SY30-3THE USE OF SOPHISMS IN SUSTAINING DISULFIRAM

Disulfiram's use is not supported by scientific evidence but nevertheless largely advocated and used. This would be less odd in case of lacking or just preliminary evidence. What is peculiar in the case of disulfiram's prescription is its persistence against evidence. Hence arise the question how it is possible that its use can be supported, i.e. by what type of arguments. The goal of an argument is to persuade, the goal of logic and argumentation is additionally to persuade for good reasons. In this sense, a good argument would give good reasons to believe the conclusion. Fallacies are bad arguments, either because they have weak logic, or because they rely on a false premise. Sophisms are intentionally used fallacies, an attempt to persuade opponents that a specific conclusion is true, by means other than by proposing relevant evidence. Proponents of fallacious arguments may use them either because they are incapable or because they are unwilling to accept their arguments to be fallacious. We therefore formulate the hypothesis that the frequency use of fallacious arguments within our otherwise supposedly evidence based discipline may be indicative of (a) a scientifically immature discipline, and/or (b) a moralistically intermingled disciplin

SY09-4TRANSLATING, HARM REDUCTION INTO POLICIES, THE SWISS EXPERIENCE

Aims. The aim of this presentation is to illustrate how Switzerland was able to play such a pioneering role in the field of addiction treatment, by creating a drug policy integrating the medical prescription of diacetylmorphine (heroin) in the therapeutic arsenal of addiction treatments. Discussion. The medical prescription of diacetylmorphine, introduced initially as a harm reduction measure, has been the exotic element of the Swiss drug policy of 1991 and probably still is one of the most controversial practices in clinical medicine despite its documented effectiveness. Coalitions of change actors, across stakeholder groups from many professions and politicians on various levels, succeeded in formulating and starting initiatives for a new drug policy and its innovations. Conclusion. In the case of Switzerland, the Swiss Confederation took a leading role by facilitating communication, encouraging scientific knowledge and bringing the various stakeholders on a platform to deliver a consensual political policymaking basis. This was facilitated by the Swiss direct democracy system. Sustained, dialogue between researchers and the users, of research enhances the likelihood of research affecting polic

Gluco-incretins regulate beta-cell glucose competence by epigenetic silencing of Fxyd3 expression.

BACKGROUND/AIMS: Gluco-incretin hormones increase the glucose competence of pancreatic beta-cells by incompletely characterized mechanisms. METHODS: We searched for genes that were differentially expressed in islets from control and Glp1r-/-; Gipr-/- (dKO) mice, which show reduced glucose competence. Overexpression and knockdown studies; insulin secretion analysis; analysis of gene expression in islets from control and diabetic mice and humans as well as gene methylation and transcriptional analysis were performed. RESULTS: Fxyd3 was the most up-regulated gene in glucose incompetent islets from dKO mice. When overexpressed in beta-cells Fxyd3 reduced glucose-induced insulin secretion by acting downstream of plasma membrane depolarization and Ca++ influx. Fxyd3 expression was not acutely regulated by cAMP raising agents in either control or dKO adult islets. Instead, expression of Fxyd3 was controlled by methylation of CpGs present in its proximal promoter region. Increased promoter methylation reduced Fxyd3 transcription as assessed by lower abundance of H3K4me3 at the transcriptional start site and in transcription reporter assays. This epigenetic imprinting was initiated perinatally and fully established in adult islets. Glucose incompetent islets from diabetic mice and humans showed increased expression of Fxyd3 and reduced promoter methylation. CONCLUSIONS/INTERPRETATION: Because gluco-incretin secretion depends on feeding the epigenetic regulation of Fxyd3 expression may link nutrition in early life to establishment of adult beta-cell glucose competence; this epigenetic control is, however, lost in diabetes possibly as a result of gluco-incretin resistance and/or de-differentiation of beta-cells that are associated with the development of type 2 diabetes

Fgf15 Neurons of the Dorsomedial Hypothalamus Control Glucagon Secretion and Hepatic Gluconeogenesis.

