Search

Objective: Alcohol use disorder (AUD) constitutes a critical public health issue and has sex-specific characteristics. Initial evidence suggests that progesterone and estradiol might reduce or increase alcohol intake, respectively. However, there is a need for a better understanding of how the menstrual cycle in females and the ratio of progesterone to estradiol in females and males influence alcohol use patterns in individuals with AUD., Methods: In this sex-separated multicenter longitudinal study, the authors analyzed 12-month data on real-life alcohol use (from 21,460 smartphone entries), menstrual cycle, and serum progesterone-to-estradiol ratios (from 667 blood samples at four individual study visits) in 74 naturally cycling females and 278 males with AUD between 2020 and 2022, using generalized and general linear mixed modeling., Results: Menstrual cycle phases were significantly associated with binge drinking and progesterone-to-estradiol ratio. During the late luteal phase, females showed a lower predicted binge drinking probability of 13% and a higher predicted marginal mean of progesterone-to-estradiol ratio of 95 compared with during the menstrual, follicular, and ovulatory phases (binge drinking probability and odds ratios vs. late luteal phase, respectively: 17%, odds ratio=1.340, 95% CI=1.031, 1.742; 19%, odds ratio=1.523, 95% CI=1.190, 1.949; and 20%, odds ratio=1.683, 95% CI=1.285, 2.206; difference in progesterone-to-estradiol ratios, respectively: -61, 95% CI=-105.492, -16.095; -78, 95% CI=-119.322, -37.039; and -71, 95% CI=-114.568, -27.534). In males, a higher progesterone-to-estradiol ratio was related to lower probabilities of binge drinking and of any alcohol use, with a 10-unit increase in the hormone ratio resulting in odds ratios of 0.918 (95% CI=0.843, 0.999) and 0.914 (95% CI=0.845, 0.988), respectively., Conclusions: These ecologically valid findings suggest that high progesterone-to-estradiol ratios can have a protective effect against problematic alcohol use in females and males with AUD, highlighting the progesterone-to-estradiol ratio as a promising treatment target. Moreover, the results indicate that females with AUD may benefit from menstrual cycle phase-tailored treatments.

Background: Alcohol consumption is a leading cause of morbidity and mortality worldwide, disproportionately affecting young men. Heavy episodic drinking is particularly prevalent among men, with this behavior peaking between the ages of 20 and 24., Aims: We sought to identify dimensions of decision-making in men that would predict the development of hazardous alcohol use through emerging adulthood., Methods: This prospective observational study profiled value-based decision-making in 198 healthy men at age 18 and assessed their alcohol involvement annually until age 24. Latent growth curve modeling estimated individual variability in trajectories of alcohol involvement and regressed this variability on five choice dimensions., Results: Low loss aversion predicted sustained heavy episodic drinking from age 18 to 24. Both high delay discounting and risk-seeking for gains independently predicted a considerably higher cumulative alcohol use during these 6 years, with high delay discounting indicating escalating consumption from age 21. Risk-seeking for gains additionally predicted meeting more criteria for Alcohol Use Disorder in these 6 years. Risk-seeking for losses was not significantly related to alcohol outcomes. Choice preferences were largely independent of each other but were correlated with choice consistency, with low consistency predicting heavy episodic drinking from age 18 to 24 beyond these associations., Conclusions: The predictive effects collectively suggest that overvaluing immediate and probabilistic incentives, rather than underestimating harm, drives hazardous drinking in young men. The differential relations of choice preferences and consistency to alcohol involvement through emerging adulthood provide distinct cognitive-behavioral patterns that warrant consideration in the development of harm reduction interventions., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

High adolescent alcohol consumption is predictive for alcohol problems later in life. To tailor interventions, early identification of risk groups for adolescent alcohol consumption is important. The IMAGEN dataset was utilized to investigate predictors for problematic alcohol consumption at age 18-20 years as a function self and parental personality and drug-related measures as well as life-events and cognitive variables all assessed at age 14 years (N = 1404). For this purpose the binary partitioning algorithm ctree was used in an explorative analysis. The algorithm recursively selects significant input variables and splits the outcome variable based on these, yielding a conditional inference tree. Four significant split variables, namely Place of residence, the Disorganization subscale of the Temperament and Character Inventory, Sex, and the Sexuality subscale of the life-events questionnaire were found to distinguish between adolescents scoring high or low on the Alcohol Use Disorders Identification Test about five years later (all p < 0.001). The analyis adds to the literature on predictors of adolescent drinking problems using a large European sample. The identified split variables could easily be collected in community samples. If their validity is proven in independent samples, they could facilitate intervention studies in the field of adolescent alcohol prevention., (Copyright © 2019. Published by Elsevier Ltd.)

Alcohol consumption during adolescence might impede normal brain development, while more excessive drinking during this period poses a risk for developing alcohol use disorder. Here it was tested whether nucleus accumbens (NAcc) resting-state functional connectivity could be associated with lifetime drinking behavior in young adults, and whether it could predict their alcohol consumption during a one-year follow-up period. The current investigation was part of the bicentric Learning and Alcohol Dependence (LeAD) population-based prospective cohort study. One hundred and eighty-four 18-year-old male social drinking volunteers without a lifetime diagnosis of psychotic, bipolar, or alcohol use disorder were recruited from the general population. Seed-based resting-state functional connectivity was calculated for the bilateral NAcc in each participant. Across the group, the association between NAcc functional connectivity and lifetime alcohol consumption was assessed (p < .05, whole-brain FWE-corrected). Individual connectivity values were then extracted from regions that demonstrated a significant association to predict drinking behavior during a one-year follow-up period (n = 143), correcting for lifetime alcohol consumption. Weaker connectivity between the left NAcc and bilateral dorsolateral prefrontal cortex, inferior frontal gyrus, left caudate nucleus, left putamen, and left insula was associated with greater lifetime alcohol consumption, as well as with greater alcohol consumption during the one-year follow-up period. Our findings underscore the relevance of fronto-striatal connectivity to the field of alcohol research. Impaired prefrontal cognitive control might mediate excessive drinking behavior and may prove a promising biomarker for risk of future alcohol (ab)use., (Copyright © 2019. Published by Elsevier B.V.)

Objective: Substance use patterns and sociodemographic variables of Berlin's party scene were investigated to derive preventive measures and harm reduction services, which meet the needs of the consumers., Methods: A questionnaire was used online and in the field among Berlin partygoers (N = 877) and structured interviews (N = 20) were conducted with professionals working in this area, including social workers, emergency medical service, police and club owners and users., Results: A risky consumption pattern was found in 67 % of participants, who also stated need for counseling and a wish for reduction of their substance use. Of all preventive measures, drug checking was requested most often. Substances with the highest prevalence were alcohol, cannabis, amphetamine, MDMA, cocaine and ketamine, whereas methamphetamine and new psychoactive substances were barely stated., Conclusion: There is an urgent need to expand current preventive measures. There is a willingness of the scene to use according services, especially by those who need it the most., Competing Interests: Die Autoren geben an, dass kein Interessenkonflikt besteht. PD Dr. med. Stephan Köhler ist Teilnehmer des Charité Clinical Scientist Programms, finanziert durch die Charité – Universitätsmedizin Berlin und Berlin Institute of Health., (© Georg Thieme Verlag KG Stuttgart · New York.)

