Understanding Of Alcohol Use Disorder Research Articles

Collaborative study on the genetics of alcoholism: The strength of collaboration, team science, and longitudinal data.

This issue contains a series of articles describing the various resources, studies, results, and future directions for the collaborative study on the genetics of alcoholism (COGA). The collaborative and integrative approach initiated by this group ~30 years ago serves as an excellent example of the strength of team science. Individually, various aspects of COGA would be limited in their impact toward improved understanding of alcohol use disorder. Collectively, their wholistic approach which spans deep longitudinal phenotypic assessments in families to include the application of large-scale omics technologies and cell-culture based molecular studies has demonstrated the power of working together.

The collaborative study on the genetics of alcoholism: Brain function.

Alcohol use disorder (AUD) and related health conditions result from a complex interaction of genetic, neural and environmental factors, with differential impacts across the lifespan. From its inception, the Collaborative Study on the Genetics of Alcoholism (COGA) has focused on the importance of brain function as it relates to the risk and consequences of alcohol use and AUD, through the examination of noninvasively recorded brain electrical activity and neuropsychological tests. COGA's sophisticated neurophysiological and neuropsychological measures, together with rich longitudinal, multi-modal family data, have allowed us to disentangle brain-related risk and resilience factors from the consequences of prolonged and heavy alcohol use in the context of genomic and social-environmental influences over the lifespan. COGA has led the field in identifying genetic variation associated with brain functioning, which has advanced the understanding of how genomic risk affects AUD and related disorders. To date, the COGA study has amassed brain function data on over 9871 participants, 7837 with data at more than one time point, and with notable diversity in terms of age (from 7 to 97), gender (52% female), and self-reported race and ethnicity (28% Black, 9% Hispanic). These data are available to the research community through several mechanisms, including directly through the NIAAA, through dbGAP, and in collaboration with COGA investigators. In this review, we provide an overview of COGA's data collection methods and specific brain function measures assessed, and showcase the utility, significance, and contributions these data have made to our understanding of AUD and related disorders, highlighting COGA research findings.

Ethanol administration during retrieval, but not consolidation, influences the relative use of multiple memory systems

The mammalian brain consists of two competing memory systems: the hippocampus-dependent cognitive memory system and dorsal striatum-dependent stimulus-response memory system, which can be influenced by drugs of abuse. The formation and retrieval of cognitive and stimulus-response memories can be acquired using a place or response strategy, respectively. The purpose of the present study was to investigate the effects of ethanol on the relative use of the cognitive and stimulus-response memory systems and its effects on retrieval and consolidation processes. The dual-solution water maze task offers a behavioral paradigm to determine the relative preference of memory systems in rats. Male Sprague-Dawley rats were trained over two days on the dual-solution water maze task and were tested on the third day of the paradigm. In Experiment 1, ethanol was administered 30 min before the test day probe trial. In Experiment 2, ethanol was administered immediately after each training session. Results from Experiment 1 showed that ethanol exposure prior to test biases animals towards preferential use of the response strategy to complete the task. In Experiment 2, post-training ethanol exposure did not bias animals towards the use of either strategy on test day. The present study indicates that ethanol biases the relative use of multiple memory systems towards the use of the stimulus-response memory system through interactions with the retrieval process but not the consolidation process. Alcohol's effect on preferential use of the stimulus-response memory system has important implications for the understanding of alcohol use disorder, general addiction, and memory function.