The counterregulatory response to hypoglycemia is an essential survival function. It is controlled by an integrated network of glucose-responsive neurons, which trigger endogenous glucose production to restore normoglycemia. The complexity of this glucoregulatory network is, however, only partly characterized. In a genetic screen of a panel of recombinant inbred mice we previously identified Fgf15, expressed in neurons of the dorsomedial hypothalamus (DMH), as a negative regulator of glucagon secretion. Here, we report on the generation of Fgf15 <sup>CretdTomato</sup> mice and their use to further characterize these neurons. We show that they were glutamatergic and comprised glucose-inhibited and glucose-excited neurons. When activated by chemogenetics, Fgf15 neurons prevented the increase in vagal nerve firing and the secretion of glucagon normally triggered by insulin-induced hypoglycemia. On the other hand, they increased the activity of the sympathetic nerve in the basal state and prevented its silencing by glucose overload. Higher sympathetic tone increased hepatic Creb1 phosphorylation, Pck1 mRNA expression, and hepatic glucose production leading to glucose intolerance. Thus, Fgf15 neurons of the DMH participate in the counterregulatory response to hypoglycemia by a direct adrenergic stimulation of hepatic glucose production while suppressing vagally induced glucagon secretion. This study provides new insights into the complex neuronal network that prevents the development of hypoglycemia

SY30-1SIX YEARS AFTER STOPPING THE PRESCRIPTION OF DISULFIRAM FOR ALCOHOL DEPENDANCE, IS IT STILL POPULAR AMONG CAREGIVERS?

A 2009 survey of the Geneva Division of Addictology healthcare team monitored their perception of the decision in 2007 to stop the prescription of Disulfiram for alcohol dependence. The decision was supported by the lack of evidence based efficacy studies. At that time the majority did not agree with the decision to stop Disulfiram and 75% still believed that Disulfiram was useful for some patients, despite the fact that most of the caregivers acknowledged that aversive treatment works mainly through psychological constraints and that this decision was based on EBM. In 2014 the same slightly modified questionnaire was submitted to the healthcare team to assess if after 6 years of practice changes the results were comparable. An online questionnaire of 15 questions ask the participants about their perception of Disufliram efficacy, the impact of stopping Disulfiram on their clinical practices and the pertinence of the decision. The results of this questionnaire will be discussed in the presentatio

SY38-2IMPULSIVITY, MOTIVATIONS AND ADDICTION TO ONLINE GAMES

Introduction. Problematic engagement in online video gaming has been considered recently in the appendix of the DSM-5. Underpinning psychological factors are yet to be clarified, mostly in adult populations. We present data from two studies investigating links between motives to play and impulsivity in one hand and excessive gaming in another hand. Methods. Online studies have been conducted on adult gamers in France (n = 516) and Switzerland (n = 1057). Problematic engagement has been assessed in France by DSM-IV-TR adapted substance dependence criteria (DAS) and by IAT in Switzerland. Motivations have been investigated using Yee's model. Impulsivity has been evaluated using respectively BIS-10 and UPPS-P. The French sample has been compared to heroin users and to healthy controls regarding impulsivity. In the Swiss study, cluster analysis has been conducted to identify subgroups of players regarding their engagement in-game, their motivations to play and their impulsivity. Results. DAS has been found to be predicted by BIS high scores as well as by competition and advancement. Problematic gamers presented higher levels of impulsivity than controls but less than heroin dependents. Three of five clusters were identified to be problematic and linked to high levels of impulsivity, achievement and escapism. Conclusion. Achievement motives to play and high impulsivity have been linked to problematic engagement in online videogames in two different samples evaluated by two different methods. Addiction to online gaming showed a difference in impulsivity traits with substance dependence and healthy controls and subgroups of problem gamers has been characterized. These data could help to design tailored treatments for excessive online gamer

P-73AN INVESTIGATION OF ADDICTIONS (SUBSTANCES AND BEHAVIORS) IN A COMMUNITY SAMPLE

Chemical and behavioral addictions are highly prevalent in our societies. Nevertheless, studies investigating a large panel of addictive behaviors in a community sample are lacking from the current literature on the topic. The aim of the current study is to explore addictive behaviors prevalence, characteristics, and interrelations in a sample of French speaking adults from the general population. Both substances (alcohol, tobacco, cannabis, drugs) and behaviors (gambling, Internet, buying, sport, work, mobile phone, eating) were considered. Several features of these addictive behaviors (involved in the triggering of the behaviors) were considered, namely, frequency, loss of control, hedonic aspects, craving, impact upon the daily living, and emotional contexts. 770 subjects answered to the online survey. Descriptive results will be presented for each conducts and their related features (prevalence, comorbidities, specific characteristics associated with each addictive behaviors). Our study thus provides a detailed overview of the current conducts' prevalence along with their co-occurrences. It also sheds some lights on how these behaviors may have an impact upon the daily living, and eventually turn into problematic behaviors. A particular emphasis is set on some behavioral conducts, like Internet gaming which is particularly salien

Glucose transporter 2 mediates the hypoglycemia-induced increase in cerebral blood flow.