Alcohol abuse is a major public health problem worldwide. Understanding the molecular mechanisms that control regular drinking may help to reduce hazards of alcohol consumption. While immunological mechanisms have been related to alcohol drinking, most studies reported changes in immune function that are secondary to alcohol use. In this report, we analyse how the gene "TRAF family member-associated NF-κB activator" (TANK) affects alcohol drinking behavior. Based on our recent discovery in a large GWAS dataset that suggested an association of TANK, SNP rs197273, with alcohol drinking, we report that SNP rs197273 in TANK is associated both with gene expression (P = 1.16 × 10-19) and regional methylation (P = 5.90 × 10-25). A tank knock out mouse model suggests a role of TANK in alcohol drinking, anxiety-related behavior, as well as alcohol exposure induced activation of insular cortex NF-κB. Functional and structural neuroimaging studies among up to 1896 adolescents reveal that TANK is involved in the control of brain activity in areas of aversive interoceptive processing, including the insular cortex, but not in areas related to reinforcement, reward processing or impulsiveness. Our findings suggest that the cortical neuroimmune regulator TANK is associated with enhanced aversive emotional processing that better protects from the establishment of alcohol drinking behavior., (© The Author(s) 2019. Published by Oxford University Press.)

Objective: Psychosocial stress is a key risk factor for substance abuse among adolescents. Recently, epigenetic processes such as DNA methylation have emerged as potential mechanisms that could mediate this relationship. The authors conducted a genome-wide methylation analysis to investigate whether differentially methylated regions are associated with psychosocial stress in an adolescent population., Methods: A methylome-wide analysis of differentially methylated regions was used to examine a sample of 1,287 14-year-old adolescents (50.7% of them female) from the European IMAGEN study. The Illumina 450k array was used to assess DNA methylation, pyrosequencing was used for technical replication, and linear regression analyses were used to identify associations with psychosocial stress and substance use (alcohol and tobacco). Findings were replicated by pyrosequencing a test sample of 413 participants from the IMAGEN study., Results: Hypermethylation in the sterile alpha motif/pointed domain containing the ETS transcription factor (SPDEF) gene locus was associated with a greater number of stressful life events in an allele-dependent way. Among individuals with the minor G-allele, SPDEF methylation moderated the association between psychosocial stress and substance abuse. SPDEF methylation interacted with lifetime stress in gray matter volume in the right cuneus, which in turn was associated with the frequency of alcohol and tobacco use. SPDEF was involved in the regulation of trans-genes linked to substance use., Conclusions: Taken together, the study findings describe a novel epigenetic mechanism that helps explain how psychosocial stress exposure influences adolescent substance abuse.

Alcohol metabolizing enzymes, such as the alcohol dehydrogenases and the aldehyde dehydrogenases, regulate the levels of acetaldehyde in the blood and play an important role in the development and maintenance of alcohol addiction. Recent genome-wide systematic searches found associations between a single nucleotide polymorphism (rs1789891, risk allele: A, protective allele: C) in the alcohol dehydrogenase gene cluster and the risk of alcohol dependence. The current study investigated the effect of this single nucleotide polymorphism on alcohol consumption, craving for alcohol, relapse risk and brain gray matter volume. Alcohol-dependent patients (n = 74) and controls (n = 43) were screened, genotyped and underwent magnetic resonance imaging scanning, and relapse data were collected during 3 months following the experiment. Alcohol-dependent A allele carriers reported increased alcohol craving and higher alcohol consumption compared with the group of alcohol-dependent individuals homozygous for the C allele, which displayed craving values similar to the control group. Further, follow-up data indicated that A allele carriers relapsed earlier to heavy drinking compared with individuals with two C alleles. Analyses of gray matter volume indicated a significant genotype difference in the patient group: individuals with two C alleles had reduced gray matter volume in the left and right superior, middle and inferior temporal gyri. Findings of the current study further support the relevance of genetic variants in alcohol metabolizing enzymes to addictive behavior, brain tissue volume and relapse risk. Genotype-dependent differences in acetaldehyde formation, implicated by earlier studies, might be the biological substrate of the genotype differences., (© 2017 Society for the Study of Addiction.)

Regular alcohol consumption affects cognitive performance and the development of dementia. So far, findings are contradicting, which might be explained in part by dose-related effects. For this narrative review, we undertook a literature search for surveys investigating the impact of alcohol consumption on cognitive performance and the development of dementia. The majority of studies observed a U-shaped relationship between regular alcohol consumption and cognitive function: frequent heavy consumption of alcohol alters brain functions and decreases cognitive performance; regular light and moderate consumption may have protective impact. In many studies, total abstainers show an inferior cognitive performance than people with moderate or light consumption. Nevertheless, policy implications are difficult to draw for at least 2 reasons: (1) the possible risks associated with alcohol consumption and (2) the potential confounders in the group of non-consumers and heavy consumers., Competing Interests: The authors declare no conflict of interest., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: Alcohol consumption is pivotal for the subsequent development of alcohol use disorders (AUD). The Alcohol Use Disorders Identification Test (AUDIT) is a recommended AUD screening tool for prevention and primary care settings. The objectives of this study were to test how many participants with heavy drinking are unidentified by the AUDIT, if proportions of unidentified participants vary over time, and whether this unidentified risk group (URG) was clinically relevant in terms of drinking behavior reports and AUD risk factors, as well as future adverse outcomes, such as craving, dependence symptoms, or depression., Methods: Our prospective cohort study followed 164 German males aged 18-19years without an alcohol dependence diagnosis over 24months. Only men were included due to higher AUD prevalence and gender-specific differences in metabolism, drinking patterns, and progression to AUD. All participants were screened via telephone interview and answered questionnaires both in person and via internet. Heavy drinking was classified using the AUDIT consumption score (AUDIT-C≥4.50). Standardized AUD diagnoses and symptoms, as well as alcohol use-related outcome criteria were assessed via standardized Composite International Diagnostic Interview (CIDI), and self-report questionnaires., Results: One in four participants (22-28% across all four follow-ups) reported heavy drinking but was unidentified by AUDIT total score (i.e. score<8), thus qualifying for URG status. The URG status did not fluctuate considerably across follow-ups (repeated-measures ANOVA, p=0.293). URG participants identified at the six-month follow-up did not generally differ from participants without URG status in terms of AUD family history or temperament (multivariate ANOVA, p=0.114), except for anxiety sensitivity (p Bonferroni <0.001). After two years, URG participants reported a similar level of adverse outcomes compared to low-risk participants (multivariate ANOVA, p=0.438), but less alcohol-related problems and less loss of control due to craving compared to high-risk participants (p Bonferroni ≤0.007)., Conclusions: Despite the considerable number of heavy-drinking individuals unidentified by AUDIT total scores, an additional classification according to AUDIT-C values did not prove useful. Combining AUDIT and AUDIT-C scores might not be sufficient for identifying AUD risk groups among young adult German males. There is an urgent need for a replication of our findings among female participants., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Randomized trials of medications for alcohol dependence (AD) often report no differences between active medications. Few studies in AD have tested hypotheses regarding which medication will work best for which patients (ie, precision medicine). The PREDICT study tested acamprosate and naltrexone vs placebo in 426 randomly assigned AD patients in a 3-month treatment. PREDICT proposed individuals whose drinking was driven by positive reinforcement (ie, reward drinkers) would have a better treatment response to naltrexone, whereas individuals whose drinking was driven by negative reinforcement (ie, relief drinkers) would have a better treatment response to acamprosate. The goal of the current analysis was to test this precision medicine hypothesis of the PREDICT study via analyses of subgroups. Results indicated that four phenotypes could be derived using the Inventory of Drinking Situations, a 30-item self-report questionnaire. These were high reward/high relief, high reward/low relief, low reward/high relief, and low reward/low relief phenotypes. Construct validation analyses provided strong support for the validity of these phenotypes. The subgroup of individuals who were predominantly reward drinkers and received naltrexone vs placebo had an 83% reduction in the likelihood of any heavy drinking (large effect size). Cutoff analyses were done for clinical applicability: individuals are reward drinkers and respond to naltrexone if their reward score was higher than their relief score AND their reward score was between 12 and 31. Using naltrexone with individuals who are predominantly reward drinkers produces significantly higher effect sizes than prescribing the medication to a more heterogeneous sample.

