuriyama, and Hiroshi Kimura. "The purification of GABA/benzodiazepine receptors by benzodiazepine affinity column chromatography and formation of antibody against the purified receptors." Neuroscience Research Supplements 1 (January 1985): S106. http://dx.doi.org/10.1016/s0921-8696(85)80199-7.

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Taguchi, Jun-Ichi, Kinya Kuriyama, and Hiroshi Kimura. "The purification of GABA/benzodiazepine receptors by benzodiazepine affinity column chromatography and formation of antibody against the purified receptors." Neuroscience Research 3 (January 1985): S106. http://dx.doi.org/10.1016/0168-0102(85)90252-4.

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Kirkness, E. F., C. F. Bovenkerk, T. Ueda, and A. J. Turner. "Phosphorylation of γ-aminobutyrate (GABA)/benzodiazepine receptors by cyclic AMP-dependent protein kinase." Biochemical Journal 259, no. 2 (April 15, 1989): 613–16. http://dx.doi.org/10.1042/bj2590613.

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Preparations of gamma-aminobutyrate (GABA)/benzodiazepine receptor from pig cerebral cortex are composed of three major bands of polypeptides (51, 55 and 57 kDa) which are purified in a ratio of approx. 2:1:1 respectively. Treatment of purified receptor preparations with cyclic AMP-dependent protein kinase resulted in major incorporation of 32P into the 55 kDa band only. The maximum incorporation achieved was 0.6 mol of 32P/mol of 55 kDa polypeptide. The phosphorylated receptor subunit (beta-subunit) displays the same apparent Mr as a band labelled irreversibly with the GABA receptor agonist [3H]muscimol. The two nonphosphorylated subunit polypeptides (51 and 57 kDa) are each labelled irreversibly with [3H]flunitrazepam and are recognized by anti-peptide antibodies specific for alpha-subunits.

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BENSON, JACK A. "A Novel Gaba Receptor in the Heart of a Primitive Arthropod, Limulus Polyphemus." Journal of Experimental Biology 147, no. 1 (November 1, 1989): 421–38. http://dx.doi.org/10.1242/jeb.147.1.421.

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1. The isolated, intact heart of the marine arachnid Limulus polyphemus continues to beat in vitro for many hours. Application of γaminobutyric acid (GABA) decreased the heart beat frequency with a threshold of 3xlO−7 moll−1 and an EC50 of 2.0±0.6xlO−5 moll−1 (mean±s.D., N = 8). At lO−4moll−1 and above the heart beat was completely and reversibly inhibited. 2. The agonist potency profile of the Limulus heart chronotropic GABA receptor was very similar to that of the vertebrate GABAA receptor: muscimol > ZAPA>GABA=⋍TACA>isoguvacine>THIP>3-aminopropane sulphonic acid> imidazole-4-acetic acid ⋍ß-guanidino proprionic acid ⋍5-aminovalerate. In contrast, the antagonist profile differed dramatically: bicuculline, pitrazepin and SR 95103, as well as the channel blocker picrotoxin, were without effect at concentrations up to 10−4moll−1. 3. The benzodiazepines clorazepate, flunitrazepam, flurazepam and diazepam, as well as the barbiturate sodium pentobarbital, were without effect on the GABA response, suggesting that the Limulus heart GABA receptor is not complexed with the benzodiazepine and barbiturate modulatory subunits that characterize vertebrate GABAA receptor. 4. The GABAB ligands baclofen, phaclophen and kojic amine were inactive on the heart. However, 3-aminopropyl-phosphonous acid (CGA147 823), a potent and highly selective GABAb agonist, was the most active of the compounds tested. It inhibited the heart beat with a threshold of about SnmolP1, an EC50 of 4.0±2.7×10−7 mol1−1, and produced total inhibition of the heart at 10−5moll−1. CGA 147 823 was inactive on the locust thoracic somal GABA receptors. 5. cis-4-aminocrotonic acid (CACA), the ligand defining a proposed GAB Actype receptor, was inactive on the heart. 6. The GABA-induced inhibition of the heart beat was enhanced by pretreatment with the GABA uptake inhibitor nipecotic acid but not with sodium valproate or ß-alanine. 7. The Limulus heart chronotropic GABA receptor appears to be of a hitherto undescribed type that differs in pharmacology from the vertebrate GABAA and GABAB receptors as well as from the well-defined GABA receptors on the somata of locust neurones and the muscle fibres of insects and the nematode Ascaris.

