Severity of alcohol dependence in patients with alcoholic liver disease.

To determine the severity of dependence on alcohol in patients with alcoholic liver disease the severity of alcohol dependence questionnaire was administered to 193 patients with various types of alcoholic liver disease established histologically, in whom a detailed history of lifetime alcohol consumption was also obtained. Only 34 patients (18%) were classified as being severely dependent compared with 56% of patients without overt liver disease who were attending a neighbouring alcohol treatment unit. There was a significant correlation between the severity of dependence and mean daily alcohol consumption (r = 0.45 and 0.39 for men and women, respectively) but not duration of drinking. Dependence scores tended to be lower in patients with cirrhosis than in those with precirrhotic liver disease, but this difference reached significance only in women. These findings confirm that patients who develop chronic alcoholic liver disease are usually only mildly dependent on alcohol and support the hypothesis that patients who escape florid symptoms of alcohol dependence are at greater risk of developing liver damage because they are able to sustain a continual consumption of alcohol over many years.     

Functional variant in a bitter-taste receptor (hTAS2R16) influences risk of alcohol dependence

A coding single-nucleotide polymorphism (cSNP), K172N, in hTAS2R16, a gene encoding a taste receptor for bitter beta -glucopyranosides, shows significant association with alcohol dependence (P = .00018). This gene is located on chromosome 7q in a region reported elsewhere to exhibit linkage with alcohol dependence. The SNP is located in the putative ligand-binding domain and is associated with an increased sensitivity to many bitter beta -glucopyranosides in the presence of the N172 allele. Individuals with the ancestral allele K172 are at increased risk of alcohol dependence, regardless of ethnicity. However, this risk allele is uncommon in European Americans (minor-allele frequency [MAF] 0.6%), whereas 45% of African Americans carry the allele (MAF 26%), which makes it a much more significant risk factor in the African American population.     

云南汉族酒精依赖综合征与COMT遗传多态性的关联研究

目的：研究儿茶酚胺氧位甲基转移酶（COMT）的不同基因型及等位基因频率在云南汉族酒精依赖综合征患者组和健康对照组的分布差异。方法：应用聚合酶链式反应．限制性片段长度多态性分析法,对COMT基因的rs2075507、rs737865、rs4680、rsl65599四个基因位点进行特异性扩增,限制性内切酶酶切分型。结果：上述4个候选基因中,COMT基因rs737865位点C／C基因型频率在健康对照组较酒依赖组高,其基因型分布在两组中有差异,且具有统计学意义（P〈0．05）。其余3个位点统计学分析均无显著性差异（P〉0．05）。单倍型分析：上述四个候选基因构建出12种主要单倍型（每种单倍型在对照组和酒依赖组中的频率至少有一个大于1％）,单倍型A—C—A—A有可能是云南汉族酒精依赖发生的一种危险因子（OR：2．865,P=0．003347）。连锁不平衡分析显示：云南汉族人群中,COMT基因的rs2075507和rs737865之间存在着强连锁（D〉0．8）。结论：在云南汉族人群中,COMT基因rs2075507、rs4680和rs165599位点与酒依赖无关联性,rs737865C／C基因型可能是酒精依赖的保护因子,可能降低嗜酒的发生率。单倍型A-C-A-A有可能是云南汉族酒精依赖发生的一种危险因子。云南汉族人群中,COMT基因的rs2075507和rs737865之间存在着强连锁。     

Cue Reactivity Is Associated with Duration and Severity of Alcohol Dependence: An fMRI Study

Introduction

With the progression of substance dependence, drug cue-related brain activation is thought to shift from motivational towards habit pathways. However, a direct association between cue-induced brain activation and dependence duration has not yet been shown. We therefore examined the relationship between alcohol cue-reactivity in the brain, cue-induced subjective craving and alcohol dependence duration and severity. Since alcohol dependence is highly comorbid with depression/anxiety, which may modulate brain responses to alcohol cues, we also examined the relation between comorbid depression/anxiety and cue-reactivity.

