Genetics of alcohol and tobacco use in humans

The field of genetics holds great promise for furthering our understanding of the etiology of drug dependence and for identifying novel targets for treatment. Genetic studies utilizing twins and families have demonstrated a considerable role for genetics in nicotine and/or alcohol dependence. Risk for alcoholism or nicotine dependence is likely to be the result of a large number of genes, each contributing a small fraction of the overall risk. While this review will focus on studies in humans, many of the candidate genes for human nicotine and alcohol dependence listed here were originally postulated to be important, based on data from animal studies. The review will briefly summarize the results from twin and adoption studies that provide estimations of heritability, the results from chromosomal linkage studies that identify regions of chromosomes that may contain relevant genes, and the results of candidate gene studies. For each topic the data will be presented for nicotine dependence, alcohol dependence, and for nicotine and alcohol dependence together. In addition, each section will review briefly some of the confounding issues in the specific type of approach utilized.     

Implications of CYP2A6 genetic variation for smoking behaviors and nicotine dependence

Nicotine is the primary addictive compound in tobacco smoke. In this review we summarize nicotine dependence and the genetics of smoking in brief before focusing on cytochrome P450 (CYP) 2A6. In humans nicotine is mainly inactivated to cotinine and CYP2A6 mediates approximately 90% of this conversion. Some, but not all, studies suggest that genetic variation in CYP2A6 may play a role in smoking. We review some of the recent findings on the influence of CYP2A6 genetic polymorphisms on nicotine kinetics, smoking behaviors, and how the gene appears to exert differential effects during various stages of smoking (eg, initiation, conversion to dependence, amount smoked during dependence, and quitting). These new findings will be put in the context of the discrepancies found in the literature. Implications of these recent findings on current and novel treatment approaches for smoking cessation and tobacco-related lung cancer will also be discussed.     

Neurobiology of relapse to alcohol in rats

Relapse to alcohol use after prolonged withdrawal periods is the major problem in the treatment of alcohol dependence in humans. However, until recently, relatively few preclinical studies concentrated on the elucidation of the neurochemical events underlying relapse to alcohol. In this article we will review recent data from studies in which alcohol-deprivation and reinstatement models were used to determine the mechanisms underlying relapse to alcohol in rats. In the alcohol-deprivation model, the intake of alcohol is determined after prolonged periods of forced abstinence in drug-experienced rats. In the reinstatement model, the ability of acute non-contingent exposure to drug or non-drug stimuli to reinstate drug seeking is determined following training for drug self-administration and subsequent extinction of the drug-reinforced behavior. We will review studies, which used these preclinical models, on the effect of specific pharmacological agents on relapse to alcohol seeking induced by re-exposure to alcohol and to alcohol-associated cues and by exposure to stress. Subsequently, we will describe potential neuronal circuits that may underlie relapse to alcohol. Finally, future directions and clinical implications of the study of relapse to alcohol in laboratory animals will be discussed briefly.     

Willingness to treat drug dependence and depression: comparisons of future health professionals

PURPOSE: Stigma-related feelings, including degree of enthusiasm and willingness to work with alcohol, drug, and mental disorder (ADM) patients, as well as anticipated success in such work, will be required for the United States to be successful in its new initiatives for ADM screening, brief intervention, and effective referral to treatment and rehabilitation services (SBIRT). This study investigates students of medicine and social work with respect to their stigma-related feelings and degree of enthusiasm or willingness to treat patients affected by alcohol dependence, nicotine dependence, or major depression. Inference is strengthened by an anonymous online survey approach, with use of randomized reinforcers to gain at least partial experimental control of nonparticipation biases that otherwise are present in student survey data. MATERIAL AND METHODS: All students on required course rosters were asked to participate in a two-part in-class and online assessment; 222 participated, with a gradient of participation induced via randomly drawn reinforcers for online survey participation. Between-group comparisons were made with a multivariate generalized linear model and generalized estimating equations approach that adjusts for covariates. RESULTS: Medical and social work students did not differ from each other with respect to their willingness to treat patients affected by major depression, alcohol dependence, or nicotine dependence, but together were less willing to treat nicotine and alcohol dependence-affected patients as compared to depression-affected patients. Personal history was not associated with the students' willingness to treat, but men were less willing to treat. Drawing strength from the randomized reinforcer experimental design nested within this survey approach, the study evidence suggests potential nonparticipation bias in standard surveys on this topic. CONCLUSION: These results indicate that future health professionals may prefer to treat depression as opposed to drug dependence conditions. For SBIRT success, curriculum change with educational interventions may be needed to increase willingness to treat patients with neuropsychiatric conditions such as drug dependence. Future research requires attention to a possible problem of nonparticipation bias in surveys of this type.     