Alcohol dependence is a mental disorder that has been associated with an imbalance in behavioral control favoring model-free habitual over model-based goal-directed strategies. It is as yet unknown, however, whether such an imbalance reflects a predisposing vulnerability or results as a consequence of repeated and/or excessive alcohol exposure. We, therefore, examined the association of alcohol consumption with model-based goal-directed and model-free habitual control in 188 18-year-old social drinkers in a two-step sequential decision-making task while undergoing functional magnetic resonance imaging before prolonged alcohol misuse could have led to severe neurobiological adaptations. Behaviorally, participants showed a mixture of model-free and model-based decision-making as observed previously. Measures of impulsivity were positively related to alcohol consumption. In contrast, neither model-free nor model-based decision weights nor the trade-off between them were associated with alcohol consumption. There were also no significant associations between alcohol consumption and neural correlates of model-free or model-based decision quantities in either ventral striatum or ventromedial prefrontal cortex. Exploratory whole-brain functional magnetic resonance imaging analyses with a lenient threshold revealed early onset of drinking to be associated with an enhanced representation of model-free reward prediction errors in the posterior putamen. These results suggest that an imbalance between model-based goal-directed and model-free habitual control might rather not be a trait marker of alcohol intake per se., (© 2017 Society for the Study of Addiction.)

Background: Impulsive decision making relates to problematic substance use. Specifically, altered delay discounting (DD) has been suggested as a behavioral marker for addiction, while other relevant facets of choice impulsivity such as probability discounting (PD) or loss aversion are clearly understudied., Methods: Two studies were performed collecting behavioral data on choice impulsivity with a value-based decision-making battery providing estimates of DD, PD for gains and losses, and loss aversion. Study (1): In a sample of 198 male 18-year-old social drinkers, we analyzed impulsive choice behavior and its association with alcohol consumption and self-report measures of substance use-related personality traits on a cross-sectional level. Additionally, the predictive value of baseline choice behavior for the trajectories of alcohol consumption over a 12-month follow-up period was evaluated. Study (2): Behavioral data on choice impulsivity were collected for 114 detoxified patients with alcohol use disorder (AUD) and 98 control participants. We analyzed group differences at baseline and assessed the predictive value of choice impulsivity for relapse to heavy alcohol use in patients during a follow-up period of 48 weeks., Results: Study (1): Only DD was associated with baseline alcohol use, but no measure of choice impulsivity predicted the drinking trajectories over the following 12 months. Study (2): Compared to the control group, AUD patients showed higher DD, lower risk aversion regarding probabilistic gains, lower risk seeking regarding probabilistic losses, and lower loss aversion facing mixed prospects. Further, shallow discounting of probabilistic losses at baseline was predictive for relapse in patients., Conclusions: All 4 domains of impulsive decision making were considerably altered in AUD patients though mostly not related to alcohol use in young adult social drinkers. This suggests that these facets of impulsive behavior may develop as consequences of chronic alcohol consumption. Furthermore, discounting of probabilistic losses might prove valuable in identifying patients vulnerable for relapse., (Copyright © 2017 by the Research Society on Alcoholism.)

Based on the knowledge that alcohol misuse causes a multitude of diseases and increased mortality, this systematic review examines whether a reduction of the individual alcohol consumption can contribute to a minimization of health risks within a harm reduction approach. In fact, the reviewed 63 studies indicate that interventions aiming at alcohol reduction (including total abstinence as one possible therapeutic aim) indeed resulted in or were associated with positive effects in harmful, hazardous or alcohol-dependent drinkers. Major benefits were observed for reducing alcohol-associated injuries, recovery of ventricular heart function in alcoholic cardiomyopathy, blood pressure lowering, normalization of biochemical parameter, body weight reduction, histological improvement in pre-cirrhotic alcohol-related liver disease and slowed progression of an already existing alcohol-attributable liver fibrosis. Furthermore, reduced withdrawal symptoms, prevalence of psychiatric episodes and duration of in-patient hospital days, improvement of anxiety and depression symptoms, self-confidence, physical and mental quality of life, fewer alcohol-related adverse consequences as well as lower psychosocial stress levels and better social functioning can result from reduced alcohol intake. The reviewed literature demonstrated remarkable socioeconomic cost benefits in areas such as the medical health-care system or workforce productivity. Individuals with heightened vulnerability further benefit significantly from alcohol reduction (e.g. hypertension, hepatitis C, psychiatric co-morbidities, pregnancy, but also among adolescents and young adults). Concluding, the reviewed studies strongly support and emphasize the importance and benefits of early initial screening for problematic alcohol use followed by brief and other interventions in first contact medical health-care facilities to reduce alcohol intake., (© 2016 Society for the Study of Addiction.)

Adolescence is a time that can set the course of alcohol abuse later in life. Sensitivity to reward on multiple levels is a major factor in this development. We examined 736 adolescents from the IMAGEN longitudinal study for alcohol drinking during early (mean age=14.37) and again later (mean age=16.45) adolescence. Conducting structural equation modeling we evaluated the contribution of reward-related personality traits, behavior, brain responses and candidate genes. Personality seems to be most important in explaining alcohol drinking in early adolescence. However, genetic variations in ANKK1 (rs1800497) and HOMER1 (rs7713917) play an equal role in predicting alcohol drinking two years later and are most important in predicting the increase in alcohol consumption. We hypothesize that the initiation of alcohol use may be driven more strongly by personality while the transition to increased alcohol use is more genetically influenced., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Adolescence is a common time for initiation of alcohol use and alcohol use disorders. Importantly, the neuro-anatomical foundation for later alcohol-related problems may already manifest pre-natally, particularly due to smoking and alcohol consumption during pregnancy. In this context, cortical gyrification is an interesting marker of neuronal development but has not been investigated as a risk factor for adolescent alcohol use. On magnetic resonance imaging scans of 595 14-year-old adolescents from the IMAGEN sample, we computed whole-brain mean curvature indices to predict change in alcohol-related problems over the following 2 years. Change of alcohol use-related problems was significantly predicted from mean curvature in left orbitofrontal cortex (OFC). Less gyrification of OFC was associated with an increase in alcohol use-related problems over the next 2 years. Moreover, lower gyrification in left OFC was related to pre-natal alcohol exposure, whereas maternal smoking during pregnancy had no effect. Current alcohol use-related problems of the biological mother had no effect on offsprings' OFC gyrification or drinking behaviour. The data support the idea that alcohol consumption during pregnancy mediates the development of neuro-anatomical phenotypes, which in turn constitute a risk factor for increasing problems due to alcohol consumption in a vulnerable stage of life. Maternal smoking during pregnancy or current maternal alcohol/nicotine consumption had no significant effect. The OFC mediates behaviours known to be disturbed in addiction, namely impulse control and reward processing. The results stress the importance of pre-natal alcohol exposure for later increases in alcohol use-related problems, mediated by structural brain characteristics., (© 2015 Society for the Study of Addiction.)

