Human neuronal stargazin-like proteins, gamma(2), gamma(3) and gamma(4); an investigation of their specific localization in human brain and their influence on Ca(V)2.1 voltage-dependent calcium channels expressed in Xenopus oocytes

Background: Stargazin (gamma(2)) and the closely related gamma(3), and gamma(4) transmembrane proteins are part of a family of proteins that may act as both neuronal voltage-dependent calcium channel (VDCC) gamma subunits and transmembrane alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproponinc (AMPA) receptor regulatory proteins (TARPs). In this investigation, we examined the distribution patterns of the stargazin-like proteins gamma(2), gamma(3), and gamma(4) in the human central nervous system (CNS). In addition, we investigated whether human gamma(2) or gamma(4) could modulate the electrophysiological properties of a neuronal VDCC complex transiently expressed in Xenopus oocytes.Results: The mRNA encoding human gamma(2) is highly expressed in cerebellum, cerebral cortex, hippocampus and thalamus, whereas gamma(3) is abundant in cerebral cortex and amygdala and gamma(4) in the basal ganglia. Immunohistochemical analysis of the cerebellum determined that both gamma(2) and gamma(4) are present in the molecular layer, particularly in Purkinje cell bodies and dendrites, but have an inverse expression pattern to one another in the dentate cerebellar nucleus. They are also detected in the interneurons of the granule cell layer though only gamma(2) is clearly detected in granule cells. The hippocampus stains for gamma(2) and gamma(4) throughout the layers of the every CA region and the dentate gyrus, whilst gamma(3) appears to be localized particularly to the pyramidal and granule cell bodies. When co-expressed in Xenopus oocytes with a Ca(V)2.1/beta(4) VDCC complex, either in the absence or presence of an alpha(2)delta(2) subunit, neither gamma(2) nor gamma(4) significantly modulated the VDCC peak current amplitude, voltage-dependence of activation or voltage-dependence of steady-state inactivation.Conclusion: The human gamma(2), gamma(3) and gamma(4) stargazin-like proteins are detected only in the CNS and display differential distributions among brain regions and several cell types in found in the cerebellum and hippocampus. These distribution patterns closely resemble those reported by other laboratories for the rodent orthologues of each protein. Whilst the fact that neither gamma(2) nor gamma(4) modulated the properties of a VDCC complex with which they could associate in vivo in Purkinje cells adds weight to the hypothesis that the principal role of these proteins is not as auxiliary subunits of VDCCs, it does not exclude the possibility that they play another role in VDCC function

Study protocol for a randomised controlled trial of Allen Carr's Easyway programme versus Lambeth and Southwark NHS for smoking cessation.

INTRODUCTION: Smoking is a major cause of ill health and is associated with several diseases including cancer, coronary heart disease and stroke. Many psychological and pharmacological smoking cessation treatments are available and although they are undoubtedly the most cost-effective health interventions available, many people still fail to maintain cessation in the longer term. Recently, National Institute for Health and Care Excellence called for comparative studies to determine the short-term and long-term effectiveness of Allen Carr's Easyway (ACE) method of stopping smoking. This study will compare the efficacy of the ACE programme and a 1-1 counselling service available via the National Health Service. METHODS AND ANALYSIS: A two-arm, parallel-group, blinded, randomised controlled trial will be conducted with people who smoke tobacco cigarettes, are aged ≥18 years and are motivated to quit. Exclusion criteria comprise self-reported mental health condition, pregnancy or respiratory disease such as chronic obstructive pulmonary disease or emphysema. The primary treatment outcome is smoking cessation 26 weeks after treatment. Participants will be analysed on an intention to treat basis at the point of randomisation. Before being randomised, the research team will not inform participants which two treatments are being compared. Once randomised researchers will be blinded to participant condition, and participants will be blinded to the condition they are not assigned to. Logistic regression will be used to estimate the effectiveness of the treatment condition on smoking cessation at 26 weeks. The following covariates will be included: baseline quit efficacy (at inclusion), age (at inclusion), gender and baseline nicotine dependency. ETHICS AND DISSEMINATION: Approval was granted by London-Fulham Research Ethics Committee (ref: 16/LO/1657). The study's findings will be published in peer-reviewed journals and disseminated at national and international conferences. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov identifier number: NCT02855255. ISRCTN registration number: ISRCTN23584477; Pre-results