The role of norharman in alcohol dependence and smoking: The potential inhibitory role of norharman on the urge for alcohol and nicotine use

The aim of this study was to investigate the role of the endogenous substance norharman in processes of alcohol and nicotine or tobacco dependence in both humans and animals. For this purpose heavy smokers and excessive alcohol drinkers were recruited, and rats were made dependent on alcohol and nicotine. Plasma concentrations of norharman were measured in drug‐naïve, drug‐free and drug‐taking situations. In addition, craving and nicotine dependence were measured in the group of heavy smokers, while in the animal studies the effect of exogenously administered norharman on the behavioural signs of alcohol and nicotine withdrawal were determined. Humans who abstained from smoking and drinking for a period of 12?h showed normal plasma levels of norharman. Resumption of smoking, but not drinking, generated elevated plasma levels of norharman, especially after smoking self‐made non‐filter cigarettes. Although craving after a period of abstinence was stronger in smokers with high tobacco dependence compared to those with low dependence, the plasma levels of norharman were only negatively related to craving among low nicotine‐dependent smokers. From the animal experiments it was concluded that nicotine intake had no effect on plasma levels of norharman. On the other hand, withdrawal symptoms elicited in nicotine‐dependent rats could be attenuated by exogenous administration of norharman. Rats made alcohol‐dependent by forced intake of an ethanol‐containing diet showed higher norharman levels in plasma and brain compared to alcohol‐naïve rats. This increase is caused by a lower clearance of norharman by the liver of alcohol‐fed rats. After stopping alcohol intake, behavioural signs of alcohol withdrawal occurred which were inhibited by pretreatment with norharman. The results indicate that norharman is involved in processes of alcohol and tobacco dependence and that this substance may be a candidate adjuvant in alleviating abstinence symptoms.     

Clinical pharmacology of nicotine: implications for understanding, preventing, and treating tobacco addiction

Understanding the basic and clinical pharmacology of nicotine provides a basis for improved prevention and treatment of tobacco addiction. Nicotine acts on nicotinic cholinergic receptors in the brain to release dopamine and other neurotransmitters that sustain addiction. Neuroadaptation and tolerance involve changes in both nicotinic receptors and neural plasticity. Nicotine addiction can occur in the context of physical dependence characterized by self-medication to modulate negative affect and/or to relieve withdrawal symptoms, as well as, in light or occasional smokers, primarily for positive reinforcement in specific situations. Nicotine is metabolized primarily by CYP2A6. Its clearance exhibits considerable individual variability that is determined by genetic, racial, and hormonal (sex) factors. Genetically slow metabolism of nicotine appears to be associated with a lower level of dependence. Nicotine dependence is highly heritable and appears to be influenced by genes coding for some nicotine receptor subtypes, some neurotransmitter genes, and genes involved in neural connectivity. Novel pharmacotherapies for nicotine dependence include partial agonists for nicotinic receptors and nicotine vaccines. Pharmacogenetic studies suggest various candidate genes and a nicotine metabolism phenotype that influence outcome. Human pharmacology studies of nicotine and smoking behavior also provide a basis for assessing the benefits and risks of long-term nicotine use for harm reduction and for a potential cigarette regulatory strategy that includes reducing nicotine content of cigarettes to nonaddictive levels.     

