Neurobiological mechanisms contributing to alcohol-stress-anxiety interactions

This article summarizes the proceedings of a symposium that was presented at a conference entitled “Alcoholism and Stress: A Framework for Future Treatment Strategies.” The conference was held in Volterra, Italy on May 6-9, 2008 and this symposium was chaired by Jeff L. Weiner. The overall goal of this session was to review recent findings that may shed new light on the neurobiological mechanisms that underlie the complex relationships between stress, anxiety, and alcoholism. Dr. Danny Winder described a novel interaction between D1 receptor activation and the corticotrophin-releasing factor (CRF) system that leads to an increase in glutamatergic synaptic transmission in the bed nucleus of the stria terminalis. Dr. Marisa Roberto presented recent data describing how protein kinase C epsilon, ethanol, and CRF interact to alter GABAergic inhibition in the central nucleus of the amygdala. Dr. Jeff Weiner presented recent advances in our understanding of inhibitory circuitry within the basolateral amygdala (BLA) and how acute ethanol exposure enhances GABAergic inhibition in these pathways. Finally, Dr. Brian McCool discussed recent findings on complementary glutamatergic and GABAergic adaptations to chronic ethanol exposure and withdrawal in the BLA. Collectively, these investigators have identified novel mechanisms through which neurotransmitter and neuropeptide systems interact to modulate synaptic activity in stress and anxiety circuits. Their studies have also begun to describe how acute and chronic ethanol exposure influence excitatory and inhibitory synaptic communication in these pathways. These findings point toward a number of novel neurobiological targets that may prove useful for the development of more effective treatment strategies for alcohol use disorders.     

Targeting dynorphin/kappa opioid receptor systems to treat alcohol abuse and dependence

This review represents the focus of a symposium that was presented at the “Alcoholism and Stress: A Framework for Future Treatment Strategies” conference in Volterra, Italy on May 3–6, 2011 and organized/chaired by Dr. Brendan M. Walker. The primary goal of the symposium was to evaluate and disseminate contemporary findings regarding the emerging role of kappa-opioid receptors (KORs) and their endogenous ligands dynorphins (DYNs) in the regulation of escalated alcohol consumption, negative affect and cognitive dysfunction associated with alcohol dependence, as well as DYN/KOR mediation of the effects of chronic stress on alcohol reward and seeking behaviors. Dr. Glenn Valdez described a role for KORs in the anxiogenic effects of alcohol withdrawal. Dr. Jay McLaughlin focused on the role of KORs in repeated stress-induced potentiation of alcohol reward and increased alcohol consumption. Dr. Brendan Walker presented data characterizing the effects of KOR antagonism within the extended amygdala on withdrawal-induced escalation of alcohol self-administration in dependent animals. Dr. Georgy Bakalkin concluded with data indicative of altered DYNs and KORs in the prefrontal cortex of alcohol dependent humans that could underlie diminished cognitive performance. Collectively, the data presented within this symposium identified the multifaceted contribution of KORs to the characteristics of acute and chronic alcohol-induced behavioral dysregulation and provided a foundation for the development of pharmacotherapeutic strategies to treat certain aspects of alcohol use disorders.     

Neurobiology and treatment in alcoholism--recent findings regarding Lesch's typology of alcohol dependence

Subtyping in alcohol dependence has become an important issue as studies have proposed different neurobiological mechanisms in alcoholism in the recent years. Studies have shown that alcohol dependence reflects a wide range of different phenotypes, including psychological, social, and neurobiological factors. Different ways of subtyping have been proposed in the last decades, one of them being Lesch's typology of alcohol dependence. Recent investigations have shown that different subtypes of Lesch's typology are associated with specific neurobiological factors which may have important implications for clinical practice. This applies in particular for genetic and neuroendocrinological factors, differences in the regulation of NMDA receptor-mediated glutamatergic neurotransmission, and in response to acamprosate and naltrexone treatment.     

Emotions, decisions, and the limits of rationality: symposium introduction.

In this symposium, three speakers describe research that examines ways in which people's decision-making is affected by emotions. In his paper, Dr. Loewenstein describes research on the properties and effects of "projection bias," the tendency to allow one's immediate, often transient, preferences to influence decisions in the future when one's preferences will be predictable different. Over-shopping on an empty stomach or failing, when not addicted, to appreciate one's future helplessness in the face of drug craving, are examples. Dr. Schwarz focuses on how experiences that accompany the thought process can influence the ease of access to information or the fluency with which new information can be processed. These meta-cognitive experiences can affect decisions. For example, recalling many risk-increasing behaviors is more difficult than recalling only a few. Drawing on this difficulty, people who recall many risk-increasing behaviors infer that they are at lower risk than people who recall merely a few risk-increasing behaviors, in contrast to what the content of recall would suggest. Finally, Dr. Bodenhausen clarifies what is meant by stereotyping, considers how stereotypes might influence decision-making processes, and discuss why this influence often might not be very desirable. He then describes research about factors that amplify the biasing impact of stereotypes in decision making processes. The authors provide examples, discuss implications of their findings for medical decision-making, and describe strategies that we might employ to minimize or eliminate the biases that might be introduced into decision-making processes.     