Background: The maintenance of harmful alcohol use can be considered a reiterated decision in favour of alcohol in concrete drinking occasions. These decisions are often made despite an intention to quit or reduce alcohol consumption. We tested if a hyperactive reward system and/or an impaired cognitive control system contribute to such unfavourable decision-making., Methods: In this fMRI study, men with modest to harmful drinking behaviour, which was measured using the Alcohol Use Disorders Identification Test (AUDIT), repeatedly made decisions between alcoholic and nonalcoholic drinks. Based on prior individual ratings, decision pairs were created with an alcoholic decision option considered more desirable but less beneficial by the participant. By correlating AUDIT scores with brain activation during decision-making, we determined areas explicitly related to pro-alcohol decisions in men with greater drinking severity., Results: Thirty-eight men participated in our study. Behaviourally, we found a positive correlation between AUDIT scores and the number of decisions for desired alcoholic drinks compared with beneficial nonalcoholic drinks. The fMRI results show that AUDIT scores were positively associated with activation in areas associated with reward and motivation processing (i.e., ventral striatum, amygdala, medial prefrontal cortex) during decisions favouring a desired, nonbeneficial alcoholic drink. Conversely, we did not find hypoactivation in areas associated with self-control (dorsolateral prefrontal cortex). These effects were not present when participants chose a desired, nonbenefical, nonalcoholic drink., Limitations: The men participating in our study had to be abstinent and would potentially consume an alcoholic drink at the end of the experiment. Hence, we did not define manifest alcohol dependence as an inclusion criterion and instead focused on less severely affected individuals., Conclusion: Our results indicate that with growing drinking severity, decisions for alcoholic drinks are associated with increasing activity in reward-associated neural systems, rather than decreasing activity in self-control-associated systems.

Alcohol abuse is highly prevalent, but little is understood about the molecular causes. Here, we report that Ras suppressor 1 (Rsu1) affects ethanol consumption in flies and humans. Drosophila lacking Rsu1 show reduced sensitivity to ethanol-induced sedation. We show that Rsu1 is required in the adult nervous system for normal sensitivity and that it acts downstream of the integrin cell adhesion molecule and upstream of the Ras-related C3 botulinum toxin substrate 1 (Rac1) GTPase to regulate the actin cytoskeleton. In an ethanol preference assay, global loss of Rsu1 causes high naïve preference. In contrast, flies lacking Rsu1 only in the mushroom bodies of the brain show normal naïve preference but then fail to acquire ethanol preference like normal flies. Rsu1 is, thus, required in distinct neurons to modulate naïve and acquired ethanol preference. In humans, we find that polymorphisms in RSU1 are associated with brain activation in the ventral striatum during reward anticipation in adolescents and alcohol consumption in both adolescents and adults. Together, these data suggest a conserved role for integrin/Rsu1/Rac1/actin signaling in modulating reward-related phenotypes, including ethanol consumption, across phyla.

Previous research on alcohol dependent patients has shown that variations in eyeblink startle response can be used as an indicator of their emotional responses to alcohol-related stimuli. Postulating that reactions on substance associated stimuli are controlled by either a negative or a positive affective processing system, we expect that abstinent alcoholics react differently (within-group) in the emotional evaluation of alcohol cues. Furthermore, we assumed the startle response to covary with medication response to acamprosate and naltrexone. We measured 74 detoxified inpatients' acoustic startle responses while they were being presented with alcohol-related images as well as affectively negative, neutral, and positive pictures before they were randomized to pharmacotherapy. Group-mean startle peak amplitudes were lowest for alcohol-related cues. The relative startle response (alcohol cues set in relation to the other stimulus categories) did not correlate with craving for alcohol (OCDS) or alcohol cue induced self-ratings of arousal, valence and craving. Patients with a lower percentage of abstinent days in the 90 days prior to the last drinking day showed a lower ("more appetitive") startle response to alcohol cues. A survival analysis using the time to first heavy drinking day as the survival criterion revealed a significant interaction between alcohol-cue startle responses and medication type. The results indicate that the psycho-physiological measure of emotional evaluation of alcohol cues includes unconscious processing not reflected by conscious self-ratings. Furthermore, our result of a differential medication effect may encourage further studies to use biological characteristics to stratify patients as a step towards individualized treatment for alcohol dependence., (Copyright © 2014 Elsevier B.V. All rights reserved.)

A comprehensive account of the causes of alcohol misuse must accommodate individual differences in biology, psychology and environment, and must disentangle cause and effect. Animal models can demonstrate the effects of neurotoxic substances; however, they provide limited insight into the psycho-social and higher cognitive factors involved in the initiation of substance use and progression to misuse. One can search for pre-existing risk factors by testing for endophenotypic biomarkers in non-using relatives; however, these relatives may have personality or neural resilience factors that protect them from developing dependence. A longitudinal study has potential to identify predictors of adolescent substance misuse, particularly if it can incorporate a wide range of potential causal factors, both proximal and distal, and their influence on numerous social, psychological and biological mechanisms. Here we apply machine learning to a wide range of data from a large sample of adolescents (n = 692) to generate models of current and future adolescent alcohol misuse that incorporate brain structure and function, individual personality and cognitive differences, environmental factors (including gestational cigarette and alcohol exposure), life experiences, and candidate genes. These models were accurate and generalized to novel data, and point to life experiences, neurobiological differences and personality as important antecedents of binge drinking. By identifying the vulnerability factors underlying individual differences in alcohol misuse, these models shed light on the aetiology of alcohol misuse and suggest targets for prevention.

Background: Alcohol-related aggression and violence are a widespread cause of personal suffering with high socioeconomic costs. In 2011, nearly one in three violent acts in Germany was committed under the influence of alcohol (31.8%). The link between alcohol consumption and aggression is promoted by various interacting factors., Methods: In this review, based on a selective search for pertinent literature in PubMed, we analyze and summarize information from original articles, reviews, and book chapters about alcohol and aggression and discuss the neurobiological basis of aggressive behavior., Results: Aggression is promoted both by the cognitive deficits arising in connection with acute or chronic alcohol use and by prior experience of violence in particular situations where alcohol was drunk. Only a minority of persons who drink alcohol become aggressive. On the other hand, alcohol abuse and dependence together constitute the second most commonly diagnosed cause of suicide (15-43%). Current research indicates that the individual tendency toward alcohol-induced aggression depends not just on neurobiological factors, but also on personal expectations of the effects of alcohol, on prior experience of violent conflicts, and on the environmental conditions of early childhood, especially social exclusion and discrimination. Gene-environment interactions affecting the serotonergic and other neurotransmitter systems play an important role. Potential (but not yet adequately validated) therapeutic approaches involve reinforcing cognitive processes or pharmacologically modulating serotonergic neurotransmission (and other target processes)., Conclusion: Alcohol-related aggression has manifold social and neurobiological causes. Specific treatments must be tested in controlled trials.

Background: Different regions of the striatum may have distinct roles in acute intoxication, alcohol seeking, dependence, and withdrawal., Methods: The recent advances are reviewed and discussed in our understanding of the role of the dorsolateral striatum (DLS), dorsomedial striatum (DMS), and ventral striatum in behavioral responses to alcohol, including alcohol craving in abstinent alcoholics, and alcohol consumption and withdrawal in rat, mouse, and nonhuman primate models., Results: Reduced neuronal activity as well as dysfunctional connectivity between the ventral striatum and the dorsolateral prefrontal cortex is associated with alcohol craving and impairment of new learning processes in abstinent alcoholics. Within the DLS of mice and nonhuman primates withdrawn from alcohol after chronic exposure, glutamatergic transmission in striatal projection neurons is increased, while GABAergic transmission is decreased. Glutamatergic transmission in DMS projection neurons is also increased in ethanol withdrawn rats. Ex vivo or in vivo ethanol exposure and withdrawal causes a long-lasting increase in NR2B subunit-containing NMDA receptor activity in the DMS, contributing to ethanol drinking. Analyses of neuronal activation associated with alcohol withdrawal and site-directed lesions in mice implicate the rostroventral caudate putamen, a ventrolateral segment of the DMS, in genetically determined differences in risk for alcohol withdrawal involved in physical association of the multi-PDZ domain protein, MPDZ, with 5-HT(2C) receptors and/or NR2B., Conclusions: Alterations of dopaminergic, glutamatergic, and GABAergic signaling within different regions of the striatum by alcohol is critical for alcohol craving, consumption, dependence, and withdrawal in humans and animal models., (Copyright © 2011 by the Research Society on Alcoholism.)