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Hablitz, John J., Mohammad H. Jalilian Tehrani, and Eugene M. Barnes. "Chronic exposure of developing cortical neurons to GABA down-regulates GABA/benzodiazepine receptors and GABA-gated chloride currents." Brain Research 501, no. 2 (November 1989): 332–38. http://dx.doi.org/10.1016/0006-8993(89)90650-1.

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Velazquez, JL, CL Thompson, EM Barnes, and KJ Angelides. "Distribution and lateral mobility of GABA/benzodiazepine receptors on nerve cells." Journal of Neuroscience 9, no. 6 (June 1, 1989): 2163–69. http://dx.doi.org/10.1523/jneurosci.09-06-02163.1989.

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Nakagawa, Yutaka, Tsuneo Iwasaki, Tsuyoshi Ishima, and Kiyoshi Kimura. "Interaction between benzodiazepine and GABA-A receptors in state-dependent learning." Life Sciences 52, no. 24 (January 1993): 1935–45. http://dx.doi.org/10.1016/0024-3205(93)90634-f.

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34

Batra, Sonali, Ashwani Kumar, and Anupam Sharma. "GABA and 5-HT Receptor Mediated Anxiolytic Effect of Essential Oil of Ferula sumbul Hook. Roots." Natural Products Journal 10, no. 3 (June 16, 2020): 262–71. http://dx.doi.org/10.2174/2210315509666190211123646.

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Background: Ferula sumbul Hook. (Umbelliferae) roots have been traditionally used as sedative in nervous disorders. Objective: The present study identifies the components of essential oil of F. sumbul roots (EOFS) using GC-MS analysis and further evaluates mechanism-based anxiolytic potential of oil. Materials and Methods: EOFS was extracted using Clevenger apparatus, and was screened for anxiolytic activity using an elevated plus maze model. A battery of models was subsequently used to confirm the anxiolytic potential of EOFS. Further, benzodiazepine (BZD) receptor antagonist flumazenil and pentylenetetrazole (PTZ) were used for investigating the possible involvement of GABA receptors. Results: GC-MS analysis of EOFS revealed the presence of 32 components comprising triterpenoids and their derivatives. The oil exhibited significant anxiolytic activity at 50 μl/kg in various models like the elevated plus maze, light/dark, mirror chamber, open-field and mCPP-induced anxiety. The observation that anxiolytic effect of EOFS was completely blocked by benzodiazepine (BZD) receptor antagonist flumazenil, and partially by pentylenetetrazole, clearly demonstrates that anxiolytic activity of the oil is mediated mainly through BZD site on GABA receptors. Further, a significant reversal of mCPP induced anxiety by EOFS strongly indicates the possible involvement of 5-HT receptors in mediating anxiolytic activity of the oil. Conclusion: Results of the present study clearly demonstrates the anxiolytic potential of EOFS and, thus, validates the traditional relevance of the plant. This is the first report not only on multi-model based antianxiety activity of EOFS but also on the possible antianxiety mechanism of the oil.

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Groundwater, Paul William, Kaiser Hamid, Irene Ng, Vikram J. Tallapragada, David E. Hibbs, and Jane Hanrahan. "The Differential Effects of Resveratrol and trans-ε-Viniferin on the GABA-Induced Current in GABAA Receptor Subtypes Expressed in Xenopus Laevis Oocytes." Journal of Pharmacy & Pharmaceutical Sciences 18, no. 4 (August 27, 2015): 328. http://dx.doi.org/10.18433/j3qw3k.

