GABA Antagonist

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Graham A.r. Johnston - One of the best experts on this subject based on the ideXlab platform.

  • Advantages of an Antagonist: bicuculline and other GABA Antagonists
    British journal of pharmacology, 2013
    Co-Authors: Graham A.r. Johnston
    Abstract:

    The convulsant alkaloid bicuculline continues to be investigated more than 40 years after the first publication of its action as an Antagonist of receptors for the inhibitory neurotransmitter GABA. This historical perspective highlights key aspects of the discovery of bicuculline as a GABA Antagonist and the sustained interest in this and other GABA Antagonists. The exciting advances in the molecular biology, pharmacology and physiology of GABA receptors provide a continuing stimulus for the discovery of new Antagonists with increasing selectivity for the myriad of GABA receptor subclasses. Interesting GABA Antagonists not structurally related to bicuculline include GABAzine, salicylidene salicylhydrazide, RU5135 and 4-(3-biphenyl-5-(4-piperidyl)-3-isoxazole. Bicuculline became the benchmark Antagonist for what became known as GABAA receptors, but not all ionotropic GABA receptors are susceptible to bicuculline. In addition, not all GABAA receptor Antagonists are convulsants. Thus there are still surprises in store as the study of GABA receptors evolves.

John E Casida - One of the best experts on this subject based on the ideXlab platform.

  • GABA receptor Antagonists and insecticides common structural features of 4 alkyl 1 phenylpyrazoles and 4 alkyl 1 phenyltrioxabicyclooctanes
    Bioorganic & Medicinal Chemistry, 2004
    Co-Authors: Robert E Sammelson, Pierluigi Caboni, Kathleen A Durkin, John E Casida
    Abstract:

    Fipronil [5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethylsulfinylpyrazole] is one of the most important insecticides. Structure-activity studies described here reveal that fipronil retains its very high binding potency at the human beta3 and house fly gamma-aminobutyric acid (GABA) receptors and toxicity to house flies on replacing the pyrazole trifluoromethylsulfinyl moiety with tert-butyl or isopropyl and the phenyl trifluoromethyl substituent with ethynyl, trifluoromethoxy, bromo or chloro. Among the compounds studied, those with other alkyl groups at the 4-position of the pyrazole, as well as phenyl substitution without one or both of the 2,6-dichloro groups, are less effective. 5-Amino-4-tert-butyl-3-cyano-1-(2,6-dichloro-4-ethynylphenyl)pyrazole is highly effective and almost isosteric with 4-tert-butyl-3-cyano-1-(4-ethynylphenyl)-2,6,7-trioxabicyclo[2.2.2]octane (the most potent 4-alkyl-1-phenyltrioxabicyclooctane) as a noncompetitive GABA Antagonist and insecticide. These findings are interpreted as three binding subsites in the GABA receptor: a hydrophobic site undergoing steric interaction with the tert-butyl or equivalent group; a hydrogen bonding site to pyrazole N-2; a pi bonding site to the face of the phenyl moiety; with supplemental enhancement by the 3-cyano and 4-ethynyl substituents.

Michael M. Morgan - One of the best experts on this subject based on the ideXlab platform.

  • defensive behaviors evoked from the ventrolateral periaqueductal gray of the rat comparison of opioid and GABA disinhibition
    Behavioural Brain Research, 2005
    Co-Authors: Michael M. Morgan, Cecilea C Clayton
    Abstract:

    Microinjection of morphine into the ventrolateral periaqueductal gray (PAG) disinhibits output neurons resulting in immobility and antinociception. Disinhibition also can be produced by microinjection of the GABA Antagonist bicuculline. If morphine and bicuculline disinhibit the same class of neurons, then the behavioral effects evoked should be the same. Microinjection of morphine (5 microg/0.4 microl) into the ventrolateral PAG produced antinociception in 46 of 85 rats (54%). Subsets of rats with and without morphine antinociception were subsequently injected with bicuculline (2.5, 5, 10, and 25 ng/0.4 microl) into the same PAG site. Microinjection of bicuculline produced an increase in hot plate latency that was independent of the effect of the prior morphine microinjection. Bicuculline administration also produced an increase in locomotor activity in most rats, not immobility as with morphine microinjections. These differences between morphine and bicuculline microinjections indicate three things: (a) disinhibition of PAG neurons whether by morphine or bicuculline is an effective means of producing antinociception; (b) the circuitry underlying the behavioral effects of morphine and bicuculline differ; (c) the ventrolateral PAG appears capable of supporting a range of defensive behaviors from immobility to flight.