Personality, motives and metacognitions as predictors of problematic Facebook Use in university students

© 2016 Elsevier Ltd.Facebook has become hugely popular among young people and adults all over the world, creating a new social phenomenon that has affected the communication patterns used by people to interact with each other. Although most people use Facebook wisely, a minority of users can show negative patterns of Facebook use, with negative consequences on personal psycho-social well-being, especially among young adults. The present study aims to test a model designed to assess the unique contribution of personality traits, motives for using Facebook and metacognitions on Problematic Facebook Use (PFU) among young adults. A total of 815 Italian university students participated in the study. Path analysis revealed that three of the four motives to use Facebook, and that two of the five metacognitions, predicted PFU. Moreover, only one personality trait (extraversion) appeared to be directly linked to PFU, while emotional stability indirectly influenced PFU via motives (coping and conformity) and metacognitions (negative beliefs about worry and cognitive confidence). In conclusion, motives and metacognitions predict PFU among young adults, and they should be taken into account to develop preventive measures and clinical interventions

Exploring the Alcohol-Behaviour Link: Myopic self-enhancement in the absence of alcohol consumption as a function of past alcohol use

Dual process accounts of the alcohol-behaviour link hypothesise that differences in drinking patterns will moderate the effects of exposure to alcohol-related cues on behaviour, such as when a placebo is administered. We test this hypothesis by adapting a paradigm used in alcohol myopia research to examine the effects of alcohol-related priming on self-enhancement behaviour among social drinkers. Participants were asked to engage in a computerised self rating task prior to being exposed to alcohol related and/or motivational primes. A staged computer error then occurred, and participants were then asked to complete their self ratings again – this method allowed for an immediate assessment of the impact of alcohol and motivational primes on self enhancement. As predicted by alcohol myopia theory, the overall effect of priming with alcohol-related cues was not significant irrespective of response-conflict manipulations. However, drinker type moderated this effect such that heavier drinkers self-enhanced more after exposure to alcohol-related cues, but only in high-conflict conditions. This suggests that the efficacy of a placebo may be significantly moderated by individual differences in reactions to alcohol-related stimuli, and that dual process accounts of the effects of alcohol on behaviour better explains this variation than alcohol myopia theory

Effect of health messages on alcohol attitudes and intentions in a sample of 16- & 17-year-old underage drinkers

Background. Responsible drinking messages (RDMs) are a key component of many education-based interventions for reducing alcohol harms. The evidence base for the effectiveness of RDMs is extremely limited, with some recent research suggesting iatrogenic effects of such messages. Objective. To examine the effects of exposure to health messages on attitudes towards drinking and drunkenness, and intentions to drink and get drunk, amongst underage drinkers. Methods. Ninety-four underage drinkers were recruited from colleges in the UK. Participants were either actively or passively exposed to one of two health messages (RDM or general wellbeing). Measures of attitudes and intentions towards drinking and drunkenness were obtained one week before and immediately after participation in the study. A unit estimation task was also included. Results. Active exposure to RDMs led to more positive attitude towards drunkenness, while passive exposure led to more negative attitudes. Passive RDM exposure led to increased intentions to get drunk in future. Wellbeing posters produced the opposite effect in some but not all of these measures. Conclusions. Exposure to RDMs may have some beneficial effects in terms of creating more negative attitudes towards alcohol consumption, but we also identified potential iatrogenic effects regarding attitudes and intentions towards drunkenness amongst an underage sample of drinkers. Further research is required to better understand optimal ways of framing RDMs to produce positive changes in attitudes, intentions and prospective drinking behaviour

The etiology and prevention of feeding intolerance paralytic ileus – revisiting an old concept

Gastro-intestinal (G-I) motility is impaired ("paralytic ileus") after abdominal surgery. Premature feeding attempts delay recovery by inducing "feeding intolerance," especially abdominal distention that compromises respiration. Controlled studies (e.g., from Sloan-Kettering Memorial Hospital) have lead to recommendations that patients not be fed soon after major abdominal surgery to avoid this complication

Do Baseline Executive Functions Mediate Prospective Memory Performance under a Moderate Dose of Alcohol?