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Purpose: The natural products resveratrol and trans-ε-viniferin have been reported to have many beneficial effects, which include the enhancement of cognition and memory. There have been no studies which have reported the effects of these compounds on the different GABAA receptor subtypes and this study aimed to address this. Methods: The effects of both resveratrol, and its dimer, trans-ε-viniferin, have been investigated on different GABAA receptor subtypes expressed in Xenopus laevis oocytes, using the two-electrode voltage clamp technique. Results: Resveratrol induced a current of 22 ± 3.53 nA in the α1β2γ2L subtype of the GABAA receptor (but not in the α5β3γ2L and α2β2γ2L subtypes) when applied alone. It also positively modulated the GABA-induced current (IGABA) in α1β2γ2L receptors, in adose-dependent manner (EC50 58.24 μM). The effects of resveratrol were not sensitive to the benzodiazepine antagonist flumazenil. trans-ε-Viniferin exhibited a different pattern of activity to resveratrol; it alone had no effect on any of the subtypes, but it did negatively modulate the GABA-induced current (IGABA) in all three subtypes. The greatest inhibition was found in the α1β2γ2L subtype (IC50 5.79 μM), with the inhibition in the α2β2γ2L (IC50 of 19.08 μM) and α5β3γ2L (IC50 of 21.05 μM) subtypes being similar. The effects of trans-ε-viniferin in α1β2γ2L and α2β2γ2L receptors werealso not sensitive to the benzodiazepine antagonist flumazenil while, in the α5β3γ2L subtype the effect was not sensitive to the inverse agonist L-655,708, indicating different binding sites for this molecule. Conclusions: The results of the present study indicate that both resveratrol and trans-ε-viniferin modulate the GABA-induced current in different ways, and that trans-ε-viniferin may be a lead compound for the discovery of agents which selectively inhibit the GABA-induced current in α1-containing subtypes.This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

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Mellor, J. R., and A. D. Randall. "Synaptically Released Neurotransmitter Fails to Desensitize Postsynaptic GABAA Receptors in Cerebellar Cultures." Journal of Neurophysiology 85, no. 5 (May 1, 2001): 1847–57. http://dx.doi.org/10.1152/jn.2001.85.5.1847.

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GABA concentration jump experiments performed on membrane patches predict that postsynaptic GABAAreceptors will become desensitized following the release of the contents of a single GABA-containing synaptic vesicle. To examine this we used a single synaptic bouton stimulation technique to directly examine whether postsynaptic GABAA receptors in cultured cerebellar granule cells exhibit transmitter-induced desensitization. In a large number of recordings, no evidence was found for desensitization of postsynaptic GABAAreceptors by vesicularly released transmitter. This was the case even when as many as 40 vesicles were released from a single bouton within 1.5 s. In addition, postsynaptic depolarization and application of the benzodiazepine flunitrazepam, manipulations previously shown to enhance desensitization of GABAA receptors, failed to unmask transmitter-induced desensitization. In contrast, a single 2- to 3-s application of a high concentration of exogenous GABA was able to depress synaptic responsiveness for up to 70 s. Furthermore, pharmacological depletion of GABA eliminated inhibitory synaptic communication, suggesting that GABA is the transmitter and the desensitization-resistant inhibitory postsynaptic currents are not mediated by a “nondesensitizing” ligand such as β-alanine. Overall our data indicate that a specific desensitization-resistant population of GABAA receptors are present at postsynaptic sites on cultured cerebellar granule cells.

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Kang, Youngnam, Mitsuru Saito, and Hiroki Toyoda. "Molecular and Regulatory Mechanisms of Desensitization and Resensitization of GABAA Receptors with a Special Reference to Propofol/Barbiturate." International Journal of Molecular Sciences 21, no. 2 (January 15, 2020): 563. http://dx.doi.org/10.3390/ijms21020563.

