Aspects Of Alcohol Dependence Research Articles

Estrogen receptor 1 gene variants and estradiol activities in alcohol dependence

ObjectiveAlcohol use disorders inflict a great individual and societal burden. Although sex hormone effects have been implicated in alcohol dependence, research has mostly neglected estrogen activities and female alcohol-dependent patients. Here, we investigated associations of estrogen receptor 1 (ESR1) genetics and serum estradiol activities with aspects of alcohol dependence. MethodSerum estradiol activities of early-abstinent alcohol-dependent in-patients (n[♂] = 113, n[♀] = 87) were followed for at median 5 days and compared with healthy controls (n[♂] = 133, n[♀] = 107). All participants were genotyped for five ESR1 single nucleotide polymorphisms (rs6902771, rs11155819, rs6557171, rs2982683, rs2982712). ResultsBioavailable estradiol levels decreased during withdrawal treatment (P[♂] < .001, P[♀] = .011). Male patients with an increase of bioavailable estradiol during withdrawal showed fewer days to (P = .033) and more alcohol-related readmissions (P < .05) during the 12-month follow-up. Higher estradiol and estradiol-to-testosterone activities were significantly related to liver, muscle, and cell count damage in male patients. Estradiol-to-testosterone activities in female patients were lower compared to female controls (total P = .013, bioavailable P = .009). Moreover, the ESR1 genotypes jointly separated alcohol-dependent patients from controls (P = .037). ConclusionOur findings support the role of ESR1 genetics in alcohol dependence and show for the first time that estradiol activities may sex-specifically predict alcohol-related sequelae and outcome following in-patient withdrawal treatment.

Ethanol and corticotropin releasing factor receptor modulation of central amygdala neurocircuitry: An update and future directions

The central amygdala is a critical brain region for many aspects of alcohol dependence. Much of the work examining the mechanisms by which the central amygdala mediates the development of alcohol dependence has focused on the interaction of acute and chronic ethanol with central amygdala corticotropin releasing factor signaling. This work has led to a great deal of success in furthering the general understanding of central amygdala neurocircuitry and its role in alcohol dependence. Much of this work has primarily focused on the hypothesis that ethanol utilizes endogenous corticotropin releasing factor signaling to upregulate inhibitory GABAergic transmission in the central amygdala. Work that is more recent suggests that corticotropin releasing factor also plays an important role in mediating anxiety-like behaviors via the enhancement of central amygdala glutamatergic transmission, implying that ethanol/corticotropin releasing factor interactions may modulate excitatory neurotransmission in this brain region. In addition, a number of studies utilizing optogenetic strategies or transgenic mouse lines have begun to examine specific central amygdala neurocircuit dynamics and neuronal subpopulations to better understand overall central amygdala neurocircuitry and the role of neuronal subtypes in mediating anxiety-like behaviors. This review will provide a brief update on this literature and describe some potential future directions that may be important for the development of better treatments for alcohol addiction.

Direct and Indirect Symptom Severity Indicators of Alcohol Dependence and the Personality Concept of the Biosocial Model

Temperament and character factors are strongly related to the developmental, clinical, and treatment aspects of alcohol dependence. This study had the aim of revealing the underlying personality structure and individual differences in the symptoms of alcohol dependence measured by multiple severity indicators. Patients with alcohol dependence exhibited higher levels of novelty seeking and harm avoidance, and lower levels of persistence, self-directedness, and cooperativeness. Especially novelty seeking was connected with more severe alcohol dependence. These characteristics could be useful targets of interventions and Temperament and Character Inventory is therefore a useful measurement to identify patients with more severe alcohol-related problems.

An exploration of violence, mental health and substance abuse in post-conflict Guatemala.