Glucose transporter 2 (Glut2)-positive cells are sparsely distributed in brain and play an important role in the stimulation of glucagon secretion in response to hypoglycemia. We aimed to determine if Glut2-positive cells can influence another response to hypoglycemia, i.e. increased cerebral blood flow (CBF). CBF of adult male mice devoid of Glut2, either globally (ripglut1:glut2 <sup>-</sup> <sup>/</sup> <sup>-</sup> ) or in the nervous system only (NG2KO), and their respective controls were studied under basal glycemia and insulin-induced hypoglycemia using quantitative perfusion magnetic resonance imaging at 9.4 T. The effect on CBF of optogenetic activation of hypoglycemia responsive Glut2-positive neurons of the paraventricular thalamic area was measured in mice expressing channelrhodopsin2 under the control of the Glut2 promoter. We found that in both ripglut1:glut2 <sup>-</sup> <sup>/</sup> <sup>-</sup> mice and NG2KO mice, CBF in basal conditions was higher than in their respective controls and not further activated by hypoglycemia, as measured in the hippocampus, hypothalamus and whole brain. Conversely, optogenetic activation of Glut2-positive cells in the paraventricular thalamic nucleus induced a local increase in CBF similar to that induced by hypoglycemia. Thus, Glut2 expression in the nervous system is required for the control of CBF in response to changes in blood glucose concentrations

Glucagon-Like Peptide-1 Protects β-Cells Against Apoptosis by Increasing the Activity of an Igf-2/Igf-1 Receptor Autocrine Loop

OBJECTIVE: The gluco-incretin hormones glucagon-like peptide (GLP)-1 and gastric inhibitory peptide (GIP) protect beta-cells against cytokine-induced apoptosis. Their action is initiated by binding to specific receptors that activate the cAMP signaling pathway, but the downstream events are not fully elucidated. Here we searched for mechanisms that may underlie this protective effect. RESEARCH DESIGN AND METHODS: We performed comparative transcriptomic analysis of islets from control and GipR(-/-);Glp-1-R(-/-) mice, which have increased sensitivity to cytokine-induced apoptosis. We found that IGF-1 receptor expression was markedly reduced in the mutant islets. Because the IGF-1 receptor signaling pathway is known for its antiapoptotic effect, we explored the relationship between gluco-incretin action, IGF-1 receptor expression and signaling, and apoptosis. RESULTS: We found that GLP-1 robustly stimulated IGF-1 receptor expression and Akt phosphorylation and that increased Akt phosphorylation was dependent on IGF-1 but not insulin receptor expression. We demonstrated that GLP-1-induced Akt phosphorylation required active secretion, indicating the presence of an autocrine activation mechanism; we showed that activation of IGF-1 receptor signaling was dependent on the secretion of IGF-2. We demonstrated, both in MIN6 cell line and primary beta-cells, that reducing IGF-1 receptor or IGF-2 expression or neutralizing secreted IGF-2 suppressed GLP-1-induced protection against apoptosis. CONCLUSIONS: An IGF-2/IGF-1 receptor autocrine loop operates in beta-cells. GLP-1 increases its activity by augmenting IGF-1 receptor expression and by stimulating secretion; this mechanism is required for GLP-1-induced protection against apoptosis. These findings may lead to novel ways of preventing beta-cell loss in the pathogenesis of diabetes

SY09-3HARM REDUCTION IN NON-SUBSTANCE RELATED ADDICTIONS

Behavioral addictions (gambling, gaming, internet use) are new challenges for policy makers, and the question arises if harm reduction is an applicable concept. Gambling addiction policies are trying to include harm reduction models (limitation of the amount of money you can bet, limitation in access to gambling venues). We will discuss if these models are valid in gaming addiction. I.E. If we only consider the classical policy models applied for reducing substances harm: supply reduction, demand reduction and harm reduction, limitations arise: for example: applying these concepts to gaming addiction is impossible. If heroin is an identified substance, games are heterogeneous in nature and are described from cognitive enhancers to highly addictive. The concept of supply should include the complex nature of video games. Reducing demand could be considered as a censure directly in conflict with human nature to produce the best and most attractive games (should unattractive cars be produced to reduce global warming). And finally harm reduction concepts in gaming will be discusse