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It is known that desensitization of GABAA receptor (GABAAR)-mediated currents is paradoxically correlated with the slowdown of their deactivation, i.e., resensitization. It has been shown that an upregulation of calcineurin enhances the desensitization of GABAAR-mediated currents but paradoxically prolongs the decay phase of inhibitory postsynaptic currents/potentials without appreciable diminution of their amplitudes. The paradoxical correlation between desensitization and resensitization of GABAAR-mediated currents can be more clearly seen in response to a prolonged application of GABA to allow more desensitization, instead of brief pulse used in previous studies. Indeed, hump-like GABAAR currents were produced after a strong desensitization at the offset of a prolonged puff application of GABA in pyramidal cells of the barrel cortex, in which calcineurin activity was enhanced by deleting phospholipase C-related catalytically inactive proteins to enhance the desensitization/resensitization of GABAAR-mediated currents. Hump-like GABAAR currents were also evoked at the offset of propofol or barbiturate applications in hippocampal or sensory neurons, but not GABA applications. Propofol and barbiturate are useful to treat benzodiazepine/alcohol withdrawal syndrome, suggesting that regulatory mechanisms of desensitization/resensitization of GABAAR-mediated currents are important in understanding benzodiazepine/alcohol withdrawal syndrome. In this review, we will discuss the molecular and regulatory mechanisms underlying the desensitization and resensitization of GABAAR-mediated currents and their functional significances.

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38

Rovira, C., and Y. Ben-Ari. "Developmental study of benzodiazepine effects on monosynaptic GABAA-mediated IPSPs of rat hippocampal neurons." Journal of Neurophysiology 70, no. 3 (September 1, 1993): 1076–85. http://dx.doi.org/10.1152/jn.1993.70.3.1076.

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1. The effects of type I (BZ1) and type II (BZ2) benzodiazepine receptor ligands on monosynaptic gamma-aminobutyric acid (GABA)A-mediated inhibitory postsynaptic potentials (IPSPs) and on responses to exogenously applied GABA were studied using intracellular recordings from CA3 pyramidal cells of rat hippocampal slices taken at different postnatal stages [postnatal day 4 (P4)-P35)]. 2. The effects of midazolam, a BZ1 and BZ2 receptor agonist, were tested on the monosynaptic IPSPs at different stages. Monosynaptic, bicuculline-sensitive IPSPs were evoked by hilar stimulation in presence of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) and N-methyl-D-aspartate (NMDA) antagonists [6-cyano-7-nitroquinoxaline-2,3-dione (10 microM) and D(-)2-amino-5-phosphonopentanoic acid (50 microM)]. Midazolam at 300 nM maximally increased the duration and amplitude of monosynaptic GABAA-mediated IPSPs in neurons from pups (P4-P6, n = 6) and young (P7-P12, n = 8) and adult (P25-P35, n = 9) rats. All the effects of midazolam on IPSPs were reversed by the antagonist Ro 15-1788 (10 microM). 3. The effect of midazolam was also tested on the response to exogenously applied GABA (5 mM) in the presence of tetrodotoxine [TTX (1 microM)]. In neurons from young rats (n = 9), midazolam (1 nM-1 microM) did not change the responses to exogenously applied GABA, whereas in adult rats (n = 8) midazolam maximally increased GABA currents at 30 nM. 4. The effect of zolpidem, a BZ1 receptor agonist, was tested on monosynaptic IPSPs and GABA currents at different stages. Zolpidem (10 nM-1 microM) was inactive in cells from young rats (n = 12). In neurons from adult rats, zolpidem maximally increased the duration and amplitude of the monosynaptic IPSPs at 300 nM (n = 5) and the amplitude of GABA current at 30-100 nM (n = 5). 5. Methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM) (300 nM), an inverse agonist of BZ1 and BZ2 receptors, decreased the amplitude and duration of monosynaptic IPSPs in neurons from pups (n = 3) and young (n = 4) and adult (n = 5) rats. In all cases, full recovery was obtained after exposure to R0 15-1788 (10 microM). DMCM (300 nM-10 microM) failed to reduce GABA responses in cells from young (n = 3) or adult (n = 7) rats. 6. Results indicate that the regulation by benzodiazepine of GABAA-mediated IPSPs varies with the developmental stage.(ABSTRACT TRUNCATED AT 400 WORDS)