Alcohol-related violence is a serious and common social problem. Moreover, violent behaviour is much more common in alcohol-dependent individuals. Animal experiments and human studies have provided insights into the acute effect of alcohol on aggressive behaviour and into common factors underlying acute and chronic alcohol intake and aggression. These studies have shown that environmental factors, such as early-life stress, interact with genetic variations in serotonin-related genes that affect serotonergic and GABAergic neurotransmission. This leads to increased amygdala activity and impaired prefrontal function that, together, predispose to both increased alcohol intake and impulsive aggression. In addition, acute and chronic alcohol intake can further impair executive control and thereby facilitate aggressive behaviour.

Context: Glutamatergic neurotransmission is implicated in alcohol-drinking behavior in animal models., Objective: To investigate whether genetic variations in glutamatergic neurotransmission genes, which are known to alter alcohol effects in rodents, contribute to the genetic basis of alcoholism in humans., Design: Association analysis of alcohol dependence and haplotype-tagging single nucleotide polymorphisms (SNPs) covering 10 glutamatergic genes. Resequencing of functional domains of these genes identified 204 SNPs. Haplotypes with a frequency of 5% or greater could be discriminated by 21 haplotype-tagging SNPs analyzed for association in 2 independent samples of alcohol-dependent adult patients and controls as well as adolescent trios., Setting: Four university medical centers in the south of Germany., Participants: One thousand three hundred thirty-seven patients and 1555 controls (study 1: 544 patients, 553 controls; study 2: 793 patients, 1002 controls). One hundred forty-four trios of 15-year-old adolescents assessed for risky drinking behavior., Main Outcome Measures: Genotype profiles for GLAST; N-methyl-d-aspartate-receptor subunits NR1, NR2A, and NR2B; MGLUR5; NNOS; PRKG2; CAMK4; the regulatory subunit of PI3K; and CREB were analyzed for association with alcohol dependence using multivariate statistical analysis. Risky adolescent drinking was tested using the transmission disequilibrium test., Results: Analysis of study 1 revealed that NR2A and MGLUR5 have the greatest relevance for human alcohol dependence among the genes selected with odds ratios of 2.35 and 1.69, respectively. Replication analysis in study 2 confirmed an association of alcohol dependence with NR2A (odds ratio, 2.01) but showed no association with MGLUR5. Combined analysis of study 1 and study 2 exhibited a more significant association on the Cochran-Mantel-Haenszel test (P < .001) for NR2A; NR2A was associated with positive family history, early onset of alcoholism, and maximum number of drinks in adults as well as risky drinking patterns in adolescents., Conclusion: Genetic variations in NR2A have the greatest relevance for human alcohol dependence among the glutamatergic genes selected for their known alteration of alcohol effects in animal models.

Background: Previous studies demonstrated an attenuation of the affect-modulated startle reflex when alcohol-dependent patients were viewing alcohol-associated pictures. This indicates an appetitive valence of these stimuli. We used the affect-modulated startle reflex to assess the effects of behavioral treatment on the emotional processing of alcohol-associated stimuli. Further, we examined whether the affect-modulated startle reflex is a predictor of treatment success., Methods: Forty-three alcohol-dependent patients (21 females, mean age 45.67 years, SD 9.45) were recruited consecutively from an inpatient alcohol detoxification facility where patients attended a 3-week detoxification program including cognitive-behavioral treatment to successfully handle high-risk situations. The eye blink component of the affect-modulated startle response, self-reported cue-induced craving and skin conductance responses to alcohol-associated and control slides were assessed before and after treatment. Changes were analyzed using repeated measures analysis of variance. Drinking behavior was assessed in the 6 months following treatment, and a regression analysis was performed to evaluate the predictive validity of the affect-modulated startle response for drinking behavior., Results: Drinking behavior as well as craving and skin conductance responses decreased significantly over time. The pattern of the affective modulation of the startle reflex was not altered over time. However, startle modulation and relapse were related, and within the group of relapsers, startle modulation was a significant predictor of drinking behavior., Conclusions: Our results suggest that the modulation of the startle reflex may reflect more enduring and permanent processes of emotional responding to alcohol-related cues than autonomic arousal and self-reported craving, and that startle modulation by alcohol-associated cues may be a better predictor of drinking behavior for relapsers than other measures. Further studies including a control condition are necessary to validate these findings., (2007 S. Karger AG, Basel)

Introduction: Excessive alcohol consumption in youth increases the risk of subsequent alcohol use disorders. Despite the recognition of genetic and environmental factors, an appropriate aetiological model is needed to take adequate preventative steps. This is in part due to the complex interactions between genotype and environment. In this article we review research on factors determining alcohol use by adolescents and on the development of an unifying model., Method: The data bank Medline Advanced was searched for topical articles that were then checked for relevance and sorted according to genetic factors, environmental factors, and their interactions., Results: Many factors, alone and in combination with others, influence juvenile alcohol consumption. Each single variable, however, can explain only a small part of the variation in consumption behaviour., Conclusion: The manifold possibilities of interactions between these factors become clear. There is a strong need for comprehensive models of juvenile alcohol use and the integration of current results into these models.

Background: A low level of response to alcohol has been associated with both the genetic constitution of the regulatory region (SLC6A4) of the human serotonin (5-hydroxytryptamine, 5-HT) transporter (5-HTT) and with future alcohol intake and an increased risk for alcoholism. To date, all studies of relevant polymorphisms have been carried out in populations in the United States., Methods: Data were extracted from a subset (n = 243) of a cohort of children who have been observed since birth through evaluation of the family history of alcoholism and psychosocial risk influences. At age 16 years, the response to alcohol was assessed with the Self-Rating of the Effects of Alcohol (SRE) questionnaire, and the average amount of alcohol intake per month was assessed during the prior 6 months. Additional variables that were measured included the 5-HTT genotype, externalizing behavior, and sociodemographic variables, such as gender and age., Results: The level of response to alcohol was significantly lower among carriers of two long alleles of the 5-HTT regulatory region compared with carriers of one or two short alleles (Mann-Whitney U = 5225.0, p = .005). In a multiple regression analysis, the level of response to alcohol and externalizing behavior but not psychosocial factors significantly predicted the average amount of alcohol intake per month., Conclusions: This study demonstrates that, independent of the assessed psychosocial variables, the 5-HTT genotype correlated with the level of response to alcohol and predicted alcohol intake among 16-year-old adolescents.

Objective: To examine the influence of several social and individual factors on adolescent alcohol consumption., Methods: A prospective longitudinal study was carried out to investigate the mental development from birth to adolescence in a cohort consisting originally of 384 children. Six different variables were assessed: alcohol consumption at the age of 16 years, sensitivity to alcohol, temperament, peer influence, parental educational behaviour, and mental disorders., Results: The majority of adolescents (97%) consumed alcohol, 24% did so at least once a week. Social factors (like negative peer influence or parental educational behaviour) and individual factors (like sensitivity to alcohol, temperament or mental disorders) predicted the amount of alcohol consumed per month at the age of 16 years., Conclusions: Early identification of at-risk adolescents appears to be essential. Successful preventive strategies include support for parental education, reduction of negative peer influence, and training in order to enhance one's perception of one's own body and sensitivity to alcohol.