Methods

We compared 30 alcohol dependent patients with 15 healthy controls and 15 depression/anxiety patients during a visual alcohol cue-reactivity task using functional magnetic resonance imaging blood oxygenated level-dependent responses and subjective craving as outcomes. Within the alcohol dependent group we correlated cue-reactivity with alcohol dependence severity and duration, with cue-induced craving and with depression/anxiety levels.

Results

Alcohol dependent patients showed greater cue-reactivity in motivational brain pathways and stronger subjective craving than depression/anxiety patients and healthy controls. Depression/anxiety was not associated with cue-reactivity, but depression severity in alcohol dependent patients was positively associated with craving. Within alcohol dependence, longer duration of alcohol dependence was associated with stronger cue-related activation of the posterior putamen, a structure involved in habits, whereas higher alcohol dependence severity was associated with lower cue-reactivity in the anterior putamen, an area implicated in goal-directed behavior preceding habit formation.

Conclusion

Cue-reactivity in alcohol dependence is not modulated by comorbid depression or anxiety. More importantly, the current data confirm the hypothesis of a ventral to dorsal striatal shift of learning processes with longer dependence duration, which could underlie increasingly habitual substance use with progressing substance dependence.     

大鼠酒精躯体依赖及动机行为研究

目的：诱导大鼠产生酒精依赖,观察大鼠产生的躯体依赖及行为学改变。方法：20只雄性SD大鼠,其中饮酒组和对照组各10只。通过6％（v／v）酒精溶液作为饮酒组大鼠唯一饮水来源共28d,测量血酒精浓度。根据旷场行为、戒断症状和强迫游泳等方法来判断是否成功诱导大鼠产生酒精躯体依赖及动机行为改变。结果：整个实验过程饮酒组大鼠血酒精浓度没有发生明显变化。饮酒组大鼠旷场测试中水平活动量在饮酒第7d比对照组显著降低（P〈0．05）;垂直活动量在饮酒第7、14d比对照组显著降低（P〈0．05）;饮酒组大鼠戒断2-48h酒精戒断评分均显著高于对照组（P〈0．01）且评分在戒断第6h最高;戒断24、48h的大鼠在强迫游泳中绝对不动时间比对照组显著延长（P〈0．05）。结论：大鼠持续饮用6％（v／v）浓度酒精溶液可以诱导出大鼠对酒精的严重躯体依赖和抑郁状态,并抑制大鼠在新奇环境中的活动能力和动机行为。     

Reduced Dopamine Transporter Availability and Neurocognitive Deficits in Male Patients with Alcohol Dependence

Dopamine plays an important role in the development of alcohol dependence, cognitive dysfunction, and is regulated via dopamine transporter activity. Although dopamine transporter activity is critically involved in alcohol dependence, studies observing this relationship are limited. Thus the current study examined whether dopamine transporter availability is associated with developing of alcohol dependence and cognitive dysfunction. Brain imaging with ^99mTc-TRODAT-1 as a ligand was used to measure dopamine transporter availability among 26 male patients with pure alcohol dependence and 22 age- and sex- matched healthy volunteers. The Wisconsin Card Sorting Test (WCST) and Tridimensional Personality Questionnaire (TPQ) were administered to assess neurocognitive functioning and personality traits, respectively. Compared to healthy controls, patients with alcohol dependence showed a significant reduction in dopamine transporter availability (p < 0.001), as well as diminished performance on the WCST (p < 0.001). Dopamine transporter availability was negatively correlated with both total and perseverative WCST errors among healthy controls, but only patients with alcohol dependence showed a positive correlation between dopamine transporter availability and a harm avoidance personality profile. Thus, reductions in dopamine transporter availability may play a pathophysiological role in the development of pure alcohol dependence, given its association with neurocognitive deficits. Moreover, personality may influence the development of pure alcohol dependence; however, additional clinical subgroups should be examined to confirm this possibility.     

