Deletion of the GABAA α2-subunit does not alter self dministration of cocaine or reinstatement of cocaine seeking

Rationale GABAA receptors containing α2-subunits are highly represented in brain areas that are involved in motivation and reward, and have been associated with addiction to several drugs, including cocaine. We have shown previously that a deletion of the α2-subunit results in an absence of sensitisation to cocaine. Objective We investigated the reinforcing properties of cocaine in GABAA α2-subunit knockout (KO) mice using an intravenous self-administration procedure. Methods α2-subunit wildtype (WT), heterozygous (HT) and KO mice were trained to lever press for a 30 % condensed milk solution. After implantation with a jugular catheter, mice were trained to lever press for cocaine (0.5 mg/kg/infusion) during ten daily sessions. Responding was extinguished and the mice tested for cue- and cocaine-primed reinstatement. Separate groups of mice were trained to respond for decreasing doses of cocaine (0.25, 0.125, 0.06 and 0.03 mg/kg). Results No differences were found in acquisition of lever pressing for milk. All genotypes acquired self-administration of cocaine and did not differ in rates of self-administration, dose dependency or reinstatement. However, whilst WT and HT mice showed a dose-dependent increase in lever pressing during the cue presentation, KO mice did not. Conclusions Despite a reported absence of sensitisation, motivation to obtain cocaine remains unchanged in KO and HT mice. Reinstatement of cocaine seeking by cocaine and cocaine-paired cues is also unaffected. We postulate that whilst not directly involved in reward perception, the α2-subunit may be involved in modulating the “energising” aspect of cocaine’s effects on reward-seeking

Deletion of the gabra2 gene results in hypersensitivity to the acute effects of ethanol but does not alter ethanol self administration

Human genetic studies have suggested that polymorphisms of the GABRA2 gene encoding the GABA(A) α2-subunit are associated with ethanol dependence. Variations in this gene also convey sensitivity to the subjective effects of ethanol, indicating a role in mediating ethanol-related behaviours. We therefore investigated the consequences of deleting the α2-subunit on the ataxic and rewarding properties of ethanol in mice. Ataxic and sedative effects of ethanol were explored in GABA(A) α2-subunit wildtype (WT) and knockout (KO) mice using a Rotarod apparatus, wire hang and the duration of loss of righting reflex. Following training, KO mice showed shorter latencies to fall than WT littermates under ethanol (2 g/kg i.p.) in both Rotarod and wire hang tests. After administration of ethanol (3.5 g/kg i.p.), KO mice took longer to regain the righting reflex than WT mice. To ensure the acute effects are not due to the gabra2 deletion affecting pharmacokinetics, blood ethanol concentrations were measured at 20 minute intervals after acute administration (2 g/kg i.p.), and did not differ between genotypes. To investigate ethanol's rewarding properties, WT and KO mice were trained to lever press to receive increasing concentrations of ethanol on an FR4 schedule of reinforcement. Both WT and KO mice self-administered ethanol at similar rates, with no differences in the numbers of reinforcers earned. These data indicate a protective role for α2-subunits, against the acute sedative and ataxic effects of ethanol. However, no change was observed in ethanol self administration, suggesting the rewarding effects of ethanol remain unchange

Role of f02 in fluid saturation of oceanic basalt.

Assessing the conditions under which magmas become fluid-saturated has important bearings on the geochemical modelling of magmas because volatile exsolution may profoundly alter the behaviour of certain trace elements that are strongly partitioned in the coexisting fluid1. Saal et al.2 report primitive melt inclusions from dredged oceanic basalts of the Siqueiros transform fault, from which they derive volatile abundances of the depleted mantle, based on the demonstration that magmas are not fluid-saturated at their eruption depth and so preserve the mantle signature in terms of their volatile contents. However, in their analysis, Saal et al.2 consider only fluid−melt equilibria, and do not take into account the homogeneous equilibria between fluid species, which, as we show here, may lead to a significant underestimation of the pressure depth of fluid saturation

Does Quantum Mechanics Clash with the Equivalence Principle - and Does it Matter?