Evaluation of the Addictions Neuroclinical Assessment (ANA) framework through deep phenotyping of problem drinkers

BackgroundTo advance the development of a neuroscience-informed understanding of alcohol use disorder (AUD) through the Addictions Neuroclinical Assessment (ANA) framework, the present study reports on deep phenotyping of a large sample of problem drinkers. MethodsParticipants (n = 1679) were primarily heavy drinkers with and without AUD, who completed a phenotypic battery of well-validated scales and behavioral measures of alcohol use and problems, mood, attention, and impulsivity. These scales were subjected to sequential factor analytic work in order to derive a factor solution that explains biobehavioral variation in the sample. To assess the construct validity of the resulting factor solution, scores on each factor were associated with demographic and clinical indicators. ResultsFactor analysis techniques using indicators of alcohol use and problems, mood, attention, and impulsivity implicated four functional domains that compliment and extend the proposed ANA domains: negative alcohol-related consequences, incentive salience, negative emotionality, and executive function. Demographic and clinical variables significantly predicted scores on all ANA domains. ConclusionsThis study provides an independent test of the recently proposed neuroscience-based ANA framework. Results largely support the novel approach in identifying four core constructs in problem drinkers. Future studies can deepen our understanding of how these domains are relevant to AUD by incorporating biomarkers.

Decreasing the stigma surrounding alcohol use disorder

IntroductionThere is a paucity of data on educational interventions that prepare students to mitigate the stigma or burden of alcohol use disorder. The objectives of this study were to (1) assess the impact of an interprofessional symposium on personal knowledge and stigma of alcohol use disorder and (2) inform future educational models. MethodsThe symposium highlighted the impact of alcohol at one private Midwestern university and reviewed the pharmacology of alcohol, diagnostic criteria for alcohol use disorder, and treatment for alcohol use disorder. Prior to and after the symposium, participants were given nine statements (two knowledge-based and seven stigma-based) about alcohol use disorder. Agreement with each statement was measuring on a five-point rating scale, and responses were collapsed into three categories: 1 = low stigma/high understanding, 2 = neutral, and 3 = high stigma/low understanding. Change between response categories before and after the symposium were analyzed using a Wilcoxon signed-ranked test (W). ResultsA total of 87 responses were collected pre-symposium and 45 responses were collected post-symposium. Both knowledge-based statements showed an increase in individual respondent understanding of alcohol use disorder as a disease. All stigma-based statements conveyed a decrease in individual respondent stigma of alcohol use disorder as a disease. Test statistics (Z) for significant items raged between Z = 3 to 5, P < .05. ConclusionsThe symposium was successful at conveying positive changes in attitudes toward alcohol use disorder.