The contribution of genetics to addiction therapy approaches

Addictions, including alcohol dependence, which is the focus of this article, are complex genetic diseases. Recently, several individual genes that contribute to the risk for alcohol dependence have been identified, and more are expected to be in the near future. Among these are genes encoding alcohol and aldehyde dehydrogenases and GABA(A) receptor subunits. These reveal pathways of vulnerability and provide targets for rational drug design. It is likely that response to particular therapies is also a complex trait influenced by genetics, but studies to explore this are just beginning. We discuss some studies on bromocriptine, naltrexone, and serotonergic agents. Adding a genetic component to treatment trials could greatly help to understand the biological basis of variations in the efficacy of therapies and, in the future, could lead to individualized choices of therapy.     

Research Update: Addictive Patterns Among Battered Women: A Pilot Study

Drug and alcohol use figures as a prominent factor in many situations of domestic violence. Patterns of misuse or abuse of these substances may signal addictive behaviors. Consequences of the addictive use of drugs and alcohol by battered women may impair the decision-making process, limiting the possible alternatives to leaving a violent home. Other women may remain in the situation because of addiction to the relationship. Information collected on the potential addictive behaviors of battered women can help determine areas of assessment and intervention. Assessment in this area can prevent severe consequences of all addictions: drugs, alcohol, nicotine, and food. While knowledge on relationship to addiction is minimal, information in this area may help to explain women's selection of mates or need to stay in a destructive relationship that sometimes results in death at the hands of her mate. Currently proposed research will explore addictive behaviors among 100 women. Women of various ages and ethnic groups will be questioned regarding general demographic material, past and current relationships, violent behavior of spouse or child, abuse of drugs, alcohol, food, and nicotine. Subjects will be temporarily housed at either a local woman's shelter for abuse, an eating disorder unit, or a private psychiatric facility for chemical dependency. Additional women in outpatient therapy for an eating disorder with a private counselor also will be surveyed. A control group of females (n = 50) not identified as victims of violence or having addictions to drugs, alcohol, food, or nicotine will be similarly surveyed. Data related to addictive behaviors will be collected via the PROMIS Questionnaire, a series of 30 similar questions identifying information on 12 different addictive areas. For this research study information will be collected on five addictive areas only. Collective data on each subject will be plotted on a specific circular graph highlighting both primary and possible cross addictions. History of relationship of violence will be assessed via the Conflict Tactic Scales (CT Scales). Demographic information will be gleaned from participants' answers to several short questions. Study results anticipate that battered women will present with a primary relationship addiction and several potential cross addictions as they battle to survive the violence of which they are a part. Information collected will serve to help others better understand the needs and coping strategies of battered women and explore why some battered women choose to stay in abusive relationships.     

Essential hypertension: genes and dreams.

Herein we review all of the data from linkage by genome scanning and from association studies in essential hypertension. Genome scans have yielded loci linked to hypertension on almost every chromosome. We tabulate all of these loci to highlight the striking inconsistency. Similarly, association studies have implicated > 66 genes to date, which we also list, but virtually all have failed to show consistent replication in other settings. Nevertheless, we believe that molecular genetics should eventually find all of the major gene variants for essential hypertension. This will be a great scientific achievement and lead to new treatments. The dream, however, of using this information in clinical genetic testing could turn out to be a nightmare. Thus at present the hype surrounding genes for complex polygenic diseases like hypertension far exceeds the reality.     

Sex differences in nicotine dependence among addictions clients accessing a smoking cessation programme in Vancouver, British Columbia, Canada

