GABA(A) receptors containing (alpha)5 subunits in the CA1 and CA3 hippocampal fields regulate ethanol-motivated behaviors: an extended ethanol reward circuitry

GABA receptors within the mesolimbic circuitry have been proposed to play a role in regulating alcohol-seeking behaviors in the alcohol-preferring (P) rat. However, the precise GABA(A) receptor subunit(s) mediating the reinforcing properties of EtOH remains unknown. We examined the capacity of intrahippocampal infusions of an alpha5 subunit-selective ( approximately 75-fold) benzodiazepine (BDZ) inverse agonist [i.e., RY 023 (RY) (tert-butyl 8-(trimethylsilyl) acetylene-5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5a] [1,4] benzodiazepine-3-carboxylate)] to alter lever pressing maintained by concurrent presentation of EtOH (10% v/v) and a saccharin solution (0.05% w/v). Bilateral (1.5-20 microgram) and unilateral (0.01-40 microgram) RY dose-dependently reduced EtOH-maintained responding, with saccharin-maintained responding being reduced only with the highest doses (e.g., 20 and 40 microgram). The competitive BDZ antagonist ZK 93426 (ZK) (7 microgram) reversed the RY-induced suppression on EtOH-maintained responding, confirming that the effect was mediated via the BDZ site on the GABA(A) receptor complex. Intrahippocampal modulation of the EtOH-maintained responding was site-specific; no antagonism by RY after intra-accumbens [nucleus accumbens (NACC)] and intraventral tegmental [ventral tegmental area (VTA)] infusions was observed. Because the VTA and NACC contain very high densities of alpha1 and alpha2 subunits, respectively, we determined whether RY exhibited a "negative" or "neutral" pharmacological profile at recombinant alpha1beta3gamma2, alpha2beta3gamma2, and alpha5beta3gamma2 receptors expressed in Xenopus oocytes. RY produced "classic" inverse agonism at all alpha receptor subtypes; thus, a neutral efficacy was not sufficient to explain the failure of RY to alter EtOH responding in the NACC or VTA. The results provide the first demonstration that the alpha5-containing GABA(A) receptors in the hippocampus play an important role in regulating EtOH-seeking behaviors

Neuromotor tolerability and behavioural characterisation of cannabidiolic acid, a phytocannabinoid with therapeutic potential for anticipatory nausea

Rationale: Anticipatory nausea (AN) is a poorly controlled side-effect experienced by chemotherapy patients. Currently, pharmacotherapy is restricted to benzodiazepine anxiolytics, which have limited efficacy, significant sedative effects, and induce dependency. The non-psychoactive phytocannabinoid, cannabidiolic acid (CBDA), has shown considerable efficacy in pre-clinical AN models, however determination of its neuromotor tolerability profile is crucial to justify clinical investigation. Provisional evidence for appetite-stimulating properties also requires detailed investigation. Objectives: To assess the tolerability of CBDA in locomotor activity, motor coordination and muscular strength tests, and additionally for ability to modulate feeding behaviours. Methods: Male Lister hooded rats administered CBDA (0.05-5 mg/kg; p.o.) were assessed in habituated open field (for locomotor activity), static beam and grip strength tests. A further study investigated whether these CBDA doses modulated normal feeding behaviour. Finally, evidence of anxiolytic-like effects in the habituated open field prompted testing of 5 mg/kg CBDA for anxiolytic-like activity in unhabituated open field, light/dark box and novelty-supressed feeding (NSF) tests. Results: CBDA had no adverse effects upon performance in any neuromotor tolerability test, however anxiolytic-like behaviour was observed in the habituated open field. Normal feeding behaviours were unaffected by any dose. CBDA (5 mg/kg) abolished the increased feeding latency in the NSF test induced by the 5-HT1AR antagonist, WAY-100,635, indicative of anxiolytic-like effects, but had no effect on anxiety-like behaviour in the novel open field or light/dark box. Conclusions: CBDA is very well tolerated and devoid of the sedative side-effect profile of benzodiazepines, justifying its clinical investigation as a novel AN treatment