Objective: Alcohol and other drugs of abuse stimulate dopamine release in the ventral striatum, which includes the nucleus accumbens, a core region of the brain reward system, and reinforce substance intake. Chronic alcohol intake is associated with down-regulation of central dopamine D(2) receptors, and delayed recovery of D(2) receptor sensitivity after detoxification is positively correlated with high risk for relapse. Prolonged D(2) receptor dysfunction in the ventral striatum may interfere with a dopamine-dependent error detection signal and bias the brain reward system toward excessive attribution of incentive salience to alcohol-associated stimuli., Method: Multimodal imaging, with the radioligand [(18)F]desmethoxyfallypride and positron emission tomography as well as functional magnetic resonance imaging (fMRI), was used to compare 11 detoxified male alcoholics with 13 healthy men. The authors measured the association of D(2)-like dopamine receptors in the ventral striatum with alcohol craving and central processing of alcohol cues., Results: Activation of the medial prefrontal cortex and striatum by alcohol-associated stimuli, relative to activation by neutral visual stimuli, was greater in the detoxified alcoholics than in the healthy men. The alcoholics displayed less availability of D(2)-like receptors in the ventral striatum, which was associated with alcohol craving severity and with greater cue-induced activation of the medial prefrontal cortex and anterior cingulate as assessed with fMRI., Discussion: In alcoholics, dopaminergic dysfunction in the ventral striatum may attribute incentive salience to alcohol-associated stimuli, so that alcohol cues elicit craving and excessive activation of neural networks associated with attention and behavior control.

Rationale: Animal experiments have provided evidence that the striatum and medial prefrontal cortex play a predominant role in the acquisition and maintenance of drug-seeking behavior., Objectives: Alcohol-associated stimuli that were regularly paired with alcohol intake may become conditioned cues and elicit a motivational response that triggers relapse in alcohol-dependent patients., Methods: We used functional magnetic resonance imaging and visual alcohol-associated and control cues to assess brain activation in ten abstinent alcoholics and control subjects. Patients were followed for 3 months, and alcohol intake was recorded., Results: Alcohol-related versus neutral visual stimuli activated the putamen, anterior cingulate and adjacent medial prefrontal cortex in alcoholics compared with healthy controls. Cue-induced activation of these brain areas was pronounced in the five alcoholics who subsequently relapsed during the observation period. A multiple regression analysis showed that, in alcoholics, the amount of subsequent alcohol intake was associated with the intensity of cue-induced brain activation but not the severity of alcohol craving, amount of previous alcohol intake or duration of abstinence before scanning., Conclusions: This pilot study showed that cue-induced activation of the anterior cingulate, medial prefrontal cortex and striatum may play a role in the attribution of incentive salience to alcohol-associated stimuli, thus increasing the motivational value and attentional processing of alcohol cues. Functional brain imaging may help to identify a group of alcoholics with an otherwise undetected high risk of relapse.

Aims: Craving for the rewarding effects of alcohol may be evoked by conditioned alcohol-like effects whereas conditioned compensatory responses may induce withdrawal relief craving. We tested the hypothesis that drinking in positive emotional states is associated with appetitive reactions to alcohol-associated cues and contributes to reward craving, while conditioned withdrawal is associated with drinking in negative situations and distressful, obsessive preoccupations with alcohol., Methods: In 38 detoxified alcoholics, the Obsessive Compulsive Drinking Scale was used to assess the craving factors 'impaired control', 'interference with social functioning' and 'obsession'. Affective responses to alcohol-associated visual stimuli were measured with the affect-modulated eyeblink startle reflex, positive and negative drinking situations with the Inventory of Drinking Situations (IDS) and withdrawal-like symptoms preceding alcohol intake with the revised Clinical Institute Assessment for Alcohol Scale (CIWA-Ar)., Results: Appetitive reactions to alcohol-associated cues correlated positively with drinking in positive situations and contributed significantly to the craving factor 'interference' with social and work functioning. The severity of withdrawal-like symptoms preceding alcohol intake contributed to the craving factor 'obsession'; however, contrary to our hypothesis, this measure of conditioned withdrawal correlated with drinking not only in negative but also in positive situations., Conclusions: Drinking in positive and negative situations, appetitive reactions to alcohol and withdrawal-like symptoms contributed differentially to the craving factors 'obsession' and 'interference', supporting the notion of different craving factors with separate underlying mechanisms.

Key Points: Question: What functional brain connections are associated with alcohol use risk in adolescents, and are these connections different for male vs female adolescents? Findings: This cohort study of 1359 adolescents identified common and distinct neurobiological substrates of alcohol use as well as sex divergence in model accuracies, such that models predicting female risk consistently outperformed models predicting male risk. Meaning: The networks identified in this study and subsequently externally validated represent candidate targets for future prevention and intervention efforts. This cohort study evaluates neuromarkers associated with alcohol use among adolescents. Importance: Alcohol misuse in adolescence is a leading cause of disability and mortality in youth and is associated with higher risk for alcohol use disorder. Brain mechanisms underlying risk of alcohol misuse may inform prevention and intervention efforts. Objective: To identify neuromarkers of alcohol misuse using a data-driven approach, with specific consideration of neurodevelopmental sex differences. Design, Setting, and Participants: Longitudinal multisite functional magnetic resonance imaging (fMRI) data collected at ages 14 and 19 years were used to assess whole-brain patterns of functional organization associated with current and future alcohol use risk as measured by the Alcohol Use Disorder Identification Test (AUDIT). Primary data were collected by the IMAGEN consortium, a European multisite study of adolescent neurodevelopment. Model generalizability was further tested using data acquired in a single-site study of college alcohol consumption conducted in the US. The primary sample was a developmental cohort of 1359 adolescents with neuroimaging, phenotyping, and alcohol use data. Model generalizability was further assessed in a separate cohort of 114 individuals. Main Outcomes and Measures: Brain-behavior model accuracy, as defined by the correspondence between model-predicted and actual AUDIT scores in held-out testing data, Bonferroni corrected across the number of models run at each time point, 2-tailed α <.008, as determined via permutation testing. Results: Among 1359 individuals in the study, the mean (SD) age was 14.42 (0.40) years, and 729 individuals (54%) were female. The data-driven, whole-brain connectivity approach identified networks associated with vulnerability for future and current AUDIT-defined alcohol use risk (primary outcome, as specified above, future: ρ, 0.22; P <.001 and present: ρ, 0.27; P <.001). Results further indicated sex divergence in the accuracies of brain-behavior models, such that female-only models consistently outperformed male-only models. Specifically, female-only models identified networks conferring vulnerability for future and current severity using data acquired during both reward and inhibitory fMRI tasks. In contrast, male-only models were successful in accurately identifying networks using data acquired during the inhibitory control—but not reward—task, indicating domain specificity of alcohol use risk networks in male adolescents only. Conclusions and Relevance: These data suggest that interventions focusing on inhibitory control processes may be effective in combating alcohol use risk in male adolescents but that both inhibitory and reward-related processes are likely of relevance to alcohol use behaviors in female adolescents. They further identify novel networks of alcohol use risk in youth, which may be used to identify adolescents who are at risk and inform intervention efforts. [ABSTRACT FROM AUTHOR]

Background: Alcohol-associated alterations of the dopaminergic (DA) system have been investigated via functional single-photon emission tomography (SPECT) positron emission tomography (PET) and imaging methods over many years, investigating presynaptic or postsynaptic markers, such as DA receptor and DA transporter availability, both with and without challenge. This review summarizes SPECT and PET studies on different levels of alcohol consumption to support the dimensional view of alcohol use disorder (AUD), ranging from acute consumption in social drinkers, individuals at high risk to patients with severe AUD and their association with blunted DA neurotransmission. Additionally, confounding factors of PET and SPECT studies of the DA system were discussed. Summary: The included studies provided strong evidence that acute alcohol administration in social drinkers is followed by a DA release, particularly in the ventral striatum. In participants with AUD, DA release appears to be impaired as administration of a psychostimulant is followed by a blunted striatal DA. Furthermore, in recently detoxified participants with AUD, in vivo dopamine D2 and D3 receptor availability appears to be reduced, which may be a predisposing factor or the result of a neuroadaptive process influencing drug-induced DA release. DA transporter availability is reduced in AUD, whereas findings with respect to DA synthesis capacity are controversial. Key Messages: The DA system seems to be differently impaired during the development and persistence of AUD. In total, challenge studies (acute alcohol or psychostimulant administration) seem to be more consistent in their findings and might be less prone to the effects of confounders. Long-term studies with larger samples are required to better evaluate the alterations during chronic consumption and prolonged abstinence. [ABSTRACT FROM AUTHOR]

