Directeur de la rédaction Pr François Paille Rédacteur en chef Pr Amine Benyamina Rédacteurs associés Dr Philippe Batel Dr Ivan Berlin Dr Laurent Karila Pr Michel Lejoyeux Pr Mickaël Naassila Rédactrice Sciences humaines Pr Myriam Tsikounas Rédactrice Sciences psychologiques Pr Isabelle Varescon-Pousson Comité de rédaction Pr Georges Brousse Pr Olivier Cottencin Dr Michel Craplet Pr Jean-Bernard Daeppen Dr Jean-Michel Delile Pr Maurice Dematteis Dr Claudine Gillet th Dr Geneviève Lafaye 17 European Society for Biomedical Research Pr Michel Reynaud Dr Alain Rigaud Dr Marc Valleur on Alcoholism Congress Directeur de la publication Pr Mickael Naassila 21-24 September 2019, Lille Comité scientifique Pr Jean Adès Pr Thomas F. Babor Pr Jean-Louis Balmès Pr Maurice Bazot Dr Mats Berglund Pr Jacques Besson Pr Jean-Pierre Blayac Pr Jonathan D. Chick Mme Marie Choquet Pr Philippe de Witte Pr Michel Escande Pr Claude Got Dr Antoni Gual Pr Momar Gueye Pr Roger Henrion Pr Denise Kandel Pr Michel Le Moal Pr Karl Mann Mme Véronique Nahoum-Grappe Dr José Maria Neves Cardoso Pr Philippe-Jean Parquet Pr Jean-Louis Pedinielli Pr Falvio Poldrugo Pr Bernard Roques Pr John A. Talbott Pr Jean-Luc Vénisse Pr Lars von Knorring Pr Jacques Weill Pr Jean-Jacques Yvorel ISSN 2554-4853 Trimestriel Société Française PRINCEPS Éditions SEPTEMBRE-DÉCEMBRE 2019 - Tome 41, n° 3-4 d’Alcoologie !BSTRACTS CONGRÈS Pr Mickael Naassila* * President 17th ESBRA Meeting 17th European Society for Biomedical Research on Alcoholism congress 21-24 September 2019, Lille – Invited talks and Symposia abstracts Invited talks forward, such as combining training with neurostimulation. Together these fndings emphasize the malleability of the addicted brain and the promise of targeted CT in the treat- Targeting biased decision making in the treatment ment of AUD. of alcohol use disorders Reinout Wiers (Amsterdam, The Netherlands) ASH-NASH synergism and its underlying mechanisms Alcohol Use Disorder (AUD) and other addictions have been Hidekazu Tsukamoto (Los Angeles, USA) characterized as a chronic brain disease from the biomedical perspective and as the unfortunate outcome of adverse social Alcohol misuse and obesity are two leading independent risk conditions from the social science perspective. We emphasize factors for alcoholic and non-alcoholic steatohepatitis (ASH biased decision making as a central characteristic in (alcohol) and NASH) around the globe. Synergistic interactions by addiction. From a therapeutic perspective, the important these factors have also increasingly been recognized. In fact, question is to what extent these biases reverse after successful the emerging evidence indicates the average BMI of some abstinence, and to what extent they can be reversed through ASH patient populations in the US may be around 30. ASH targeted training. Two types of Cognitive Training (CT) and alcoholic cirrhosis occur as the consequences of alco- can be distinguished: those in which general abilities are hol addiction which dictates heavy drinking and sustained trained (e.g., working memory training) and those in which blood alcohol levels (BAL) due to physical dependence. Tis initial motivational reactions to alcohol are targeted, so called condition can be reproduced in rodents by intragastric fee- cognitive biases (Cognitive Bias Modifcation, CBM, Wiers ding of ethanol diet which also allows precise reproduction 2018). I will review the state of afairs in both. Training of of the synergism between sustained BAL and overfeeding- general abilities takes a long time, but does show promise for induced obesity. Tis model exhibits heightened steatohepa- a subgroup of patients. CBM has shown to increase one-year titis, M1 macrophage activation, nitrosative stress driven by abstinence in several large clinical trials, with efect sizes Notch-dependent mitochondrial metabolic reprogramming. similar to medication for alcohol (NNT=12). It is also beco- Moderate alcohol intake may also synergistically work with ming clear for which individuals CBM shows most promise NASH to promote liver cancer development. Evidence sug- as an add-on treatment (those with a strong cue-reactivity gests social drinking is sufcient enough to promote live can- and/or impulsivity), and we are beginning to understand cer incidence in NASH-cirrhosis patients. Tis synergism is the neurocognitive mechanisms underlying training efects reproduced in mice injected with the hepatocarcinogen DEN (e.g., reduced cue-reactivity). CT shows modest but reliable and fed alcohol-containing Western diet. Tumor promotion efects as add-on to regular psychosocial treatment, but does in this model is dependent on activation of hepatic stellate not appear to work in the absence of psychosocial treatment, cells (HSC) driven by Wnt--catenin-mediated overexpres- nor in the absence of motivation to change (e.g. in proof- sion of stearoyl-CoA-desaturase (SCD), which in turn esta- of-principle studies in students). Finally, I will sketch ways blishes a SCD-LRP5/6-Wnt positive loop to amplify Wnt- Alcoologie et Addictologie. 