乙醛在小鼠酒依赖性行为中的作用研究

乙醛为酒精代谢的中间产物,但其在酒依赖中的作用不清楚.通过条件化位置偏好(CPP)和条件化味觉偏好(CTP)试验,分析乙醛对小鼠乙醇依赖性行为的影响,研究乙醛在酒依赖中的作用.研究发现,经0.8%乙醇预处理7d后,小鼠训练8次则表现出对乙醇的条件化位置偏好(n=6,P<0.01),而经乙醛训练的小鼠则对乙醛无明显条件化偏好行为(n=6,P>0.05).当用0.8%乙醇、0.4%乙醛混合训练乙醇依赖性小鼠时,其位置偏好行为减弱(n=6,P<0.01).10%乙醇预处理的小鼠味觉偏好乙醇(n=6,P<0.01),而当乙醇中加入1%乙醛时,其味觉偏好现象减弱(n=6,P<0.01).1%乙醛训练7d后的小鼠不表现对乙醇的味觉偏好,但选择摄入乙醛及乙醇、乙醛混合溶液的量有所增加.结果表明乙醛在小鼠酒依赖行为中可能存在一定促进作用.     

Phytotherapeutic approach to alcohol dependence: New old way?

Alcohol abuse and dependence represent a worldwide problem from both medical and social points of view. In Italy it is estimated that there are about one million alcohol-dependent subjects. The pharmacological treatment of patients with alcohol dependence plays a key role in order to achieve alcohol abstinence and prevent relapse. At present, the possible utility of the complementary medicines in the treatment of alcohol dependence is controversial. In the last years, pre-clinical and clinical data from traditional medicines suggest that novel pharmacological approaches for treatment of alcoholism and alcohol abuse may stem from natural substances. The present review summarizes the findings of the effects of phytotherapy in alcohol addiction.     

Substance use in remand prisoners: a consecutive case study.

OBJECTIVES: To determine the prevalence of drug and alcohol use among newly remanded prisoners, assess the effectiveness of prison reception screening, and examine the clinical management of substance misusers among remand prisoners. DESIGN: A consecutive case study of remand prisoners screened at reception for substance misuse and treatment needs and comparison of findings with those of prison reception screening and treatment provision. SETTING: A large adult male remand prison (Durham). SUBJECTS: 548 men aged 21 and over awaiting trial. MAIN OUTCOME MEASURES: Prevalence of substance misuse; treatment needs of substance misusers; effectiveness of prison reception screening for substance misuse; provision of detoxification programmes. RESULTS: Before remand 312 (57%) men were using illicit drugs and 181 (33%) met DSM-IV drug misuse or dependence criteria; 177 (32%) men met misuse or dependence criteria for alcohol. 391 (71%) men were judged to require help directed at their drug or alcohol use and 197 (36%) were judged to require a detoxification programme. The prison reception screen identified recent illicit drug use in 131 (24%) of 536 men and problem drinking in 103 (19%). Drug use was more likely to be identified by prison screening if an inmate was using multiple substances, using opiates, or had a diagnosis of abuse or dependence. 47 (9%) of 536 inmates were prescribed treatment to ease the symptoms of substance withdrawal. CONCLUSIONS: The prevalence of substance misuse in newly remanded prisoners is high. Prison reception health screening consistently underestimated drug and alcohol use. In many cases in which substance use is identified the quantities and numbers of different substances being used are underestimated. Initial management of inmates identified by prison screening as having problems with dependence producing substances is poor. Few receive a detoxification programme, so that many are left with the option of continuing to use drugs in prison or facing untreated withdrawal.     

