Antagonists of Ionotropic Receptors for the Inhibitory Neurotransmitter GABA: Therapeutic Indications

Agents that antagonize the action of GABA on ionotropic receptors are widely used to probe the function of this neurotransmitter. Three such agents are in common use: bicuculline, gabazine, and picrotoxinin. These three agents produce convulsions on systemic administration but act in significantly different ways. Bicuculline is a competitive antagonist of GABAA receptors. Gabazine is also a competitive antagonist of GABAA receptors, interacting with different residues on the receptors. Picrotoxinin is a noncompetitive antagonist acting on the chloride channel of GABAA and several other ionotropic CYS-loop receptors including glycine, GABAC, and 5-HT3 receptors. Many other structurally diverse agents are now known to act as GABA receptor antagonists, providing opportunities for the discovery of agents with selectivity for the myriad of ionotropic GABA receptors. TPMPA is a selective antagonist for GABAC receptors, which are insensitive to bicuculline. Like TPMPA, many antagonists of ionotropic GABA receptors are not convulsants, indicating that there is still much to be learnt about GABA function in the brain from the study of such agents and their possible therapeutic uses. The most recently discovered GABAA receptor nonconvulsive antagonist is S44819, which is subtype selective for α5-containing receptors, and is arousing much interest in relation to cognition

Muscimol as an Ionotropic GABA Receptor Agonist

Abstract Muscimol, a psychoactive isoxazole from Amanita muscaria and related mushrooms, has proved to be a remarkably selective agonist at ionotropic receptors for the inhibitory neurotransmitter GABA. This historic overview highlights the discovery and development of muscimol and related compounds as a GABA agonist by Danish and Australian neurochemists. Muscimol is widely used as a ligand to probe GABA receptors and was the lead compound in the development of a range of GABAergic agents including nipecotic acid, tiagabine, 4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol, (Gaboxadol Ò ) and 4-PIOL

Effect of Method of Delivering Nicarbazin to Mallards on Plasma 4,4′-Dinitrocarbanilide Levels and Reproduction

Nicarbazin (NCZ), a coccidiostat used in the poultry industry, has been developed as a contraceptive for resident Canada geese. We tested the efficacy of NCZ as a contraceptive using mallards (Anas platyrhynchos) as a model for Canada geese. Nicarbazin-treated corn was fed ad libitum for 14 d at 0, 750, 1,000, or 1,500 ppm. Plasma and egg levels of 4,4′-dinitrocarbanilide (DNC), the active anticoccidial component of NCZ, differed among treatment groups in a dose-response relationship, but plasma levels did not differ between sexes. Nicarbazin caused a decrease in egg weight, but there was no effect of NCZ on the numbers of eggs laid per female per day. Nicarbazin did not significantly impact bird health. An additional trial tested the effect of the method of NCZ delivery on plasma DNC levels. Mallards were given NCZ daily for 12 d either by gavage with a corn oil suspension, gavage with a water suspension, peroral administration of a capsule, or feeding 500 mg of NCZ/kg of pelleted feed ad libitum. The method of delivery significantly affected plasma DNC levels, with the highest levels in the corn oil suspension group and the lowest levels in the pelleted feed group. This is likely due to decreased availability of NCZ in a pellet compared with gavage with a suspension or capsule. Mallards receiving 34.2 mg of NCZ/kg of BW when fed cracked corn coated with NCZ daily for 14 d had higher plasma DNC levels than those obtained by liquid gavage, capsule, or pelleted NCZ feed. For maximum effect in the field, NCZ should be coated onto corn. A higher concentration of NCZ is needed in pelleted feed to obtain comparable plasma DNC levels to allow for the decreased absorption of DNC

Identification of single-site gold catalysis in acetylene hydrochlorination

There remains considerable debate over the active form of gold under operating conditions of a recently validated gold catalyst for acetylene hydrochlorination. We have performed an in situ x-ray absorption fine structure study of gold/carbon (Au/C) catalysts under acetylene hydrochlorination reaction conditions and show that highly active catalysts comprise single-site cationic Au entities whose activity correlates with the ratio of Au(I):Au(III) present. We demonstrate that these Au/C catalysts are supported analogs of single-site homogeneous Au catalysts and propose a mechanism, supported by computational modeling, based on a redox couple of Au(I)-Au(III) species. View Full Tex

