PL1FOUR DECADES OF RESEARCH ON THE LEVEL OF RESPONSE TO ALCOHOL AS A RISK FACTOR FOR ALCOHOLISM: FROM IDEA TO PREVENTIONPL2A NEW GENETIC SUBTYPE OF ALCOHOLISM: PRE-CLINICAL AND CLINICAL DATA LEADING TO PERSONALIZED TREATMENT AND NEW TREATMENT GOALSPL3ALCOHOL AND CANCERPL4GLUTAMATE, WHAT ELSE?

This lecture reviews research that began in 1973 regarding the low level of response to alcohol (low LR) as a risk factor for heavy drinking. Subsequent efforts refined the idea, tested the hypothesis cross-sectionally, evaluated whether the phenotype predicted heavy drinking and alcohol problems, researched how LR contributed to alcoholism, and began testing ways to use these data to decrease adverse alcohol outcomes. Each step led to redefining the idea, and to new and previously unrecognized ways to take the research on a different tack. The results revealed that LR can be measured reliably as a low response at a given BAC or as a self-report of the number of drinks usually needed for effects, with both measures predicting heavy drinking and alcohol problems. Family and twin studies demonstrated a ∼ 50% heritability for LR, while human and animal studies identified a range of genes that contribute to the low alcohol response. Prospective investigations in the U.S. and U.K. revealed environmental and attitudinal characteristics that partially mediate how LR contributes to adverse alcohol outcomes. Recent functional brain imaging studies revealed a general neurocognitive inefficiency in information processing that may form the basis of how LR operates. These steps led to a prevention protocol where young subjects with a low LR are taught about their risk and offered advice on how to decrease their drinking, with promising results. The process was not always linear, and the ups and downs of the work over the years required persistence and many rewarding collaborations. # PL2 A NEW GENETIC SUBTYPE OF ALCOHOLISM: PRE-CLINICAL AND CLINICAL DATA LEADING TO PERSONALIZED TREATMENT AND NEW TREATMENT GOALS {#article-title-2} Ethanol is a drug with multiple pharmacological effects that make it desirable and often taken to excess. One important effect is the activation of the endogenous opioid system, an effect discovered conclusively in animal models and clinical trials in the 1980s. The importance of this effect was demonstrated by studies showing that blocking opioid receptors prevents Dopamine release in the reward system. Humans report decreased pleasure from alcohol while on naltrexone and drinking is decreased in both animals and humans. This treatment benefit is most prominent in individuals with a family history of alcoholism. An allelic variant in the human µ opioid receptor gene was associated with a dramatic response to naltrexone treatment. Genetic “Knock-in” studies showed that the allele produced increased dopamine response to alcohol in mice and increased alcohol preference compared to mice with the standard human gene. PET studies in humans show that those with the allele show an enhanced ventral striatal dopamine response to specific blood alcohol levels compared to humans carrying the standard allele. Recent European clinical trials also reported decreased heavy drinking after treatment with nalmefene, another opioid receptor antagonist. Prospective studies are currently underway to determine whether selection of treatment for alcoholic patients based on opioid receptor genotype improves results. If successful, this would be the first example of personalized medicine in psychiatry. # PL3 ALCOHOL AND CANCER {#article-title-3} Approximately 3.6% of all cancers worldwide derive from chronic alcohol drinking. Alcohol is a risk factor for cancers of upper aerodigestive tract, the liver, the colorectum and the breast. Although the mechanisms for alcohol associated carcinogenesis are not completely understood, most recent research has focused on acetaldehyde (AA). AA binds to proteins with morphologic and functional damage, generate neoantigens, and to DNA producing carcinogenic DNA-adducts. The most important functions injured by AA are those involved in methyl transfer, anti-oxidative defense and DNA repair. Indeed, it has been shown that individuals who accumulate AA after drinking have an increased risk for various cancers. These are individuals polymorphic for the AA-dehydrogenase 2 (ALDH2) and alcohol-dehydrogenase 1C (ADH1C). In addition, most important in ethanol mediated carcinogenesis is oxidative stress. Most relevant is the induction of cytochrome P450 2E1 (CYP2E1) resulting in the production of reactive oxygen species (ROS) with lipid peroxidation and the occurrence of lipid peroxidation products such as 4-hydroxynonenal, which can bind to DNA forming carcinogenic etheno DNA-adducts. It has been shown in cell cultures, animal experiments and in liver and esophageal biopsies from humans that hepatic CYP2E1 correlates with these carcinogenic DNA lesions. In animals, inhibition of CYP2E1 results in a significant reduction of hepatic tumors after ethanol consumption. Other mechanisms in alcohol-mediated carcinogenesis include alterations of intracellular signal transduction, epigenetic changes and the interaction with retinoic acid metabolism. Alcohol related carcinogenesis may interact with other factors such as smoking, diet and comorbidities, and depends on genetic susceptibility. # PL4 GLUTAMATE, WHAT ELSE? {#article-title-4} The dopaminergic mesocorticolimbic system is strongly related to the addictive processes and particularly to the reward induced by psychoactive drugs. Nevertheless the reward induced by alcohol seems to be very low as compared to other drugs. Indeed the dopamine release remained low compared to cocaine, amphetamine or even nicotine. The ascending dopaminergic system is under the control of central neuro-amines like GABA and glutamate, which are able to sharply regulate the release of dopamine. It is now well agreed that a dysbalance between neuro-inhibitory and neuro-excitatory amino acids can be held responsible, at least for a large part, for the ethanol withdrawal symptoms leading to craving as well as relapse. The brain's most prevalent inhibitory transmitter substance is gamma-aminobutyric acid (GABA) and the most important excitatory transmitter is L-glutamate (GLU). While there is no clear evidence that ethanol alters extracellular GABA concentrations, a hypofunction of GABAA receptors was observed leading to an enhanced function of NMDA receptors and thus responsible to the increase in the behavioural susceptibility during ethanol withdrawal. This dysbalance between neuro-inhibitory and neuro-excitatory amino acids may be responsible for the seizures, anxiety, hyperexcitability and even neuronal death due to excitotoxicity. Since DA and GLU can be co-released in the mesocorticolimbic system, glutamate can thus exacerbate the reward induced by alcohol or even modify the cognition about alcohol by giving to alcohol false-information about the positive reward induced. Glutamate can thus be able to enhance the reward value of alcohol to a level, which is normally low considering dopamine release alone.