  • behavioral evidence linking opioid sensitive GABAergic neurons in the ventrolateral periaqueductal gray to morphine tolerance
    Neuroscience, 2003
    Co-Authors: Michael M. Morgan, C C Clayton, D A Lane
    Abstract:

    Tolerance develops to the antinociceptive effects of morphine with repeated microinjections into the ventrolateral periaqueductal gray (PAG). This tolerance could be caused by adaptations within the PAG or anywhere along the descending pathway (rostral ventromedial medulla to spinal cord). If tolerance is caused by a change along the descending pathway, then tolerance should develop to direct activation of PAG output neurons. However, if tolerance is caused by a change to neurons within the PAG, then tolerance will not occur with repeated direct activation of PAG output neurons. This hypothesis was tested by assessing antinociception following repeated microinjections of the GABA Antagonist bicuculline and the excitatory amino acid kainate into the ventrolateral PAG. Microinjection of bicuculline and kainate produces antinociception by disinhibition and direct excitation of ventrolateral PAG output neurons, respectively. Repeated administration of these drugs into the ventrolateral PAG produced antinociception with no evidence of tolerance. That is, the hot-plate latency and responsiveness to intraplantar formalin administration was comparable whether rats received the drug for the first or fifth time. Moreover, microinjection of bicuculline or kainate produced comparable antinociception in rats pretreated with these drugs and saline-treated control rats. These data demonstrate that repeated activation of ventrolateral PAG output neurons is not sufficient to produce tolerance. Thus, tolerance must be caused by a change in neurons preceding output neurons in this circuit, presumably opioid-sensitive GABAergic neurons.

Jerome M Siegel - One of the best experts on this subject based on the ideXlab platform.

  • GABA release in the dorsal raphe nucleus role in the control of rem sleep
    American Journal of Physiology-regulatory Integrative and Comparative Physiology, 1997
    Co-Authors: Douglas A Nitz, Jerome M Siegel
    Abstract:

    The cessation of firing of serotonergic dorsal raphe neurons is a key controlling event of rapid eye movement (REM) sleep. We tested the hypothesis that this cessation of activity is due to gamma-aminobutyric acid (GABA) release using the in vivo microdialysis technique. We found that REM sleep is accompanied by a selective increase in GABA release, but not by a change in glutamate or glycine release in the dorsal raphe nucleus. Microinjection of the GABA agonist muscimol into the dorsal raphe increased REM sleep, although microperfusion of the GABA Antagonist picrotoxin blocked REM sleep. These results implicate GABA release as a critical element in the production of the REM sleep state and in the control of discharge in serotonergic neurons across the sleep/wake cycle.

Roger P Simon - One of the best experts on this subject based on the ideXlab platform.

  • deep prepiriform cortex modulates kainate induced hippocampal injury
    Neuroscience, 1994
    Co-Authors: S Shimosaka, Roger P Simon
    Abstract:

    As seizure propagation within limbic structures is mediated in part by a small area of deep prepiriform cortex (area tempestas), we investigated the role of area tempestas in modulating hippocampal injury induced by systemic kainate administration. Injury was quantitated by counting the numbers of neurons that stained for the 72,000 mol. wt heat shock protein and with acid-fuchsin dye. Status epilepticus induced these markers of neuronal injury in the CA1 and CA3a regions of the hippocampus, thalamus, piriform cortex and the amygdaloid complex. Microinjection of 2-amino-7-phosphonoheptanoic acid, a competitive Antagonist of the N-methyl-D-aspartate subclass of the glutamate receptor, into area tempestas prior to systemic administration of kainate attenuated both heat shock protein induction and acid-fuchsin labeling in CA1 and CA3a pyramidal neurons without reducing the duration of electrographic seizures. Injections of bicuculline, a GABA Antagonist, into area tempestas produced hippocampal damage when given with subcytotoxic doses of intravenous kainate. Thus, area tempestas may be a uniquely sensitive anatomical structure involved not just in seizure propagation but also in modulating the extent and pattern of damage induced in hippocampal neurons as a result of prolonged, systemically induced seizures. These effects are due in part to excitatory and inhibitory projections to neurons in area tempestas.