ACCESSIBLE SUMMARY: ? The purpose of this study was to examine differences in substance use disorders, psychiatric disorders and nicotine dependence among 323 women and men accessing a smoking cessation programme in an addiction treatment setting in Vancouver, British Columbia, Canada. ? Individuals with substance use and psychiatric disorders have smoking prevalence rates nearly double that of the general population. Yet, there are distinct differences between men and women in their smoking behaviour and responses to smoking cessation treatment. Few studies have examined such sex differences among individuals with substance use and psychiatric disorders. ? The study found that compared with individuals with no psychiatric diagnosis, those with a mood, anxiety and psychotic disorders were significantly more likely to be female; whereas compared with those without a substance use disorder, individuals with alcohol, cocaine or marijuana disorder were more likely to be male. Moreover, among women having an anxiety disorder history and smoking a greater number of cigarettes per day were significantly associated with high nicotine dependence. Among men, smoking a greater number of cigarettes per day and having a lower confidence in quitting were significantly associated with high nicotine dependence. ? These findings suggest the need for appropriate assessment of smoking behaviour and nicotine dependence among individuals accessing addictions treatment services. Moreover, these findings further provide evidence of the need for tailored interventions for tobacco dependence among men and women with histories of substance use and psychiatric disorder. ABSTRACT: Most individuals in drug treatment programmes use tobacco and are dependent on nicotine. For 323 participants (65% men, mean age = 49.3 years) with a history of substance use disorder (SUD) and/or psychiatric disorders (PD) enrolled in a tobacco dependence clinic programme, we compared baseline characteristics among women and men and examined factors associated with nicotine dependence (ND). Individuals with mood, anxiety and psychotic disorders were more likely to be female, whereas men were more likely to be characterized by alcohol, cocaine and marijuana use, older age, older age at smoking initiation and higher confidence in quitting smoking scores. In stratified multivariate analyses, among women, history of an anxiety disorder and a greater number of cigarettes smoked per day were associated with higher ND scores; among men, a greater number of cigarettes smoked per day and higher confidence in quitting scores were associated with higher ND scores. Given the differences in smoking, SUD and PD histories between women and men accessing addiction treatment, and differential associations with ND, it is important to further explore factors that may enhance tailored treatments and inform future studies examining biological and psychosocial factors for tobacco use in SUD and PD treatment populations.     

Genetic analysis for nicotine dependence

Smoking cessation is extremely important to prevent the development of the serious diseases, such as COPD and cancers. Absorbed nicotine through smoking into the body is mainly metabolized by cytochrome P450 (CYP) 2A6. On the other, the nicotine acts in the brain through neuronal nicotinic acetylcholine receptors (nAChRs), which regulate the addictive properties of nicotine. Many associated studies have implicated genetic backgrounds influence smoking behavior and nicotine dependence. In these concepts, we here discuss the genes related to nicotine dependence from the pharmacokinetic and pharmacodynamic aspects of nicotine. Referring to the genome association studies, better understanding the molecular mechanisms of nicotine dependence would help to design targeted, more effective therapies for the tobacco-related diseases and smoking cessation program.     

Nicotine dependence criteria and nicotine withdrawal symptoms in relation to pain among an adult general population sample

Background: Evidence has shown that people who have smoked at any point in life have a higher probability of pain than those who have never smoked. The goal of this study was to analyze whether there are associations between nicotine dependence including nicotine withdrawal with pain and the number of pain locations. Methods: Data stems from a cross‐sectional survey study with a probability sample of residents of a northern German area with 4075 study participants, aged 18–64 years (participation rate 70.2%). Face‐to‐face in‐home computer‐aided interviews (Composite International Diagnostic Interview) were used to assess single pain locations, the diagnostic criteria of nicotine dependence, alcohol dependence, depressive, and anxiety disorders according to the Diagnostic and Statistical manual of the American Psychiatric Association (DSM‐IV). Results: Ever smokers with three or more nicotine dependence criteria after controlling for alcohol dependence, depressive, anxiety disorders, age and gender revealed an odds ratio (OR) of 4.2 (95% confidence interval, CI, 2.0–9.0) compared to ever smokers without nicotine dependence criteria, and ever smokers with four or more nicotine withdrawal symptoms displayed an OR of 3.6 (CI 1.5–8.7) compared to ever smokers who had not experienced withdrawal symptoms. Current smokers who used 20 or more cigarettes per day had an OR of 0.5 (CI 0.3–0.8) of experiencing pain in three or more locations compared to former smokers. Conclusion: Nicotine dependence criteria are associated with a higher probability of pain than having no nicotine dependence criteria in this general population sample.     