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Marino Jr., Raul, Reina Benabou, and Salomon Benabou. "Therapeutic effects of flunitrazepan in dystonias and torticollis preliminary communication." Arquivos de Neuro-Psiquiatria 51, no. 2 (June 1993): 285–86. http://dx.doi.org/10.1590/s0004-282x1993000200025.

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A new form of clinical treatment is proposed for dystonias and torticollis using flunitrazepan (FN), a powerful agonist of all benzodiazepine receptors of GABA neurons. FN has a specific effect in dystonic patients, specially those in which the hypnotic effect of this drug is absent or diminished, thus suggesting the existence of two different neurochemical categories of dystonias.

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40

Saano, V., L. Rägo, E. Tupala, and M. M. Airaksinen. "Changes in GABA-benzodiazepine receptor complex and in peripheral benzodiazepine receptors in male mice after copulation." Pharmacology Biochemistry and Behavior 51, no. 2-3 (June 1995): 529–33. http://dx.doi.org/10.1016/0091-3057(95)00071-4.

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41

Doble, A., T. Canton, C. Malgouris, JM Stutzmann, O. Piot, MC Bardone, C. Pauchet, and JC Blanchard. "The mechanism of action of zopiclone." European Psychiatry 10, S3 (1995): 117s—128s. http://dx.doi.org/10.1016/0924-9338(96)80093-9.

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SummaryThe mechanism of action of the cyclopyrrolone hypnotic drug zopiclone involves allosteric modulation of the GABAA receptor. Zopiclone displaces the binding of [3H]-flunitrazepam with an affinity of 28 nM, and enhances the binding of the channel blocker [35S]-TBPS. The binding of zopiclone, unlike that of hypnotic benzodiazepines, is not facilitated by GABA. Zopiclone does not distinguish between GABAA receptors containing different α-subunits (BZ1 and BZ2 phenotype). Studies with protein-modifying agents (eg diethylpyrocarbonate) and photoaffinity labelling suggest that cyclopyrrolones bind to a domain on the GABAA receptor different from the benzodiazepine binding domain. The consequence of this interaction with the GABAA receptor is to potentiate responses to GABA, as can be demonstrated by electrophysiological methods. Subchronic treatment of mice with high doses of zopiclone does not produce the changes in sensitivity of the GABAA receptor that are observed with hypnotic benzodiazepines.

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Kilpatrick, Gavin J., Margaret S. McIntyre, Richard F. Cox, Jeffrey A. Stafford, Gregory J. Pacofsky, Gwyer G. Lovell, Robert P. Wiard, et al. "CNS 7056." Anesthesiology 107, no. 1 (July 1, 2007): 60–66. http://dx.doi.org/10.1097/01.anes.0000267503.85085.c0.