With an eye on developing a quantum theory of gravity, many physicists have recently searched for quantum challenges to the equivalence principle of general relativity. However, as historians and philosophers of science are well aware, the principle of equivalence is not so clear. When clarified, we think quantum tests of the equivalence principle won't yield much. The problem is that the clash/not-clash is either already evident or guaranteed not to exist. Nonetheless, this work does help teach us what it means for a theory to be geometric.Comment: 12 page

Factorization Properties of Soft Graviton Amplitudes

We apply recently developed path integral resummation methods to perturbative quantum gravity. In particular, we provide supporting evidence that eikonal graviton amplitudes factorize into hard and soft parts, and confirm a recent hypothesis that soft gravitons are modelled by vacuum expectation values of products of certain Wilson line operators, which differ for massless and massive particles. We also investigate terms which break this factorization, and find that they are subleading with respect to the eikonal amplitude. The results may help in understanding the connections between gravity and gauge theories in more detail, as well as in studying gravitational radiation beyond the eikonal approximation.Comment: 35 pages, 5 figure

The impact of unhealthy food sponsorship vs. pro-health sponsorship models on young adults' food preferences: A randomised controlled trial

Background: Unhealthy foods are promoted heavily, through food company sponsorship of elite sport, resulting in extensive exposure among young adults who are avid sport spectators. This study explores the effects of sponsorship of an elite sporting event by: (A) non-food brands (control), (B) unhealthy food brands, (C) healthier food brands, or (D) an obesity prevention public health campaign on young adults' brand awareness, attitudes, image perceptions, event-sponsor fit perceptions, and preference for food sponsors' products. Methods: A between-subjects web-based experiment was conducted, consisting of four sponsorship conditions (A through D) featuring three product categories within each condition. Australian adults (N = 1132) aged 18-24 years were recruited via a national online panel. Participants viewed promotional videos and news stories about an upcoming international, multi-sport event (with sponsor content edited to reflect each condition), completed a distractor task, and then answered questions assessing the response variables. Regression analyses were conducted to test for differences by sponsorship condition on the respective outcome measures. Results: Compared to the control condition, unhealthy food sponsorship promoted higher awareness of, and more favourable attitudes towards, unhealthy food sponsor brands. Unhealthy food sponsorship also led to greater perceived event-sponsor fit and transfer of perceptions of the sporting event to the unhealthy food sponsor brands, relative to the control group. Exposure to sponsorship for healthier foods produced similar sponsorship effects for healthier food sponsor brands, as well as prompting a significant increase in the proportion of young adults showing a preference for these products. Obesity prevention campaign sponsorship promoted higher campaign awareness and perceived event-sponsor fit, but did not impact food attitudes or preference for unhealthy versus healthier foods. Conclusion: Findings suggest that restricting elite sport sponsorship to healthier food brands that meet set nutritional criteria could help promote healthier eating among young adults. Sporting organisations should be encouraged to seek sponsorship from companies who produce healthier food brands and government-funded social marketing campaigns. Clinical trial registration: Australian New Zealand Clinical Trials Registry (ANZCTR) registration number ACTRN12618000368235. Retrospectively registered 12 March 2018

The Role of Auditory Features Within Slot-Themed Social Casino Games and Online Slot Machine Games

Over the last few years playing social casino games has become a popular entertainment activity. Social casino games are offered via social media platforms and mobile apps and resemble gambling activities. However, social casino games are not classified as gambling as they can be played for free, outcomes may not be determined by chance, and players receive no monetary payouts. Social casino games appear to be somewhat similar to online gambling activities in terms of their visual and auditory features, but to date little research has investigated the cross over between these games. This study examines the auditory features of slot-themed social casino games and online slot machine games using a case study design. An example of each game type was played on three separate occasions during which, the auditory features (i.e., music, speech, sound effects, and the absence of sound) within the games were logged. The online slot-themed game was played in demo mode. This is the first study to provide a qualitative account of the role of auditory features within a slot-themed social casino game and an online slot machine game. Our results found many similarities between how sound is utilised within the two games. Therefore the sounds within these games may serve functions including: setting the scene for gaming, creating an image, demarcating space, interacting with visual features, prompting players to act, communicating achievements to players, providing reinforcement, heightening player emotions and the gaming experience. As a result this may reduce the ability of players to make a clear distinction between these two activities, which may facilitate migration between game

Extremely high He isotope ratios in MORB-source mantle from the proto-Iceland plume