Polymorphisms in coagulation factor genes and their impact on arterial and venous thrombosis

Arterial and venous thromboses, with their clinical manifestations such as stroke, myocardial infarction (MI), or pulmonary embolism, are the major causes of death in developed countries. Several studies in twins and siblings have shown that genetic factors contribute significantly to the development of these diseases. Since the advent of molecular genetics in medicine, it has been a focus of interest to elucidate the role of mutations in various candidate genes and their impact on hemostatic disorders such as arterial and venous thromboses. In this article, we review the current knowledge of the contribution of polymorphisms in coagulation factors to the development of thrombotic diseases. We show that in arterial thrombosis, results are controversial. Only for factor XIII 34Leu a protective effect on the development of myocardial infarction has been demonstrated in several studies. No other single polymorphism in a coagulation factor could be confirmed as a relevant risk factor, although there is evidence for a role of factor V Arg506Gln, factor VII Arg353Gln, and vWF Thr789Ala polymorphisms in patient subgroups. Further studies will be necessary to confirm the value of testing for genetic polymorphisms in arterial thrombosis. A large body of data is available on the role of factor V Arg506Gln and the prothrombin G20210A mutation in venous thrombosis. Some papers already recommend diagnosis and treatment strategies. We will discuss these recent publications on venous thrombosis in our review.     

Drug abuse, dependence, and addiction in chronic pain patients.

It is claimed that a significant percentage of chronic pain patients suffer from drug/alcohol abuse/dependency/addiction. To address this question, 24 articles alluding to chronic pain patient drug/alcohol dependence/addiction were reviewed according to the following criteria: method for drug misuse diagnosis, which drug misuse diagnosis used (abuse, dependence, or addiction), and percentage of patients within each diagnostic category of drug misuse. The result of the review indicated that only seven studies utilized acceptable diagnostic criteria and/or definitions for the drug misuse diagnoses and gave percentages of drug misuse. Within these seven studies, the prevalence percentages for the diagnoses for drug abuse, drug dependence, and drug addiction were in the range of 3.2-18.9%. It is concluded that these diagnoses occur in a significant percentage of chronic pain patients. However, there is little evidence in these studies that addictive behaviors are common within the chronic pain population.     

Post-menopausal hormone replacement therapy and stroke risk

This paper will review available data bearing on the relationship of post-menopausal hormone replacement therapy to the risk of first or recurrent ischaemic stroke. Although experimental data from both human and animal studies will be briefly mentioned, the bulk of evidence is from observational epidemiological studies. As such, the limitations of observational studies, particularly as applied to the health effects of post-menopausal hormone replacement therapy, will be emphasized. We conclude that there is no compelling consistent evidence that post-menopausal hormone replacement therapy either decreases or increases stroke risk. There are, however, reasons to be concerned that this therapy may contribute to stroke risk.     

Implications of genome wide association studies for addiction: Are our a priori assumptions all wrong?

Substantial genetic contributions to addiction vulnerability are supported by data from twin studies, linkage studies, candidate gene association studies and, more recently, Genome Wide Association Studies (GWAS). Parallel to this work, animal studies have attempted to identify the genes that may contribute to responses to addictive drugs and addiction liability, initially focusing upon genes for the targets of the major drugs of abuse. These studies identified genes/proteins that affect responses to drugs of abuse; however, this does not necessarily mean that variation in these genes contributes to the genetic component of addiction liability. One of the major problems with initial linkage and candidate gene studies was an a priori focus on the genes thought to be involved in addiction based upon the known contributions of those proteins to drug actions, making the identification of novel genes unlikely. The GWAS approach is systematic and agnostic to such a priori assumptions. From the numerous GWAS now completed several conclusions may be drawn: (1) addiction is highly polygenic; each allelic variant contributing in a small, additive fashion to addiction vulnerability; (2) unexpected, compared to our a priori assumptions, classes of genes are most important in explaining addiction vulnerability; (3) although substantial genetic heterogeneity exists, there is substantial convergence of GWAS signals on particular genes. This review traces the history of this research; from initial transgenic mouse models based upon candidate gene and linkage studies, through the progression of GWAS for addiction and nicotine cessation, to the current human and transgenic mouse studies post-GWAS.     