It has been suggested that autistic traits are associated with less frequent alcohol use in adolescence. Our study seeks to examine the relationship between autistic traits and alcohol use in a large adolescent population. Leveraging data from the IMAGEN cohort, including 2045 14-year-old adolescents that were followed-up to age 18, we selected items on social preference/skills and rigidity from different questionnaires. We used linear regression models to (1) test the effect of the sum scores on the prevalence of alcohol use (AUDIT-C) over time, (2) explore the relationship between autistic traits and alcohol use patterns, and (3) explore the specific effect of each autistic trait on alcohol use. Higher scores on the selected items were associated with trajectories of less alcohol use from the ages between 14 and 18 (b = − 0.030; CI 95% = − 0.042, − 0.017; p < 0.001). Among adolescents who used alcohol, those who reported more autistic traits were also drinking less per occasion than their peers and were less likely to engage in binge drinking. We found significant associations between alcohol use and social preference (p < 0.001), nervousness for new situations (p = 0.001), and detail orientation (p < 0.001). Autistic traits (social impairment, detail orientation, and anxiety) may buffer against alcohol use in adolescence. [ABSTRACT FROM AUTHOR]

Social exclusion contributes to alcohol consumption, whereas the development of alcohol dependence (AD) can in turn lead to the social exclusion of people with AD. Previous research observed altered neural responses to experimentally induced social exclusion (i.e., Cyberball game) in patients with AD. In addition, inflammation has been associated with both social behaviours and AD. Our study aimed to investigate the dynamic behavioural response and the inflammatory effects of social exclusion in male patients with a history of AD. To this end, we analysed dynamic changes in ball tossing during a partial exclusion Cyberball game and the cytokine interleukin (IL)‐1b in saliva in 31 male patients who had a history of AD and 29 gender‐matched healthy controls without AD. Participants were included in the first 2 min of the Cyberball game and then excluded by one of the two co‐players in the proceeding 5 min. Saliva was collected three times: one before and two after the Cyberball game. Across groups, participants passed the ball more often to the excluder during the partial exclusion period. Analysis using piece‐wise linear mixed models showed that patients rapidly increased ball tosses to the excluder upon exclusion, which lasted to the late response phase, whereas the early behavioural response to exclusion took longer for controls. There was no significant change of salivary IL‐1b level to exclusion in either patients or controls. The results indicate a distinct dynamic behavioural response to social exclusion in male patients with a history of AD. [ABSTRACT FROM AUTHOR]

Objectives: Even low to moderate levels of alcohol consumption can have detrimental health consequences, especially in older adults (OA). Although many studies report an increase in the proportion of drinkers among OA, there are regional variations. Therefore, we examined alcohol consumption and the prevalence of hazardous alcohol use (HAU) among men and women aged 50+ years in four European regions and investigated predictors of HAU. Methods: We analyzed data of N = 35,042 participants of the European SHARE study. We investigated differences in alcohol consumption (units last week) according to gender, age and EU-region using ANOVAs. Furthermore, logistic regression models were used to examine the effect of income, education, marital status, history of a low-quality parent–child relationship and smoking on HAU, also stratified for gender and EU-region. HAU was operationalized as binge drinking or risky drinking (<12.5 units of 10 ml alcohol/week). Results: Overall, past week alcohol consumption was 5.0 units (±7.8), prevalence of HAU was 25.4% within our sample of European adults aged 50+ years. Male gender, younger age and living in Western Europe were linked to both higher alcohol consumption and higher risks of HAU. Income, education, smoking, a low-quality parent–child relationship, living in Northern and especially Eastern Europe were positively associated with HAU. Stratified analyses revealed differences by region and gender. Conclusions: HAU was highly prevalent within this European sample of OA. Alcohol consumption and determinants of HAU differed between EU-regions, hinting to a necessity of risk-stratified population-level strategies to prevent HAU and subsequent alcohol use disorders. [ABSTRACT FROM AUTHOR]

Pavlovian cues can influence ongoing instrumental behaviour via Pavlovian‐to‐instrumental transfer (PIT) processes. While appetitive Pavlovian cues tend to promote instrumental approach, they are detrimental when avoidance behaviour is required, and vice versa for aversive cues. We recently reported that susceptibility to interference between Pavlovian and instrumental control assessed via a PIT task was associated with risky alcohol use at age 18. We now investigated whether such susceptibility also predicts drinking trajectories until age 24, based on AUDIT (Alcohol Use Disorders Identification Test) consumption and binge drinking (gramme alcohol/drinking occasion) scores. The interference PIT effect, assessed at ages 18 and 21 during fMRI, was characterized by increased error rates (ER) and enhanced neural responses in the ventral striatum (VS), the lateral and dorsomedial prefrontal cortices (dmPFC) during conflict, that is, when an instrumental approach was required in the presence of an aversive Pavlovian cue or vice versa. We found that a stronger VS response during conflict at age 18 was associated with a higher starting point of both drinking trajectories but predicted a decrease in binge drinking. At age 21, high ER and enhanced neural responses in the dmPFC were associated with increasing AUDIT‐C scores over the next 3 years until age 24. Overall, susceptibility to interference between Pavlovian and instrumental control might be viewed as a predisposing mechanism towards hazardous alcohol use during young adulthood, and the identified high‐risk group may profit from targeted interventions. [ABSTRACT FROM AUTHOR]

Background: Alcohol use disorder is characterized by perseverative alcohol use despite negative consequences. This hallmark feature of addiction potentially relates to impairments in behavioral flexibility, which can be measured by probabilistic reversal learning (PRL) paradigms. We here aimed to examine the cognitivemechanisms underlying impaired PRL task performance in patients with alcohol use disorder (AUDP) using computational models of reinforcement learning. Methods: Twenty-eight early abstinent AUDP and 27 healthy controls (HC) performed an extensive PRL paradigm. We compared conventional behavioral variables of choices (perseveration; correct responses) between groups. Moreover, we fitted Bayesian computational models to the task data to compare differences in latent cognitive variables including reward and punishment learning and choice consistency between groups. Results: AUDP and HC did not significantly differ with regard to direct perseveration rates after reversals. However, AUDP made overall less correct responses and specifically showed decreased win-stay behavior compared to HC. Interestingly, AUDP showed premature switching after no or little negative feedback but elevated proneness to stay when accumulation of negative feedback would make switching a more optimal option. Computational modeling revealed that AUDP compared to HC showed enhanced learning from punishment, a tendency to learn less from positive feedback and lower choice consistency. Conclusion: Our data do not support the assumption that AUDP are characterized by increased perseveration behavior. Instead our findings provide evidence that enhanced negative reinforcement and decreased non-drug-related reward learning as well as diminished choice consistency underlie dysfunctional choice behavior in AUDP. [ABSTRACT FROM AUTHOR]