Guatemala's 36-year civil war officially ended in December 1996 after some 200,000 deaths and one million refugees. Despite the ceasefire, Guatemala continues to be a violent country with one of the highest homicide rates in the world. We investigated potential associations between violence, mental health, and substance abuse in post-conflict Guatemala using a community-based survey of 86 respondents living in urban and rural Guatemala. Overall, 17.4% of our respondents had at least one, direct violent experience during the civil war. In the post-conflict period, 90.7% of respondents reported being afraid that they might be hurt by violence, 40.7% screened positive for depression, 50.0% screened positive for PTSD, and 23.3% screened positive for alcohol dependence. Potential associations between prior violent experiences during the war and indicators of PTSD and aspects of alcohol dependence were found in regression-adjusted models (p < 0.05). Certain associations between prior civil war experiences, aspects of PTSD and alcohol dependence in this cohort are remarkable, raising concerns for the health and safety of the largely indigenous populations we studied. Higher than expected rates of depression, PTSD, and substance abuse in our cohort may be related to the ongoing violence, injury and fear that have persisted since the end of the civil war. These, in turn, have implications for the growing medical and surgical resources needed to address the continuing traumatic and post-traumatic complications in the post-conflict era. Limitations of the current study are discussed. These findings are useful in beginning to understand the downstream effects of the Guatemalan civil war, although a much larger, randomly sampled survey is now needed.

Gender-specific associations between trauma cognitions, alcohol cravings, and alcohol-related consequences in individuals with comorbid PTSD and alcohol dependence.

The current study examined gender-specific associations between trauma cognitions, alcohol cravings and alcohol-related consequences in individuals with dually diagnosed PTSD and alcohol dependence (AD). Participants (N = 167) had entered a treatment study for concurrent PTSD and AD; baseline information was collected from participants about PTSD-related cognitions in three areas: (a) Negative Cognitions About Self, (b) Negative Cognitions About the World, and (c) Self-Blame. Information was also collected on two aspects of AD: alcohol cravings and consequences of AD. Gender differences were examined while controlling for PTSD severity. The results indicate that Negative Cognitions About Self are significantly related to alcohol cravings in men but not women, and that interpersonal consequences of AD are significantly related to Self-Blame in women but not in men. These findings suggest that for individuals with comorbid PTSD and AD, psychotherapeutic interventions that focus on reducing trauma-related cognitions are likely to reduce alcohol cravings in men and relational problems in women.

Editorial: Pharmacotherapy of Alcohol Dependence: Past, Present and Future Research

Alcohol dependence represents a chronic, relapsing condition with a multifactorial aetiology that includes genetic, neurobiological,psychological, and environmental components. Evidence for the effectiveness of medications in alcohol dependence treatment along with the increased number of compounds available is increasing the use of adjunctive pharmacotherapies. In particular, pharmacotherapies could conceivably address some of the biological aspects of alcohol dependence. Treating a complex behavioral disorder such as alcohol dependence with both pharmacotherapy and psychosocial therapy may give people the best options for recovery. To address the exciting developments in the use of pharmacotherapies for alcohol dependence, we planned this special issue for Current Pharmaceutical Design, entitled "Old and new pharmacotherapies in the management of patients with alcohol dependence". The overall purpose of this special issue is to provide a resource, that researchers and clinicians interested in the pharmacotherapy of alcohol dependence may use, as well as to stimulate how current findings and ongoing research may improve the treatment of our alcohol-dependent patients

From QTL to Candidate Gene: A Genetic Approach to Alcoholism Research

A major focus of research in alcohol-related disorders is to identify the genes and pathways that modulate alcohol-seeking behavior. In light of this, animal models have been established to study various aspects of alcohol dependence. The selectively bred alcohol-preferring (P) and -nonpreferring (NP) lines were developed from Wistar rats to model high and low voluntary alcohol consumption, respectively. Using inbred P and NP strains, a strong QTL (LOD-9.2) for alcohol consumption was identified on rat chromosome 4. To search for candidate genes that underlie this chromosomal region, complementary molecular-based strategies were implemented to identify genetic targets that likely contribute to the linkage signal. In an attempt to validate these genetic targets, corroborative studies have been utilized including pharmacological studies, knock-out/transgenic models as well as human association studies. Thus far, three candidate genes, neuropeptide Y (Npy), alpha-synuclein (Snca), and corticotrophin-releasing factor receptor 2 (Crhr2), have been identified that may account for the linkage signal. With the recent advancements in bioinformatics and molecular biology, QTL analysis combined with molecular-based strategies provides a systematic approach to identify candidate genes that contribute to various aspects of addictive behavior.