Future possibilities in migraine genetics

Migraine with and without aura (MA and MO, respectively) have a strong genetic basis. Different approaches using linkage-, candidate gene- and genome-wide association studies have been explored, yielding limited results. This may indicate that the genetic component in migraine is due to rare variants; capturing these will require more detailed sequencing in order to be discovered. Next-generation sequencing (NGS) techniques such as whole exome and whole genome sequencing have been successful in finding genes in especially monogenic disorders. As the molecular genetics research progresses, the technology will follow, rendering these approaches more applicable in the search for causative migraine genes in MO and MA. To date, no studies using NGS in migraine genetics have been published. In order to gain insight into the future possibilities of migraine genetics, we have looked at NGS studies in other diseases and have interviewed three experts in the field of genetics and complex traits. The experts’ ideas suggest that the preferred NGS approach depends on the expected effect size and the frequency of the variants of interest. Family-specific variants can be found by sequencing a small number of individuals, while a large number of unrelated cases are needed to find common and rare variants. NGS is currently hampered by high cost and technical problems concurrent with analyzing large amounts of data generated, especially by whole genome sequencing. As genome-wide association chips, exome sequencing and whole genome sequencing gradually become more affordable, these approaches will be used on a larger scale. This may reveal new risk variants in migraine which may offer previously unsuspected biological insights.     

尼古丁依赖的脑功能MRI研究进展

近年来,随着功能磁共振技术的发展,越来越多的研究者运用这种技术以探讨尼古丁依赖的神经生物学机制。作者主要总结了尼古丁神经药理作用的脑功能成像研究进展,证实了尼古丁依赖与多巴胺奖赏环路、认知、渴求脑环路之间的相关性。这些研究发现将为人类认识尼古丁依赖的大脑功能改变提供了一定的客观证据,深入认识与尼古丁依赖相关的脑功能状态可能有助于从药理学和行为学上改进戒烟的治疗。     

The role of pregnane neurosteroids in ethanol withdrawal: behavioral genetic approaches

Within the last 20 years, rapid nongenomic actions of steroid hormones have been demonstrated to occur via an interaction with ligand-gated ion channels. For example, the pregnane neurosteroid allopregnanolone (ALLOP) is a potent positive modulator of gamma-aminobutyric acid(A) (GABA(A)) receptors. The physiological significance of fluctuations in endogenous ALLOP levels has been investigated with regard to disease states and the effect of therapeutic agents on ALLOP levels. Because the pharmacological profile of ALLOP is similar to that of ethanol (EtOH), the modulatory effect of pregnane neurosteroids on EtOH dependence and withdrawal will be the focus of this review. Data on the effects of chronic EtOH exposure and withdrawal on pregnane neurosteroid levels, biosynthetic enzymes, and changes in neurosteroid sensitivity will be summarized. Results from genetic animal models indicate that seizure-prone animals have a persistent decrease in endogenous ALLOP levels during EtOH withdrawal in conjunction with tolerance to ALLOP's anticonvulsant effect. Manipulation of endogenous ALLOP levels with finasteride also markedly reduced the severity of chronic EtOH withdrawal. Gene mapping studies provide a hint for an interaction between genes for GABA(A) receptor subunits and the biosynthetic enzyme 5alpha-reductase. Overall, the results are suggestive of a relationship between endogenous pregnane neurosteroid levels and behavioral changes in excitability during EtOH withdrawal, consistent with recent findings in humans. While the findings with ALLOP emphasize the therapeutic potential of neurosteroid treatment during EtOH withdrawal, the gene mapping studies suggest that pregnane neurosteroid biosynthesis may represent a target for therapeutic intervention in the treatment of alcohol dependence.