Prefrontal Response and Frontostriatal Functional Connectivity to Monetary Reward in Abstinent Alcohol-Dependent Young Adults

Although altered function in neural reward circuitry is widely proposed in models of addiction, more recent conceptual views have emphasized the role of disrupted response in prefrontal regions. Changes in regions such as the orbitofrontal cortex, medial prefrontal cortex, and dorsolateral prefrontal cortex are postulated to contribute to the compulsivity, impulsivity, and altered executive function that are central to addiction. In addition, few studies have examined function in these regions during young adulthood, when exposure is less chronic than in typical samples of alcohol-dependent adults. To address these issues, we examined neural response and functional connectivity during monetary reward in 24 adults with alcohol dependence and 24 psychiatrically healthy adults. Adults with alcohol dependence exhibited less response to the receipt of monetary reward in a set of prefrontal regions including the medial prefrontal cortex, lateral orbitofrontal cortex, and dorsolateral prefrontal cortex. Adults with alcohol dependence also exhibited greater negative correlation between function in each of these regions and that in the nucleus accumbens. Within the alcohol-dependent group, those with family history of alcohol dependence exhibited lower mPFC response, and those with more frequent drinking exhibited greater negative functional connectivity between the mPFC and the nucleus accumbens. These findings indicate that alcohol dependence is associated with less engagement of prefrontal cortical regions, suggesting weak or disrupted regulation of ventral striatal response. This pattern of prefrontal response and frontostriatal connectivity has consequences for the behavior patterns typical of addiction. Furthermore, brain-behavior findings indicate that the potential mechanisms of disruption in frontostriatal circuitry in alcohol dependence include family liability to alcohol use problems and more frequent use of alcohol. In all, these findings build on the extant literature on reward-circuit function in addiction and suggest mechanisms for disrupted function in alcohol dependence.     

Association of CHRM2 polymorphisms with severity of alcohol dependence

The cholinergic muscarinic 2 receptor (CHRM2) gene has been considered a candidate gene for the alcohol dependence in that it might underpin certain risk factors for this condition. This study examined variations in the CHRM2 between the patients with alcohol dependence and population controls in Korean and explored the associations between CHRM2 polymorphisms and severity of symptoms in the patients with alcohol dependence. One hundred and fifty-five patients with alcohol dependence, defined by the Alcohol Use Disorders Identification Test (AUDIT) and the Alcohol Dependence Scale (ADS) to measure the severity of symptoms, and one hundred and ninety-five population controls were drawn in the study. Three single nucleotide polymorphisms (SNPs) of CHRM2 were genotyped using the TaqMan assay and analyzed with the severity of symptoms of alcohol dependence. We found that although SNP rs324650 showed marginal association with the risk of alcohol dependence (P = 0.03), the significance of the result was not sustained after multiple corrections. SNP rs1824024 was significantly associated with the AUDIT and ADS scores in patients (P = 0.005 and 0.003, respectively). These findings suggested that the muscarinic acetylcholine function might be related not with alcohol dependence itself but with the severity of alcohol dependence in Korean population.     

Alcohol dependence, temper and personality

This review focuses on classical and recent research work in the field of alcohol dependence. Data from psychopathological studies trying to determine a "pre-addictive" personality are exposed. More recent studies assess personality disorders and dimensions of temperament associated to alcohol dependence. Sensation seeking, antisocial personality and novelty seeking appear as the main psychological parameters involved in dependence. Sensation seeking is a dimension of personality often associated to behavioral dependence. Sensation seeking is assessed with a five-component scale including general factor, thrill and adventure seeking, experience-seeking, disinhibition, and boredom susceptibility. Patients presenting alcohol dependence have a higher level of sensation seeking. Neurophysiological and genetic studies try to correlate these personality features to biological parameters. Preliminary results of these works are presented and discussed.     