Prospective memory (PM) is memory for delayed intentions. While deleterious effects of acute doses of alcohol on PM have been documented previously using between-subjects comparisons, the current study adopted a single blind placebo-controlled within-subjects design to explore whether the extent to which alcohol-related impairments in PM are mediated by executive functions (EFs). To this end, 52 male social drinkers with no history of substance-related treatment were tested using two parallel versions of a clinical measure of PM (the Memory for Intentions Test; Raskin et al., 2010), and a battery of EF measures. Testing took place on two occasions, with the order of administration of the alcohol and placebo conditions being fully counterbalanced. Overall, PM was worse under alcohol and participants showed deficits on five of the six subscales making up the clinical test. Hierarchical multiple regression analyses demonstrated that EFs did not predict PM performance decrements overall but did predict performance when time cues were presented and when verbal responses were required. Phonemic fluency was the strongest of the EF predictors; a greater capacity to gain controlled access to information in long-term memory predicted a smaller difference between placebo- and alcohol-related performance on both the time cue and verbal response scales. PM is crucial to compliance with, and response to, both therapy programs and alcohol harm prevention campaigns. The results indicate that individual differences in cognitive function need to be taken into account when designing such interventions in order to increase their effectiveness

Direct Interaction of PP2A Phosphatase with GABAB Receptors Alters Functional Signaling

Addictive drugs usurp the brain's intrinsic mechanism for reward, leading to compulsive and destructive behaviors. In the ventral tegmental area (VTA), the center of the brain's reward circuit, GABAergic neurons control the excitability of dopamine (DA) projection neurons and are the site of initial psychostimulant-dependent changes in signaling. Previous work established that cocaine/methamphetamine exposure increases protein phosphatase 2A (PP2A) activity, which dephosphorylates the GABABR2 subunit, promotes internalization of the GABAB receptor (GABABR) and leads to smaller GABABR-activated G-protein-gated inwardly rectifying potassium (GIRK) currents in VTA GABA neurons. How the actions of PP2A become selective for a particular signaling pathway is poorly understood. Here, we demonstrate that PP2A can associate directly with a short peptide sequence in the C terminal domain of the GABABR1 subunit, and that GABABRs and PP2A are in close proximity in rodent neurons (mouse/rat; mixed sexes). We show that this PP2A-GABABR interaction can be regulated by intracellular Ca2+ Finally, a peptide that potentially reduces recruitment of PP2A to GABABRs and thereby limits receptor dephosphorylation increases the magnitude of baclofen-induced GIRK currents. Thus, limiting PP2A-dependent dephosphorylation of GABABRs may be a useful strategy to increase receptor signaling for treating diseases.SIGNIFICANCE STATEMENT Dysregulation of GABAB receptors (GABABRs) underlies altered neurotransmission in many neurological disorders. Protein phosphatase 2A (PP2A) is involved in dephosphorylating and subsequent internalization of GABABRs in models of addiction and depression. Here, we provide new evidence that PP2A B55 regulatory subunit interacts directly with a small region of the C-terminal domain of the GABABR1 subunit, and that this interaction is sensitive to intracellular Ca2+ We demonstrate that a short peptide corresponding to the PP2A interaction site on GABABR1 competes for PP2A binding, enhances phosphorylation GABABR2 S783, and affects functional signaling through GIRK channels. Our study highlights how targeting PP2A dependent dephosphorylation of GABABRs may provide a specific strategy to modulate GABABR signaling in disease conditions