Alterations in Homocysteine Metabolism Among Alcohol Dependent Patients - Clinical, Pathobiochemical and Genetic Aspects

Addiction research focusing on homocysteine metabolism and its association with aspects of alcohol dependence has revealed important findings. Recent literature on this topic has been taken into account for the review provided. Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in the homocysteine metabolism. Plasma homocysteine levels are influenced by the single-nucleotide polymorphism (SNP) MTHFR C677T. Besides genetic factors, environmental factors have an impact on homocysteine plasma levels too. Thus, chronic alcohol intake is associated with elevated homocysteine plasma concentrations. Elevation of plasma homocysteine concentration is considered as a predictor for the occurrence of alcohol withdrawal seizures and--as homocysteine is a cardiovascular risk factor--might contribute to the higher risk for myocardial infarction among alcohol dependent patients. Homocysteine acts as an N-methyl-D-aspartate (NMDA) receptor agonist and has excitotoxic effects. Furthermore, it has been demonstrated that homocysteine has neurotoxic effects especially on dopaminergic neurons. As the rewarding effects of alcohol are mediated by the dopaminergic system, a homocysteine-dependent impairment of the reward system possibly leads to an altered drinking behaviour according to the deficit hypothesis of addiction. Homocysteine is involved in the metabolism of methyl groups and DNA-methylation plays a role in regulation of gene expression. Therefore it has been suggested that homocysteine is an important epigenetic factor. It remains to be determined whether alcohol dependent patients benefit from homocysteine lowering strategies, e.g., via supplementation of folate, vitamin B6 and B12. In this respect it is not clear yet, if a supplementation therapy can reduce the risk for the occurrence of alcohol withdrawal seizures.

Neuroprotective and Abstinence-Promoting Effects of Acamprosate

Acamprosate is an abstinence-promoting drug widely used in the treatment of alcohol dependence but which has a mechanism of action that has remained obscure for many years. Recently, evidence has emerged that this drug may interact with excitatory glutamatergic neurotransmission in general and as an antagonist of the metabotropic glutamate receptor subtype 5 (mGluR5) in particular. These findings provide, for the first time, a satisfactory, unifying hypothesis that can bring together and explain the diverse neurochemical effects of acamprosate. Glutamic acid is involved in several aspects of alcohol dependence and withdrawal, many of which can be modified by acamprosate. For example, during chronic exposure to alcohol, the glutamatergic system becomes upregulated, leaving the brain exposed to excessive glutamatergic activity when alcohol is abruptly withdrawn. The surge in glutamic acid release that occurs following alcohol withdrawal can be attenuated by acamprosate. The elevated extracellular levels of glutamic acid observed in withdrawal, together with supersensitivity of NMDA receptors, may expose vulnerable neurons to excitotoxicity, possibly contributing to the neuronal loss sometimes observed in chronic alcohol dependence. In vitro studies suggest that the excitotoxicity produced by ethanol can effectively be blocked by acamprosate. Moreover, glutamatergic neurotransmission plays an important role in the acquisition of cue-elicited drinking behaviours, which again can be modulated by acamprosate. In conclusion, the glutamatergic hypothesis of the mechanism of action of acamprosate helps explain many of its effects in human alcohol dependence and points the way to potential new activities, such as neuroprotection, that merit exploration in the clinic.