Introduction: The emergence of Pavlovian-to-instrumental transfer (PIT) research in the human neurobehavioral domain has been met with increased interest over the past two decades. A variety of PIT tasks were developed during this time; while successful in demonstrating transfer phenomena, existing tasks have limitations that should be addressed. Herein, we introduce two PIT paradigms designed to assess outcome-specific and general PIT within the context of addiction. Materials and Methods: The single-lever PIT task, based on an established paradigm, replaced button presses with joystick motion to better assess avoidance behavior. The full transfer task uses alcohol and nonalcohol rewards associated with Pavlovian cues and instrumental responses, along with other gustatory and monetary rewards. We constructed mixed-effects models with the addition of other statistical analyses as needed to interpret various behavioral measures. Results: Single-lever PIT: both versions were successful in eliciting a PIT effect (joystick: p < 0.001, ηp2 = 0.36, button-box: p < 0.001, ηp2 = 0.30). Full transfer task: it was determined that the alcohol and nonalcoholic reward cues selectively primed their respective reward-associated responses (gustatory version: p < 0.001, r = 0.59, and monetary version: p < 0.001, r = 0.84). The appetitive/aversive cues resulted in a general transfer effect (gustatory: p < 0.001, ηp2 = 0.09, and monetary: p < 0.001, ηp2 = 0.17). Discussion/Conclusion: Single-lever PIT: PIT was observed in both task versions. We posit that the use of a joystick is more advantageous for the analysis of avoidance behavior. It evenly distributes movement between approach and avoid trials, which is relevant to analyzing fMRI data. Full transfer task: While gustatory conditioning has been used in the past to elicit transfer effects, we present the first paradigm that successfully elicits both specific and general transfers in humans with gustatory alcohol rewards. [ABSTRACT FROM AUTHOR]

A mechanism known as Pavlovian-to-instrumental transfer (PIT) describes a phenomenon by which the values of environmental cues acquired through Pavlovian conditioning can motivate instrumental behavior. PIT may be one basic mechanism of action control that can characterize mental disorders on a dimensional level beyond current classification systems. Therefore, we review human PIT studies investigating subclinical and clinical mental syndromes. The literature prevails an inhomogeneous picture concerning PIT. While enhanced PIT effects seem to be present in non-substance-related disorders, overweight people, and most studies with AUD patients, no altered PIT effects were reported in tobacco use disorder and obesity. Regarding AUD and relapsing alcohol-dependent patients, there is mixed evidence of enhanced or no PIT effects. Additionally, there is evidence for aberrant corticostriatal activation and genetic risk, e.g., in association with high-risk alcohol consumption and relapse after alcohol detoxification. In patients with anorexia nervosa, stronger PIT effects elicited by low caloric stimuli were associated with increased disease severity. In patients with depression, enhanced aversive PIT effects and a loss of action-specificity associated with poorer treatment outcomes were reported. Schizophrenic patients showed disrupted specific but intact general PIT effects. Patients with chronic back pain showed reduced PIT effects. We provide possible reasons to understand heterogeneity in PIT effects within and across mental disorders. Further, we strengthen the importance of reliable experimental tasks and provide test-retest data of a PIT task showing moderate to good reliability. Finally, we point toward stress as a possible underlying factor that may explain stronger PIT effects in mental disorders, as there is some evidence that stress per se interacts with the impact of environmental cues on behavior by selectively increasing cue-triggered wanting. To conclude, we discuss the results of the literature review in the light of Research Domain Criteria, suggesting future studies that comprehensively assess PIT across psychopathological dimensions. [ABSTRACT FROM AUTHOR]

Background: Impaired decision making, a key characteristic of alcohol dependence (AD), manifests in continuous alcohol consumption despite severe negative consequences. The neural basis of this impairment in individuals with AD and differences with known neural decision mechanisms among healthy subjects are not fully understood. In particular, it is unclear whether the choice behavior among individuals with AD is based on a general impairment of decision mechanisms or is mainly explained by altered value attribution, with an overly high subjective value attributed to alcohol‐related stimuli. Methods: Here, we use a functional magnetic resonance imaging (fMRI) monetary reward task to compare the neural processes of model‐based decision making and value computation between AD individuals (n = 32) and healthy controls (n = 32). During fMRI, participants evaluated monetary offers with respect to dynamically changing constraints and different levels of uncertainty. Results: Individuals with AD showed lower activation associated with model‐based decision processes in the caudate nucleus than controls, but there were no group differences in value‐related neural activity or task performance. Conclusions: Our findings highlight the role of the caudate nucleus in impaired model‐based decisions of alcohol‐dependent individuals. [ABSTRACT FROM AUTHOR]

Background: While drinking alcohol, one must choose between the immediate rewarding effects and the delayed reward of a healthier lifestyle. Individuals differ in their devaluation of a delayed reward based on the time required to receive it, i.e., delay discounting (DD). Previous studies have shown that adolescents discount more steeply than adults and that steeper DD is associated with heavier alcohol use in both groups. Methods: In a large‐scale longitudinal study, we investigated whether higher rates of DD are an antecedent or a consequence of alcohol use during adolescent development. As part of the IMAGEN project, 2220 adolescents completed the Monetary Choice Questionnaire as a DD measure, the Alcohol Use Disorders Identification Test, and the Timeline Follow Back interview at ages 14, 16, 18, and 22. Bivariate latent growth curve models were applied to investigate the relationship between DD and drinking. To explore the consequences of drinking, we computed the cumulative alcohol consumption and correlated it with the development of discounting. A subsample of 221 participants completed an intertemporal choice task (iTeCh) during functional magnetic resonance imaging at ages 14, 16, and 18. Repeated‐measures ANOVA was used to differentiate between high‐risk and low‐risk drinkers on the development of neural processing during intertemporal choices. Results: Overall, high rates of DD at age 14 predicted a greater increase in drinking over 8 years. In contrast, on average, moderate alcohol use did not affect DD from ages 14 to 22. Of note, we found indicators for less brain activity in top‐down control areas during intertemporal choices in the participants who drank more. Conclusions: Steep DD was shown to be a predictor rather than a consequence of alcohol use in low‐level drinking adolescents. Important considerations for future longitudinal studies are the sampling strategies to be used and the reliability of the assessments. [ABSTRACT FROM AUTHOR]

Pavlovian‐to‐instrumental transfer (PIT) tasks examine the influence of Pavlovian stimuli on ongoing instrumental behaviour. Previous studies reported associations between a strong PIT effect, high‐risk drinking and alcohol use disorder. This study investigated whether susceptibility to interference between Pavlovian and instrumental control is linked to risky alcohol use in a community sample of 18‐year‐old male adults. Participants (N = 191) were instructed to 'collect good shells' and 'leave bad shells' during the presentation of appetitive (monetary reward), aversive (monetary loss) or neutral Pavlovian stimuli. We compared instrumental error rates (ER) and functional magnetic resonance imaging (fMRI) brain responses between the congruent and incongruent conditions, as well as among high‐risk and low‐risk drinking groups. On average, individuals showed a substantial PIT effect, that is, increased ER when Pavlovian cues and instrumental stimuli were in conflict compared with congruent trials. Neural PIT correlates were found in the ventral striatum and the dorsomedial and lateral prefrontal cortices (lPFC). Importantly, high‐risk drinking was associated with a stronger behavioural PIT effect, a decreased lPFC response and an increased neural response in the ventral striatum on the trend level. Moreover, high‐risk drinkers showed weaker connectivity from the ventral striatum to the lPFC during incongruent trials. Our study links interference during PIT to drinking behaviour in healthy, young adults. High‐risk drinkers showed higher susceptibility to Pavlovian cues, especially when they conflicted with instrumental behaviour, indicating lower interference control abilities. Increased activity in the ventral striatum (bottom‐up), decreased lPFC response (top‐down), and their altered interplay may contribute to poor interference control in the high‐risk drinkers. [ABSTRACT FROM AUTHOR]