Nucleon Charge and Magnetization Densities from Sachs Form Factors

Relativistic prescriptions relating Sachs form factors to nucleon charge and magnetization densities are used to fit recent data for both the proton and the neutron. The analysis uses expansions in complete radial bases to minimize model dependence and to estimate the uncertainties in radial densities due to limitation of the range of momentum transfer. We find that the charge distribution for the proton is significantly broad than its magnetization density and that the magnetization density is slightly broader for the neutron than the proton. The neutron charge form factor is consistent with the Galster parametrization over the available range of Q^2, but relativistic inversion produces a softer radial density. Discrete ambiguities in the inversion method are analyzed in detail. The method of Mitra and Kumari ensures compatibility with pQCD and is most useful for extrapolating form factors to large Q^2.Comment: To appear in Phys. Rev. C. Two new figures and accompanying text have been added and several discussions have been clarified with no significant changes to the conclusions. Now contains 47 pages including 21 figures and 2 table

Children struggle beyond preschool-age in a continuous version of the ambiguous figures task

Children until the age of five are only able to reverse an ambiguous figure when they are informed about the second interpretation. In two experiments, we examined whether children’s difficulties would extend to a continuous version of the ambiguous figures task. Children (Experiment 1: 66 3- to 5-year olds; Experiment 2: 54 4- to 9-year olds) and adult controls saw line drawings of animals gradually morph—through well-known ambiguous figures—into other animals. Results show a relatively late developing ability to recognize the target animal, with difficulties extending beyond preschool-age. This delay can neither be explained with improvements in theory of mind, inhibitory control, nor individual differences in eye movements. Even the best achieving children only started to approach adult level performance at the age of 9, suggesting a fundamentally different processing style in children and adults

Owning the problem: Media portrayals of overweight dogs and the shared determinants of the health of human and companion animal populations

Weight-related health problems have become a common topic in Western mass media. News-coverage has also extended to overweight pets, particularly since 2003 when the U.S. National Academy of Sciences announced that obesity was also afflicting co-habiting companion animals in record numbers. To characterize and track views in popular circulation on causes, consequences and responsibilities vis-à-vis weight gain and obesity, in pets as well as in people, this study examines portrayals of overweight dogs that appeared from 2000 through 2009 in British, American and Australian mass media. The ethnographic content analysis drew inspiration from the literature in population health, animal-human relationships, communication framing and the active nature of texts in cosmopolitan societies. Three main types of media articles about overweight dogs appeared during this period: 1) reports emphasizing facts and figures; 2) stories emphasizing personal prescriptions for dog owners, and 3) societal critiques. To help ordinary people make sense of canine obesity, media articles often highlight that dogs share the lifestyle of their human companion or owner, yet the implications of shared social and physical environments is rarely considered when it comes to solutions. Instead, media coverage exhorts people who share their lives with overweight dogs to ‘own the problem’ and, with resolve, to normalize their dog’s physical condition by imposing dietary, exercise and relationship changes, thereby individualizing culpability rather than linking it to broader systemic issues. Keywords: Companion animals; Media; Narrative analysis; Obesity; Public understandin

Exploring consumer exposure pathways and patterns of use for chemicals in the environment

AbstractHumans are exposed to thousands of chemicals in the workplace, home, and via air, water, food, and soil. A major challenge in estimating chemical exposures is to understand which chemicals are present in these media and microenvironments. Here we describe the Chemical/Product Categories Database (CPCat), a new, publically available (http://actor.epa.gov/cpcat) database of information on chemicals mapped to “use categories” describing the usage or function of the chemical. CPCat was created by combining multiple and diverse sources of data on consumer- and industrial-process based chemical uses from regulatory agencies, manufacturers, and retailers in various countries. The database uses a controlled vocabulary of 833 terms and a novel nomenclature to capture and streamline descriptors of chemical use for 43,596 chemicals from the various sources. Examples of potential applications of CPCat are provided, including identifying chemicals to which children may be exposed and to support prioritization of chemicals for toxicity screening. CPCat is expected to be a valuable resource for regulators, risk assessors, and exposure scientists to identify potential sources of human exposures and exposure pathways, particularly for use in high-throughput chemical exposure assessment