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Abstract Background: A new benzodiazepine derivative, CNS 7056, has been developed to permit a superior sedative profile to current agents, i.e., more predictable fast onset, short duration of sedative action, and rapid recovery profile. This goal has been achieved by rendering the compound susceptible to metabolism via esterases. The authors now report on the profile of CNS 7056 in vitro and in vivo. Methods: The affinity of CNS 7056 and its carboxylic acid metabolite, CNS 7054, for benzodiazepine receptors and their selectivity profiles were evaluated using radioligand binding. The activity of CNS 7056 and midazolam at subtypes (α1β2γ2, α2β2γ2, α3β2γ2, α5β2γ2) of the γ-aminobutyric acid type A (GABAA) receptor was evaluated using the whole cell patch clamp technique. The activity of CNS 7056 at brain benzodiazepine receptors in vivo was measured in rats using extracellular electrophysiology in the substantia nigra pars reticulata. The sedative profile was measured in rodents using the loss of righting reflex test. Results: CNS 7056 bound to brain benzodiazepine sites with high affinity. The carboxylic acid metabolite, CNS 7054, showed around 300 times lower affinity. CNS 7056 and CNS 7054 (10 μm) showed no affinity for a range of other receptors. CNS 7056 enhanced GABA currents in cells stably transfected with subtypes of the GABAA receptor. CNS 7056, like midazolam and other classic benzodiazepines, did not show clear selectivity between subtypes of the GABAA receptor. CNS 7056 (intravenous) caused a dose-dependent inhibition of substantia nigra pars reticulata neuronal firing and recovery to baseline firing rates was reached rapidly. CNS 7056 (intravenous) induced loss of the righting reflex in rodents. The duration of loss of righting reflex was short (< 10 min) and was inhibited by pretreatment with flumazenil. Conclusions: CNS 7065 is a high-affinity and selective ligand for the benzodiazepine site on the GABAA receptor. CNS 7056 does not show selectivity between GABAA receptor subtypes. CNS 7056 is a potent sedative in rodents with a short duration of action. Inhibition of substantia nigra pars reticulata firing and the inhibition of the effects of CNS 7056 by flumazenil show that it acts at the brain benzodiazepine receptor.

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Pangratz-Fuehrer, Susanne, Uwe Rudolph, and John R. Huguenard. "Giant Spontaneous Depolarizing Potentials in the Developing Thalamic Reticular Nucleus." Journal of Neurophysiology 97, no. 3 (March 2007): 2364–72. http://dx.doi.org/10.1152/jn.00646.2006.

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The thalamic reticular nucleus (nRt) provides a major source of inhibition in the thalamo-cortical circuit and is critically involved in the generation of spindle oscillations. Here we describe the properties of thalamic giant depolarizing potentials (tGDPs) that were observed in nRt during early development. tGDPs persisted in presence of ionotropic glutamate antagonists but were completely abolished by GABAAR antagonist SR 35591. tGDPs occurred primarily between p3 and p8 (in 30–50% of cells) and occasionally up until p15. tGDPs lasted 0.4–3 s with peak conductances of 2–13 nS and occurred at frequencies between 0.02 and 0.06 Hz. We used mice with a benzodiazepine-insensitive α3 subunit [α3(H126R)] to probe for the identity of the GABA receptors responsible for tGDP generation. Benzodiazepine enhancement of tGDP amplitude and duration persisted in nRt neurons in α3(H126R) mice, indicating that the GABAARs containing α3 are not critical for tGDP generation and suggesting that tGDPs are mediated by GABAARs containing the α5 subunit, which is transiently expressed in nRt neurons in early postnatal development. Furthermore we found that exogenous GABA application depolarized nRt neurons younger than p8, indicating elevated [Cl−]i at this developmental stage. Taken together, these data suggest that in immature nRt, long-lasting depolarizing responses mediated by GABA receptors could trigger Ca2+ entry and play a role in functional development of the spindle-generating circuitry.

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TSUKAMOTO, Shuji. "Structure-binding relationships of gamma-aminobutyric acid (GABA) and its relatives with GABA and benzodiazepine receptors." Okayama Igakkai Zasshi (Journal of Okayama Medical Association) 98, no. 3-4 (1986): 313–21. http://dx.doi.org/10.4044/joma1947.98.3-4_313.

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Khan, Imran, Nasiara Karim, Waqar Ahmad, Abeer Abdelhalim, and Mary Chebib. "GABA-A Receptor Modulation and Anticonvulsant, Anxiolytic, and Antidepressant Activities of Constituents fromArtemisia indicaLinn." Evidence-Based Complementary and Alternative Medicine 2016 (2016): 1–12. http://dx.doi.org/10.1155/2016/1215393.