The high <sup>3</sup>He/<sup>4</sup>He ratio of volcanic rocks thought to be derived from mantle plumes is taken as evidence for the existence of a mantle reservoir that has remained largely undegassed since the Earth's accretion. The helium isotope composition of this reservoir places constraints on the origin of volatiles within the Earth and on the evolution and structure of the Earth's mantle. Here we show that olivine phenocrysts in picritic basalts presumably derived from the proto-Iceland plume at Baffin Island, Canada, have the highest magmatic <sup>3</sup>He/<sup>4</sup>He ratios yet recorded. A strong correlation between <sup>3</sup>He/<sup>4</sup>He and <sup>87</sup>Sr/<sup>86</sup>Sr, <sup>143</sup>Nd/<sup>144</sup>Nd and trace element ratios demonstrate that the <sup>3</sup>He-rich end-member is present in basalts that are derived from large-volume melts of depleted upper-mantle rocks. This reservoir is consistent with the recharging of depleted upper-mantle rocks by small volumes of primordial volatile-rich lower-mantle material at a thermal boundary layer between convectively isolated reservoirs. The highest <sup>3</sup>He/<sup>4</sup>He basalts from Hawaii and Iceland plot on the observed mixing trend. This indicates that a <sup>3</sup>He-recharged depleted mantle (HRDM) reservoir may be the principal source of high <sup>3</sup>He/<sup>4</sup>He in mantle plumes, and may explain why the helium concentration of the 'plume' component in ocean island basalts is lower than that predicted for a two-layer, steady-state model of mantle structure

Biochemical autoregulatory gene therapy for focal epilepsy.

Despite the introduction of more than one dozen new antiepileptic drugs in the past 20 years, approximately one-third of people who develop epilepsy continue to have seizures on mono- or polytherapy1. Viral-vector-mediated gene transfer offers the opportunity to design a rational treatment that builds on mechanistic understanding of seizure generation and that can be targeted to specific neuronal populations in epileptogenic foci2. Several such strategies have shown encouraging results in different animal models, although clinical translation is limited by possible effects on circuits underlying cognitive, mnemonic, sensory or motor function. Here, we describe an autoregulatory antiepileptic gene therapy, which relies on neuronal inhibition in response to elevations in extracellular glutamate. It is effective in a rodent model of focal epilepsy and is well tolerated, thus lowering the barrier to clinical translation

Quadriceps force generation in patients with osteoarthritis of the knee and asymptomatic participants during patellar tendon reflex reactions: an exploratory cross-sectional study

BACKGROUND: It has been postulated that muscle contraction is slower in patients with osteoarthritis of the knee than asymptomatic individuals, a factor that could theoretically impair joint protection mechanisms. This study investigated whether patients with osteoarthritis of the knee took longer than asymptomatic participants to generate force during reflex quadriceps muscle contraction. This was an exploratory study to inform sample size for future studies. METHODS: An exploratory observational cross sectional study was carried out. Two subject groups were tested, asymptomatic participants (n = 17), mean (SD) 56.7 (8.6) years, and patients with osteoarthritis of the knee, diagnosed by an orthopaedic surgeon, (n = 16), age 65.9 (7.8) years. Patellar tendon reflex responses were elicited from participants and measured with a load cell. Force latency, contraction time, and force of the reflex response were determined from digitally stored data. The Mann-Whitney U test was used for the between group comparisons in these variables. Bland and Altman within-subject standard deviation values were calculated to evaluate the measurement error or precision of force latency and contraction time. RESULTS: No significant differences were found between the groups for force latency (p = 0.47), contraction time (p = 0.91), or force (p = 0.72). The two standard deviation measurement error values for force latency were 27.9 ms for asymptomatic participants and 16.4 ms for OA knee patients. For contraction time, these values were 29.3 ms for asymptomatic participants and 28.1 ms for OA knee patients. Post hoc calculations revealed that the study was adequately powered (80%) to detect a difference between the groups of 30 ms in force latency. However it was inadequately powered (59%) to detect this same difference in contraction time, and 28 participants would be required in each group to reach 80% power. CONCLUSION: Patients with osteoarthritis of the knee do not appear to have compromised temporal parameters or magnitude of force generation during patellar tendon reflex reactions when compared to a group of asymptomatic participants. However, these results suggest that larger studies are carried out to investigate this area further