Koob Discusses Neurobiology of AUD at APA Spring Highlights Meeting

Back to table of contents Previous article Next article Clinical & ResearchFull AccessKoob Discusses Neurobiology of AUD at APA Spring Highlights MeetingTerri D'ArrigoTerri D'ArrigoSearch for more papers by this authorPublished Online:17 Jun 2020https://doi.org/10.1176/appi.pn.2020.6b20AbstractThe director of the National Institute on Alcohol Abuse and Alcoholism described how heavy alcohol use changes neurotransmitters and brain circuitry in people vulnerable to alcohol use disorder (AUD).The emotions of people with alcohol use disorder do not return to a stable state after a bout of drinking, says George F. Koob, Ph.D.NIAAAUnderstanding the neurobiology of alcohol use disorder (AUD) can help address the stigma associated with the condition, George F. Koob, Ph.D., director of the National Institute on Alcohol Abuse and Alcoholism (NIAAA) explained in a presentation at the virtual APA Spring Highlights Meeting in April.“Consideration of alcohol use disorder within a neurobiological framework reinforces alcohol use disorder as a health condition rather than as a moral failing,” he said. “This characterization may help reduce stigma, although stigma remains a pervasive barrier to treatment.”In his presentation, Koob described a conceptual neurobiological framework for improving the diagnosis, prevention, and treatment of AUD. This framework accounts for how alcohol use can change neurotransmitters and the circuitry of the brain, particularly with respect to the emotional impact of withdrawal after a binge of heavy drinking. Koob explained that after drinking, people who are vulnerable to developing AUD may experience a phenomenon that he calls “hyperkatifeia” in which they feel increased emotional pain and distress. They then turn to drinking to relieve their emotional pain, further changing the neurotransmitters and circuitry of the brain.“People with alcohol use disorder don’t recover their normal mood and emotional state after they drink,” Koob said. “Then they drink to fix the problem that alcohol caused. When you start doing that, that’s when you cross the line [to AUD], in my opinion.”He added that several factors—including one’s genetic makeup, history of childhood trauma, and co-occurring mental illness—can make it even more difficult for some people to return to a normal emotional state after they drink.“In my opinion the hangover you get from a binge is the beginning of … the change in neurotransmitters,” Koob said. He added that although neurotransmitters most likely recover in the aftermath of infrequent or early alcohol abuse, if people continue to binge or drink heavily, they may develop hyperkatifeia and eventually AUD.Koob also discussed potential treatments. He explained that acamprosate, one of the three medications approved by the Food and Drug Administration for treating AUD, reverses the effects of glutamate, one of the neurotransmitters involved in craving. (The other medications are disulfiram and naltrexone.)“There were quite a few clinical studies done for its approval, most of them showing pretty dramatic increases in abstaining [from alcohol use]. It works best for patients who have the low-level irritability and hyperkatifeia associated with abstinence,” he said.Koob noted the promise of mifepristone (also known as RU 486), citing a study that showed it could reduce alcohol-cued craving and drinking in people with AUD while improving liver function.Although understanding of AUD and treatment have come a long way since the NIAAA was created 50 years ago, significant challenges remain, Koob said.“We have a lot of work to do on sex differences, how exposure to alcohol during adolescence makes one more vulnerable to alcohol use disorder, and the [impact] of aging. We certainly could do with more and better novel behavioral treatments,” he said, noting that the increase in telehealth in response to the COVID-19 pandemic could be a move in the right direction.He added that there is a need to understand the neurobiology of the high co-occurrence of AUD with other mental illnesses, particularly posttraumatic stress disorder, anxiety disorders, and major depressive episodes. ■ ISSUES NewArchived

Advances in the science and treatment of alcohol use disorder.

Alcohol is a major contributor to global disease and a leading cause of preventable death, causing approximately 88,000 deaths annually in the United States alone. Alcohol use disorder is one of the most common psychiatric disorders, with nearly one-third of U.S. adults experiencing alcohol use disorder at some point during their lives. Alcohol use disorder also has economic consequences, costing the United States at least $249 billion annually. Current pharmaceutical and behavioral treatments may assist patients in reducing alcohol use or facilitating alcohol abstinence. Although recent research has expanded understanding of alcohol use disorder, more research is needed to identify the neurobiological, genetic and epigenetic, psychological, social, and environmental factors most critical in the etiology and treatment of this disease. Implementation of this knowledge in clinical practice and training of health care providers is also needed to ensure appropriate diagnosis and treatment of individuals suffering from alcohol use disorder.

Oxytocin blocks enhanced motivation for alcohol in alcohol dependence and blocks alcohol effects on GABAergic transmission in the central amygdala.

Oxytocin administration has been reported to decrease consumption, withdrawal, and drug-seeking associated with several drugs of abuse and thus represents a promising pharmacological approach to treat drug addiction. We used an established rat model of alcohol dependence to investigate oxytocin’s effects on dependence-induced alcohol drinking, enhanced motivation for alcohol, and altered GABAergic transmission in the central nucleus of the amygdala (CeA). Intraperitoneal oxytocin administration blocked escalated alcohol drinking and the enhanced motivation for alcohol in alcohol-dependent but not nondependent rats. Intranasal oxytocin delivery fully replicated these effects. Intraperitoneal administration had minor but significant effects of reducing locomotion and intake of non-alcoholic palatable solutions, whereas intranasal oxytocin administration did not. In dependent rats, intracerebroventricular administration of oxytocin or the oxytocin receptor agonist PF-06655075, which does not cross the blood-brain barrier (i.e., it would not diffuse to the periphery), but not systemic administration of PF-06655075 (i.e., it would not reach the brain), decreased alcohol drinking. Administration of a peripherally restricted oxytocin receptor antagonist did not reverse the effect of intranasal oxytocin on alcohol drinking. Ex vivo electrophysiological recordings from CeA neurons indicated that oxytocin decreases evoked GABA transmission in nondependent but not in dependent rats, whereas oxytocin decreased the amplitude of spontaneous GABAergic responses in both groups. Oxytocin blocked the facilitatory effects of acute alcohol on GABA release in the CeA of dependent but not nondependent rats. Together, these results provide converging evidence that oxytocin specifically and selectively blocks the enhanced motivation for alcohol drinking that develops in alcohol dependence likely via a central mechanism that may result from altered oxytocin effects on CeA GABA transmission in alcohol dependence. Neuroadaptations in endogenous oxytocin signaling may provide a mechanism to further our understanding of alcohol use disorder.