2019 ; 41 (3) : 232-282 232 Congress -catenin pathway in HSC and tumor microenvironment, etheno DNA-adducts and the severity of fbrosis. First results leading to tumor-promoting lipid metabolic reprogramming. of the efect of CYP2E1 inhibition by chlormethiazole, a Tese fndings highlight the causal roles of morphogen- specifc CYP2E1 inhibitor on ALD can be expected soon. driven metabolic reprogramming in steatohepatitis and liver tumor development promoted by ASH-NASH synergism. Young investigator symposium Applying precision medicine to alcohol and drug use disorders Henry R Kranzler1 (1 Philadelphia, USA) Nicotine increases alcohol self-administration via µ-opioid receptor activity in the ventral tegmental Although most medications approved to treat alcohol use area disorder (AUD) and opioid use disorder (OUD) have been E. Domi1, A. Hansson2, P. Marvin2, E.Barbier1, Xu Li1, E. Augier1, shown to be efcacious in placebo-controlled trials, efect M. Heilig1 (1 Linkoping, Sweden, 2 Mannheim, Germany) sizes vary among them. Even medications with the largest efect sizes, however, are not efcacious for all (or perhaps Alcohol and nicotine are the most commonly co-abused even most) patients treated with them. Recent eforts to en- drugs, with a large majority of alcoholics diagnosed with a hance the therapeutic efects of these medications have used comorbid addiction to nicotine. Te endogenous opioid sys- a precision medicine approach, including the use of pharma- tem is involved in the rewarding properties of both alcohol cogenetics (PGx) to identify genetic predictors of treatment and nicotine. We previously found that CERC-501, a highly response. Tis lecture will discuss recent developments in the selective KOR antagonist reduced escalated alcohol self-ad- PGx of AUD and OUD. Specifc topics to be covered are: ministration induced by the intermittent access to alcohol 1) a variant in the mu-opioid receptor gene (OPRM1) and 20%. In here we tested the efect of CERC-501 on escalation response to naltrexone treatment of AUD, 2) a variant in the of alcohol drinking induced by nicotine. Chronic nicotine eli- kainate receptor gene and response to topiramate treatment cited a robust and specifc escalation of alcohol drinking wit- of AUD, 3) a variant near OPRM1 and usual methadone hout afecting saccharin self-administration and locomotion. dose for treating OUD, and 4) a variant in the delta-opioid CERC-501 did not suppress nicotine-induced increased alco- receptor gene (OPRD1) and response to buprenorphine hol self-administration in opposite to naltrexone which bloc- treatment of OUD. Findings from these studies underscore ked escalated drinking. Our in situ hybridization data showed the potential utility of a precision medicine approach to trea- a diferent pattern of expression and functional activation of ting alcohol and drug use disorders and some of the obstacles MORs in alcohol escalation induced by nicotine, while KORs to be overcome in advancing the feld. expression and activity was not afected by the combination The role of CYP2E1 in alcoholic liver disease and of the two drugs. Specifcally, our data showed an increased expression and a decreased function of MORs in the ventral alcohol mediated carcinogenesis 1 1 1 tegmental area of alcohol-escalated rats. Nicotine induced Helmut K. Seitz , Sebastian Mueller ( Heidelberg, Germany) escalation of alcohol self-administration was also accompa- nied by decreased p-DARPP32 in nucleus accumbens shell. Various factors are involved in the pathogenesis of alcoholic Tis suggest that nicotine pretreatment reduces the rewarding liver disease (ALD) and ethanol mediated carcinogenesis. In value of alcohol and therefore mediates alcohol escalation. addition to genetic, epigenetic and immunologic mechanisms, In conclusion our results also suggest that targeting µ rather acetaldehyde associated toxicity, oxidative stress as well as than −opioid receptors may represent a promising phar- cytokine mediated infammation are of major importance. macotherapeutic approach for the treatment of alcohol use Oxidative stress with the generation of reactive oxygen spe- disorders where alcohol consumption is driven by nicotine. cies (ROS) develops either in infammation (alcoholic hepa- titis) or during oxidation of ethanol via cytochrome P4502E1 Unveiling the alcohol-dependent alterations of (CYP2E1). CYP2E1 is induced by ethanol, oxidizes ethanol local translation in