Validation of differential GDAP1 DNA methylation in alcohol dependence and its potential function as a biomarker for disease severity and therapy outcome

Alcohol dependence is a severe disorder contributing substantially to the global burden of disease. Despite the detrimental consequences of chronic alcohol abuse and dependence, effective prevention strategies as well as treatment options are largely missing to date. Accumulating evidence suggests that gene-environment interactions, including epigenetic mechanisms, play a role in the etiology of alcohol dependence. A recent epigenome-wide study reported widespread alterations of DNA methylation patterns in alcohol dependent patients compared to control individuals. In the present study, we validate and replicate one of the top findings from this previous investigation in an independent cohort: the hypomethylation of GDAP1 in patients. To our knowledge, this is the first independent replication of an epigenome-wide finding in alcohol dependence. Furthermore, the AUDIT as well as the GSI score were negatively associated with GDAP1 methylation and we found a trend toward a negative association between GDAP1 methylation and the years of alcohol dependency, pointing toward a potential role of GDAP1 hypomethylation as biomarker for disease severity. In addition, we show that the hypomethylation of GDAP1 in patients reverses during a short-term alcohol treatment program, suggesting that GDAP1 DNA methylation could also serve as a potential biomarker for treatment outcome. Our data add to the growing body of knowledge on epigenetic effects in alcohol dependence and support GDAP1 as a novel candidate gene implicated in this disorder. As the role of GDAP1 in alcohol dependence is unknown, this novel candidate gene should be followed up in future studies.     

Screening and diagnosis of alcoholism in the primary care setting.

As many as 20% of patients seeing their primary physicians may suffer from alcohol abuse and dependence. Often the problem goes unrecognized. In this article I summarize what is known regarding the natural history, risk factors, and available screening techniques for alcoholism. Ultimately, a diagnosis of alcoholism is based on a patient''s history, and there are various approaches to obtaining a thorough alcohol history and overcoming patient denial regarding an alcohol problem. Primary physicians have an important role in educating patients about alcoholism.     

Catecholamine content of the rat brain at different stages of experimental alcoholism

Changes in the noradrenaline (NA) content in the hypothalamus, dopamine (DA) and homovanillic acid (HVA) in the striatum were determined in rats after chronic alcohol administration. A single injection of alcohol (2.5 g/kg i.p.) provoked a 30% decrease in NA only in rats predisposed to ethanol intake. Voluntary intake of 15% ethanol for 10 days made the NA content return to normal, the 4-month use of ethanol did not change whereas the 8-month use reduced the NA content by 17%, DA by 31% and raised the content of HVA by 25%. Twenty-four hours after alcohol abstinence the HVA content dropped by 13%. It is concluded that the noradrenergic system is involved in the formation and development of alcohol motivation and that the dopaminergic system participates in the development of the physical dependence and abstinence.     

Temporal pattern in consumption of the first drink of the day in alcohol-dependent persons

Loss of control over drinking and the craving for alcohol are cardinal signs of alcohol dependence. Our clinical practice indicates that these cravings do not occur randomly during the day, but at the same times each day for the same patient. To validate this hypothesis that alcohol-dependent patients have a circadian rhythmic craving in their desire for their first drink of the day, we asked 217 persons diagnosed as alcohol-dependent according to DSM-IV criteria to complete a questionnaire that surveyed whether this craving occurred at a fixed time each day. Of the respondents, 82% reported it did; 87% of them could state the time of day they consumed their first daily drink; and 80% reported that the time of their first drink of the day did not vary much from one day to the next. The most frequent time of consuming the first drink of alcohol was between 09:00 and 11:00 h, and it was independent of the subjects' sleep-wake routine (the delay between the hours of wake-up and the time of the first urge for alcohol was 3:45 +/- 3:30 h) and lunch or dinner time. This rhythmicity seems to be a pertinent criterion for alcohol dependence syndrome.     

Amperometric alcohol electrode with extended linearity and reduced interferences.

Conventional amperometric alcohol electrodes were constructed with oxygen- and hydrogen peroxide-base sensors and a much improved electrode was designed by placing a hydrophobic, gas-permeable membrane over the conventional hydrogen peroxide-based alcohol electrode. The immobilization of alcohol oxidase with glutaraldehyde was also studied and optimized. The upper linear ranges of the conventional and newly designed alcohol electrodes were 0.02 and 0.5% ethanol, respectively. The hydrophobic membrane of the new design eliminated the classical electrochemical interferences of hydrogen peroxide-based electrodes and the typical pH dependence of enzymatic systems.     