Insights from intoxicated Drosophila.

Our understanding of alcohol use disorder (AUD), particularly alcohol's effects on the nervous system, has unquestionably benefited from the use of model systems such as Drosophila melanogaster. Here, we briefly introduce the use of flies in alcohol research, and highlight the genetic accessibility and neurobiological contribution that flies have made to our understanding of AUD. Future fly research offers unique opportunities for addressing unresolved questions in the alcohol field, such as the neuromolecular and circuit basis for cravings and alcohol-induced neuroimmune dysfunction. This review strongly advocates for interdisciplinary approaches and translational collaborations with the united goal of confronting the major health problems associated with alcohol abuse and addiction.

Gene-edited CRISPy Critters for alcohol research.

Genetically engineered animals are powerful tools that have provided invaluable insights into mechanisms of alcohol action and alcohol-use disorder. Traditionally, production of gene-targeted animals was a tremendously expensive, time consuming, and technically demanding undertaking. However, the recent advent of facile methods for editing the genome at very high efficiency is revolutionizing how these animals are made. While pioneering approaches to create gene-edited animals first used zinc finger nucleases and subsequently used transcription activator-like effector nucleases, these approaches have been largely supplanted in an extremely short period of time with the recent discovery and precocious maturation of the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) system. CRISPR uses a short RNA sequence to guide a non-specific CRISPR-associated nuclease (Cas) to a precise, single location in the genome. Because the CRISPR/Cas system can be cheaply, rapidly, and easily reprogrammed to target nearly any genomic locus of interest simply by recoding the sequence of the guide RNA, this gene-editing system has been rapidly adopted by numerous labs around the world. With CRISPR/Cas, it is now possible to perform gene editing directly in early embryos from every species of animals that is of interest to the alcohol field. Techniques have been developed that enable the rapid production of animals in which a gene has been inactivated (knockout) or modified to harbor specific nucleotide changes (knockins). This system has also been used to insert specific DNA sequences such as reporter or recombinase genes into specific loci of interest. Genetically engineered animals created with the CRISPR/Cas system (CRISPy Critters) are being produced at an astounding pace. Animal production is no longer a significant bottleneck to new discoveries. CRISPy animal studies are just beginning to appear in the alcohol literature, but their use is expected to explode in the near future. CRISPy mice, rats, and other model organisms are sure to facilitate advances in our understanding of alcohol-use disorder.

Desistance and Severity of Alcohol Use Disorder: A Lifespan-Developmental Investigation.

Key to an understanding of alcohol use disorder (AUD) are the drinking-related reductions that begin in young adulthood and continue throughout the adult lifespan. Research is needed to precisely characterize the form of these reductions, including possible developmental differences across the lifespan. Using U.S.-representative data, we estimated multiple-group Markov models characterizing longitudinal transitions among five drinking statuses and differences in transition patterns across six adult age periods. While past research indicates relative developmental stability in overall AUD-desistance rates, we found far higher rates of Severe-AUD desistance in young adulthood relative to later ages. Especially considering the dramatic change reflected by Severe-AUD desistance (from 6+ symptoms to 0-1 symptoms), this result indicates a substantial developmental shift, with Severe-AUD-desistance rates peaking at 43-50% across ages 25-34 and then dropping to 22-24% across ages 35-55. We discuss implications regarding practical significance of young-adult "maturing out" and predictions regarding lifespan variability in desistance mechanisms.