Stokes tomography of radio pulsar magnetospheres. I. Linear polarization

Polarimetric studies of pulsar radio emission traditionally concentrate on how the Stokes vector (I, Q, U, V) varies with pulse longitude, with special emphasis on the position angle (PA) swing of the linearly polarized component. The interpretation of the PA swing in terms of the rotating vector model is limited by the assumption of an axisymmetric magnetic field and the degeneracy of the output with respect to the orientation and magnetic geometry of the pulsar; different combinations of the latter two properties can produce similar PA swings. This paper introduces Stokes phase portraits as a supplementary diagnostic tool with which the orientation and magnetic geometry can be inferred more accurately. The Stokes phase portraits feature unique patterns in the I-Q, I-U, and Q-U planes, whose shapes depend sensitively on the magnetic geometry, inclination angle, beam and polarization patterns, and emission altitude. We construct look-up tables of Stokes phase portraits and PA swings for pure and current-modified dipole fields, filled core and hollow cone beams, and two empirical linear polarization models, L/I = \cos \theta_0 and L/I = \sin \theta_0, where \theta_0 is the colatitude of the emission point. We compare our look-up tables to the measured phase portraits of 24 pulsars in the European Pulsar Network online database. We find evidence in 60% of the objects that the radio emission region may depart significantly from low altitudes, even when the PA swing is S-shaped and/or the pulse-width-period relation is well satisfied. On the other hand, the data are explained adequately if the emission altitude exceeds ~10% of the light cylinder radius. We conclude that Stokes phase portraits should be analysed concurrently with the PA swing and pulse profiles in future when interpreting radio pulsar polarization data.Comment: 60 pages, 58 figures, submitted to MNRAS, accepted 13 Oct 201

Tsunami awareness and preparedness in Aotearoa New Zealand:The evolution of community understanding

After catastrophic events such as the 2004 Indian Ocean tsunami and the 2011 Great East Japan earthquake and tsunami there is a clear need for vulnerable countries like Aotearoa New Zealand to get prepared for tsunami. In the last ten years, the New Zealand government initiated major efforts to raise awareness of tsunami risk among coastal residents. This study explores tsunami awareness, preparedness, and evacuation intentions among residents of the East Coast of the North Island in a 2015 survey. The ten chosen locations also participated in a tsunami survey in 2003, with results demonstrating that tsunami awareness rose in the twelve years between the surveys. The 2015 survey also included questions on preparedness and intended action. Even though coastal residents know they live in a tsunami prone area, preparedness is relatively low and high expectations of a formal warning remain, even for a local source tsunami scenario. Furthermore, survey respondents had unrealistic ideas of evacuation procedures. When asked about their evacuation intentions, respondents intended to undertake a number of different actions before evacuating their homes, which could cause significant delays in the evacuation process. Most respondents were also reluctant to evacuate on foot and prefer using their vehicles instead, which could create dangerous traffic congestion. These surveyed intentions are consistent with a study of actual evacuation behaviours in the subsequent 2016 Kaikōura earthquake and tsunami, providing validation for the survey indicators. This paper identifies the procedures least understood by the public and offers some solutions to improve tsunami preparedness.</p

Giant Pulses with Nanosecond Time Resolution detected from the Crab Pulsar at 8.5 and 15.1 GHz

We present a study of shape, spectra and polarization properties of giant pulses (GPs) from the Crab pulsar at the very high frequencies of 8.5 and 15.1 GHz. Studies at 15.1 GHz were performed for the first time. Observations were conducted with the 100-m radio telescope in Effelsberg in Oct-Nov 2007 at the frequencies of 8.5 and 15.1 GHz as part of an extensive campaign of multi-station multi-frequency observations of the Crab pulsar. A selection of the strongest pulses was recorded with a new data acquisition system, based on a fast digital oscilloscope, providing nanosecond time resolution in two polarizations in a bandwidth of about 500 MHz. We analyzed the pulse shapes, polarisation and dynamic spectra of GPs as well as the cross-correlations between their LHC and RHC signals. No events were detected outside main pulse and interpulse windows. GP properties were found to be very different for GPs emitted at longitudes of the main pulse and the interpulse. Cross-correlations of the LHC and RHC signals show regular patterns in the frequency domain for the main pulse, but these are missing for the interpulse GPs. We consider consequences of application of the rotating vector model to explain the apparent smooth variation in the position angle of linear polarization for main pulse GPs. We also introduce a new scenario of GP generation as a direct consequence of the polar cap discharge. We find further evidence for strong nano-shot discharges in the magnetosphere of the Crab pulsar. The repetitive frequency spectrum seen in GPs at the main pulse phase is interpreted as a diffraction pattern of regular structures in the emission region. The interpulse GPs however have a spectrum that resembles that of amplitude modulated noise. Propagation effects may be the cause of the differences.Comment: Astronomy & Astrophysics (accepted