Basic research on heredity and alcohol: Implications for clinical application

Abstract

Alcoholism has been described as a behavioral condition comprised of symptoms of alcohol dependence and the psycho‐socio‐biologic consequences of chronic alcohol dependence. Progress in clarifying the role of genetic factors in explaining differences in onset of dependence upon alcohol, frequency of consequences of chronic alcohol use, and transmission of patterns of alcoholism within a family pedigree has been based upon use of diagnostic methods that reliably and validly separate alcohol dependence from alcohol abuse. Twin methods, which control for genotypic variation, and adoption studies, which control for differences in rearing, have provided significant support for a genetic vulnerability hypothesis for development of alcoholism and a genetic heterogeneity hypothesis for type of alcoholism. The author reviews data from basic and clinical investigation of two subtypes of alcoholism: one associated with antisocial personality, and one that is “familial” (family‐history‐positive alcoholism). Significant differences in onset and clinical course for these subtypes suggest that differential plans for matching treatment to the individual alcoholic may be warranted.     

中枢单胺类神经递质在酒精依赖中的分子作用机制

酒精依赖是以失去控制地饮用酒精为特征的慢性、复发性脑疾病, 业已成为严重的社会问题。中枢单胺类神经递质(包括多巴胺、5-羟色胺等)在酒精依赖症的发生、发展和系统功能失调中发挥着重要作用。文章探讨了单胺类神经递质关键调控点多巴胺受体、5-羟色胺受体、转运体、酪氨酸羟化酶、色氨酸羟化酶及单胺氧化酶基因等在酒精依赖中的作用机制, 结合本实验室在基因敲除小鼠模型方面的研究进展提出了酒精依赖分子机制的研究策略。在系统评述中枢单胺类神经递质介导的酒精依赖分子作用机制的基础上, 结合本实验室在酪氨酸羟化酶激活剂钙调蛋白依赖的蛋白激酶Ⅱ方面的研究成果探讨了可用于酒精依赖症治疗的作用靶点, 提出通过调整基因调控区的甲基化程度和改变pre-mRNA的选择性剪切等表观遗传学策略预防和治疗酒精依赖症, 同时根据基因多态性研究结果提出对酒精依赖症患者进行个性化预防和治疗的新策略。     

The effect of changes of the content of membrane cholesterol and the effect of benzyl alcohol on the activity of the intrinsic Mg2+-ATPase from the erythrocyte plasma membrane of the flounder (Platichthys flesus L.)

Extraction of membrane cholesterol and incorporation of cholesteryl hemisuccinate into the membrane affect the activity of the membrane-bound Mg2+-ATPase. Increasing the ratio of cholesterol to phospholipid from 0.30 mg/mg in the control membranes to 0.45-0.90 in the enriched membranes results in a slight increase of the activity of about 20%. Diminishing the ratio of cholesterol to phospholipid to about one tenth of the ratio of the control membrane results in a decrease of the activity to about 30% of the untreated control. Benzyl alcohol inactivates the membrane-bound enzyme. Digitonin-solubilized Mg2+-ATPase is also inactivated by benzyl alcohol. For concentrations below 20 mM the dependence of the solubilized and the membrane-bound enzymes are virtually identical, and linearly dependent on alcohol concentration. This linear relationship continues up to 70 mM for the solubilized enzyme, while inhibition of the membrane-bound form shows a slightly steeper dependence on inhibitor concentration. It is suggested that the activity of the native Mg2+-ATPase depends on the organization of the lipid phase of the membrane and that addition of benzyl alcohol or depletion of cholesterol results in a disorganization of the lipid phase which in turn results in diminished activity.