First description and evaluation of SNPs in the ADH and ALDH genes in a population of alcoholics in Central-West Brazil.

Worldwide, different studies have reported an association of alcohol-use disorder (AUD) with different types of Single Nucleotide Polymorphisms (SNPs) in the genes for aldehyde dehydrogenase (ALDH) and alcohol dehydrogenase (ADH). In Brazil, there is little information about the occurrence of these SNPs in the AUD population and an absence of studies characterizing the population in the Central-West Region of Brazil. Actually, in Brazil, there are more than 4 million people with AUD. Despite the major health hazards of AUD, information on alcohol consumption and its consequences are not well understood. Therefore, it is extremely important to characterize these SNPs for the better understanding of AUD as a genetic disease in the Brazilian population. The present study, unlike other studies in other countries, is done with a subject population that shows a significant amount of racial homogenization. We evaluated the presence of SNPs in the ADH (ADH1B, ADH1C, and ADH4) and ALDH (ALDH2) genes in alcohol users of Goiânia, State of Goiás - Brazil, and then we established a possible relationship with AUD by allelic and genotypic study. This study was conducted with a population of people with AUD (n=99) from Goiás Alcohol Dependence Recovery Center (GO CEREA) and Psychosocial Care Center for Alcohol and Drugs (CAPS AD), and with a population of people without AUD as controls (n=100). DNA was extracted from whole-blood samples and the genotyping was performed using TaqMan® SNP genotyping assays. For characterization and evaluation of SNPs in the population, genotype frequency, allele frequency, haplotype frequency, Hardy-Weinberg equilibrium, and linkage disequilibrium were analyzed. Statistical analyses were calculated by GENEPOP 4.5 and Haploview software. The allele 1 was considered as "wild" (or *1) and allele 2 as mutant (or *2). Significant differences were found for ADH1B*, ADH4*2, and ALDH2*2 SNPs when the genotype and allele frequencies were analyzed. In addition, four haplotypes were observed between ADH1B*2 and ADH1C*2 through linkage disequilibrium analysis. The genetic variants may be associated with protection against AUD in the population studied.

Alcohol use disorder clinical course research: informing clinicians' treatment planning now and in the future.

The clinical course of alcohol use disorder (AUD) has been widely researched over the past half-century and has been used to advance our understanding of the treatment of AUD. Nevertheless, new directions in AUD clinical course research could enhance its value in informing clinical decision-making in patient-centered treatment of AUD. An overview, a critical analysis, and a discussion of AUD clinical course research are presented. This article discusses three research directions that promote the advancement of the knowledge regarding the clinical course of AUD to better inform clinical decision-making in patient-centered treatment of AUD. Specifically, we hypothesized that (a) real-time data collection of the clinical course of AUD via ecological momentary assessment would help elucidate near real-time associations between risk factors and alcohol use, (b) future research designs should use person-centered and dynamic analyses of alcohol use over time, and (c) adaptive treatment designs would provide personalized and optimized AUD treatment. Consequently, the field will advance the development of clinical decision-making support systems to better inform clinicians and clients in making informed AUD treatment decisions. In addition, such research would advance clinical practice with more attention to theory and expansion of the study of the clinical course of AUD to include areas of life functioning besides alcohol use. These research directions have the potential to build a scientific knowledge base that could improve our understanding of AUD among individuals with alcohol problems, would allow providers to predict patient outcomes during and after treatment, and would offer practical strategies regarding steps that could ultimately improve the clinical course of AUD.