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Artemisia indica, also known as “Mugwort,” has been widely used in traditional medicines. However, few studies have investigated the effects of nonvolatile components ofArtemisia indicaon central nervous system’s function. Fractionation ofArtemisia indicaled to the isolation of carnosol, ursolic acid, and oleanolic acid which were evaluated for their effects on GABA-A receptors in electrophysiological studies inXenopusoocytes and were subsequently investigated in mouse models of acute toxicity, convulsions (pentylenetetrazole induced seizures), depression (tail suspension and forced swim tests), and anxiety (elevated plus maze and light/dark box paradigms). Carnosol, ursolic acid, and oleanolic acid were found to be positive modulators ofα1β2γ2L GABA-A receptors and the modulation was antagonized by flumazenil. Carnosol, ursolic acid, and oleanolic acid were found to be devoid of any signs of acute toxicity (50–200 mg/kg) but elicited anticonvulsant, antidepressant, and anxiolytic activities. Thus carnosol, ursolic acid, and oleanolic acid demonstrated CNS activity in mouse models of anticonvulsant, antidepressant, and anxiolysis. The anxiolytic activity of all three compounds was ameliorated by flumazenil suggesting a mode of action via the benzodiazepine binding site of GABA-A receptors.

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Moor, Eytan, Peter DeBoer, and Ben H. C. Westerink. "GABA receptors and benzodiazepine binding sites modulate hippocampal acetylcholine release in vivo." European Journal of Pharmacology 359, no. 2-3 (October 1998): 119–26. http://dx.doi.org/10.1016/s0014-2999(98)00642-6.

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Oka, Jun-Ichiro, and T. Philip Hicks. "A functional role of GABA/benzodiazepine receptors in cat primary somatosensory cortex." Neuroscience Research Supplements 5 (January 1987): S7. http://dx.doi.org/10.1016/0921-8696(87)90035-1.

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Kochman, Ronald L., and Cyndi K. Sepulveda. "Aging does not alter the sensitivity of benzodiazepine receptors to GABA modulation." Neurobiology of Aging 7, no. 5 (September 1986): 363–65. http://dx.doi.org/10.1016/0197-4580(86)90163-6.

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Oka, J. I., and T. P. Hicks. "Benzodiazepines and synaptic processing in the spatial domain within the cat's primary somatosensory cortex." Canadian Journal of Physiology and Pharmacology 68, no. 8 (August 1, 1990): 1025–40. http://dx.doi.org/10.1139/y90-156.