Finding Paradigms for the Future of Alcoholism Research: An Interdisciplinary Perspective

This is a review article and critique of current research strategies in the alcohol field. Although the alcohol field is proud of its multidisciplinary tradition and scientific findings within specific disciplines, there are very few models of cross-disciplinary research and communication. Currently, the favored model of risk is genetic; the favored model of pathophysiology is molecular neuroscience; and the favored model of clinical investigation is narrowly categorical. If there is a hierarchy within science that is based on explanatory power, then models of alcoholism emerging from neuroscience, molecular biology, and genetics should be able to accommodate (if not account for) the findings on clinical aspects of alcohol dependence, as well as data on differential risk, course, and recovery that come from the behavioral and social sciences. The first section of this article reviews the most popular models of alcohol dependence over the past 40 years. I argue that the currently fashionable categorical approach to diagnosis in DSM-IV (and ICD-10) has failed to serve as a framework for interdisciplinary research and has failed to meet the needs of human geneticists, population-based researchers, psychosocial researchers, basic scientists working in animal models, and patient-oriented researchers. I argue for a return to the dimensional approach to diagnosis in the alcohol dependence syndrome construct. In the second section of the article, I lay out an agenda for revitalized patient-oriented research in the alcohol field, as a bridge between basic biological research and innovations in clinical practice, as well as the key to a valid diagnostic system that can inform research strategies in genetics and population-based research. In the third section of the article, I highlight the interface between genetic and psychosocial models of risk and propose a possible structure for future collaboration. I conclude with a plea to funding agencies and investigators to translate discipline-based scientific findings into a science relevant to alcoholism by addressing the challenges and opportunities of an interdisciplinary research agenda on the pathophysiology of alcohol dependence and the multidimensional sources of risk.

Drinking patterns and problems in China

Although problem drinking in China is known to be a less severe issue than in many other countries, the pattern of alcohol use has been changing during the past two decades. The most notable changes are an increase in the sale of alcoholic beverages, the increase in per capita alcohol consumption, and an increase in the incidence of alcoholic related problems (Hao 1995). Unlike in western industrialized countries, however, reliable data on alcohol production, marketing, and various alcohol-related problems are not readily available in China. There is no systematic recording of most of the necessary information. Research on various aspects of alcohol dependence, particularly with a public health perspective, has only begun in the last 20 years. But they remain the best sources for the time being and do convey various trends and patterns as well as indicate the current magnitude of the problems.

Chromosomes 12 and 16 workshop

Recent linkage results independently derived from a large French Canadian pedigree and Danish kindreds coupled with supportive data from other studies provide compelling evidence for a bipolar disorder susceptibility locus on chromosome 12q23-q24. The idea is further strengthened by the finding that Darier's disease, which maps to this region, has been shown to cosegregate with affective disorder in a family. This linkage finding, however, was not supported in other independent genome scans. On chromosome 16, bipolar families from Denmark exhibited suggestive linkage with D16S510, on 16p13. Multipoint nonparametric analysis on the NIMH Genetics Initiative bipolar pedigrees yielded increased allele sharing that maximized ∼18 cM proximal to the latter locus. In contrast, evidence of linkage was not detected in other panels of bipolar families that were presented. At 16p13, a maximum multipoint lod score of 4 for a latent class-derived phenotype that has aspects of alcohol dependence was found in a genome scan of 105 families from the Collaborative Study of the Genetics of Alcoholism, identifying a potential vulnerability locus. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:255–259, 1999. Published 1999 Wiley-Liss, Inc.

Chromosomes 12 and 16 workshop.

Recent linkage results independently derived from a large French Canadian pedigree and Danish kindreds coupled with supportive data from other studies provide compelling evidence for a bipolar disorder susceptibility locus on chromosome 12q23-q24. The idea is further strengthened by the finding that Darier's disease, which maps to this region, has been shown to cosegregate with affective disorder in a family. This linkage finding, however, was not supported in other independent genome scans. On chromosome 16, bipolar families from Denmark exhibited suggestive linkage with D16S510, on 16p13. Multipoint nonparametric analysis on the NIMH Genetics Initiative bipolar pedigrees yielded increased allele sharing that maximized approximately 18 cM proximal to the latter locus. In contrast, evidence of linkage was not detected in other panels of bipolar families that were presented. At 16p13, a maximum multipoint lod score of 4 for a latent class-derived phenotype that has aspects of alcohol dependence was found in a genome scan of 105 families from the Collaborative Study of the Genetics of Alcoholism, identifying a potential vulnerability locus.