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In the primary somatosensory cortex of cats, the size of the receptive fields (RFs) of cutaneously responsive neurones is under the control of γ-aminobutyric acid (GABA) mediated inhibition when the cells are situated in rapidly adapting (RA) background regions. Cells located in slowly adapting (SA) or low-velocity rapidly adapting (LVRA) background regions do not appear to be affected by GABA significantly in the spatial domain, although other response properties such as threshold and firing pattern are under the influence of bicuculline methiodide (BMI) sensitive processes. The GABA receptor is one component of the oligomeric complex that includes the benzodiazepine (Bzd) binding site, the barbiturate recognition site, and the Cl− ionophore. Owing to current debates about the possible existence of endogenous ligands of Bzd receptors, we have examined whether Bzd agonists, in addition to GABA and BMI, have RF-modulating actions on RA S1 neurones and have assessed the effectiveness of the Bzd antagonist, Ro 15-1788, in this experimental paradigm. Ro 15-1788 is an imidazobenzodiazepine that acts as a specific competitive antagonist of Bzds by exerting high-affinity interactions with that Bzd receptor through which anticonvulsant effects of flurazepam (flu) and diazepam are expressed. This has been shown previously in neurochemical, behavioral, neurological, and pharmacological studies. Ro 15-1788 has little or no affinity for nonneuronal binding sites in the CNS. Ro 15-1788 binding does not displace GABA from its own binding site but does compete for all major Bzd ligands that act as pharmacological agonists and inverse agonists of the Bzd receptor through which anticonvulsant and convulsant effects are expressed. Bzd agonists elevated the threshold for somatic activation, depressed spontaneous activity, and decreased RF size. One exception in this regard was midazolam, which sometimes decreased somatic thresholds and increased spontaneous discharges. These latter effects were reversed at higher doses of the agonist. BMI returned RFs to control sizes when the drug was administered concurrently with Bzd agonists, or it caused RFs to assume greater than normal sizes, depending on the strength of current ejecting the antagonist. Ro 15-1788 given alone decreased response thresholds, increased spontaneous firing, and sometimes enlarged RFs. This antagonist also reversed the RF size-decreasing action of flu, diazepam, and midazolam. Quantitative analyses of air-puffer responses evoked from low-threshold, S1 cells revealed that Bzds do not selectively attenuate spatial summation, but that they act preferentially in the surround, or in the peripheral, regions of cutaneous excitatory RFs. Bzd receptors act in the spatial domain on neurones in SA and LVRA, as well as in RA background regions. However, it appears that these receptors function in SA and LVRA areas with less effectiveness than in RA regions. The data may be interpreted as demonstrating an involvement of Bzd receptors in cortical sensory processing through a modulation of the RF-shaping action of intracortical inhibitory processes mediated by GABA.Key words: benzodiazepine receptors, somatosensory cortex, receptive field, γ-aminobutyric acid, bicuculline, flurazepam.

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Bouairi, Euguenia, Harriet Kamendi, Xin Wang, Christopher Gorini, and David Mendelowitz. "Multiple Types of GABAA Receptors Mediate Inhibition in Brain Stem Parasympathetic Cardiac Neurons In the Nucleus Ambiguus." Journal of Neurophysiology 96, no. 6 (December 2006): 3266–72. http://dx.doi.org/10.1152/jn.00590.2006.

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Recent work suggests neurons can have different types of γ-aminobutyric acid type A (GABAA) receptors that mediate phasic inhibitory postsynaptic currents (IPSCs) and tonic currents. This study examines the diversity of GABAergic synaptic currents in parasympathetic cardioinhibitory neurons that receive rhythmic bursts of GABAergic neurotransmission. Focal application of gabazine (25 μM) to cardiac vagal neurons in vitro did not change the frequency of firing in spontaneously active neurons or the resting membrane potential; however, picrotoxin (100 μM) significantly depolarized cardiac vagal neurons and increased their firing. Similarly, gabazine (25 μM) selectively blocked GABAergic IPSCs but did not change holding current in cardiac vagal neurons, whereas picrotoxin (100 μM) not only blocked GABAergic IPSCs but also rapidly decreased the tonic current. Because the tonic current could be attributable to activation of GABA receptors by ambient GABA or, alternatively, spontaneous opening of constitutively active GABA channels, an antagonist for the GAT-1 GABA transporter NO-711 (10 μM) was applied to distinguish between these possibilities. NO-711 did not significantly alter the holding current in these neurons. The benzodiazepine flunitrazepam (1 μM) significantly increased the tonic current and GABAergic IPSC decay time; surprisingly, however, in the presence of gabazine flunitrazepam failed to elicit any change. These results suggest cardiac vagal neurons possess gabazine-sensitive GABAA receptors that mediate phasic synaptic currents, a gabazine-insensitive but picrotoxin-sensitive extrasynaptic tonic current that when blocked depolarizes and increases the firing rate of cardiac vagal neurons, and benzodiazepines recruit a third type of GABAA receptor that is sensitive to gabazine and augments the extrasynaptic tonic current.

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Journal articles on the topic 'Receptors, GABA-Benzodiazepine'

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