Urocortins: CRF's siblings and their potential role in anxiety,depression and alcohol drinking behavior

It is widely accepted that stress, anxiety, depression and alcohol abuse-related disorders are in large part controlled by corticotropin-releasing factor (CRF) receptors. However, evidence is accumulating that some of the actions on these receptors are mediated not by CRF, but by a family of related Urocortin (Ucn) peptides Ucn1, Ucn2 and Ucn3. The initial narrow focus on CRF as the potential main player acting on CRF receptors appears outdated. Instead it is suggested that CRF and the individual Ucns act in a complementary and brain region-specific fashion to regulate anxiety-related behaviors and alcohol consumption. This review, based on a symposium held in 2011 at the research meeting on “Alcoholism and Stress” in Volterra, Italy, highlights recent evidence for regulation of these behaviors by Ucns. In studies on stress and anxiety, the roles of Ucns, and in particular Ucn1, appear more visible in experiments analyzing adaptation to stressors rather than testing basal anxiety states. Based on these studies, we propose that the contribution of Ucn1 to regulating mood follows a U-like pattern with both high and low activity of Ucn1 contributing to high anxiety states. In studies on alcohol use disorders, the CRF system appears to regulate not only dependence-induced drinking, but also binge drinking and even basal consumption of alcohol. While dependence-induced and binge drinking rely on the actions of CRF on CRFR1 receptors, alcohol consumption in models of these behaviors is inhibited by actions of Ucns on CRFR2. In contrast, alcohol preference is positively influenced by actions of Ucn1, which is capable of acting on both CRFR1 and CRFR2. Because of complex distribution of Ucns in the nervous system, advances in this field will critically depend on development of new tools allowing site-specific analyses of the roles of Ucns and CRF.     

A report on the Fetal Alcohol Spectrum Disorders Study Group meeting of 2012, theme title, “Biomarkers for FASD”

The 2012 meeting of the Fetal Alcohol Spectrum Disorders Study Group (FASDSG) focused on the development and ethics of biomarkers for fetal alcohol exposure. This one-day international conference brought students and trainees together with clinicians and researchers to discuss the latest research on FASD. One keynote speaker discussed the value of profiling epigenetic modifications in readily available fetal tissues to diagnose fetal exposure to environmental agents, while the second speaker discussed the ethics of biomarker development within the context of core principles of justice, autonomy, beneficence and non-maleficence. Three sessions of short data talks informed the audience of research advances with particular emphasis on the diagnosis of FASD. Other activities included updates on FASD-related activities by representatives of government agencies, a report on the implementation FASD-related diagnostic criteria in the fifth edition of the Diagnostic and Statistical Manual (DSM-5) of the American Psychiatric Association and a networking lunch, and the presentation of the “Merit Award” to Dr. Nathan Muraski for his work on behavioral outcomes of fetal alcohol exposure. The capstone of the meeting was the presentation of the “Henri Rosett” award to Dr. Denis Viljoen, in recognition of his role in raising awareness about the incidence of FASD in South Africa and in promoting FASD prevention and treatment programs as chairperson and chief executive officer of the Foundation for Alcohol Related Research (FARR).     

Health policy and genetic endowments: Understanding sources of response to Minimum Legal Drinking Age laws

This paper uses policy‐induced variation in legal access to alcohol in the United States to explore interactions between genetic predispositions and health behaviors. It is well known that Minimum Legal Drinking Age (MLDA) laws have discrete impacts on binge drinking behaviors, but less is known about heterogeneity of the effects and the characteristics of individuals most and least affected. Using the Add Health data, this paper explores differential policy effects based on polygenic scores (PGS), which are genome‐wide summary measures predicting health outcomes. Specifically, we leverage PGS for alcoholism and for a broader set of risk‐taking behaviors to explore heterogeneities in response to the policy and consider mechanisms for the responses. Like previous literature using the Add Health and other datasets, we find main effects of MLDA in increasing recent binge drinking episodes by approximately 5 percentage points. We find MLDA effects are concentrated entirely in individuals with high PGS for alcohol use. We are also able to compare these results with measures of parental alcoholism as a global proxy for family history.     

Interactions between cannabinoid and opioid receptor systems in the mediation of ethanol effects

Over the past few years, advances in the investigation of the neurochemical circuits involved in the development and treatment of alcohol dependence have identified peptides and receptors as potential key targets in the treatment of problems related to alcohol consumption. The endogenous opioid system is modified by alcohol intake in areas of the brain related to reward systems, and differential basal levels of opioid gene expression are found in rodents with a high preference for ethanol. This suggests a greater vulnerability to alcohol consumption in relation to differences in genetic background. Further evidence of the involvement of opioid peptides in alcohol dependence is the ability of the opioid antagonist naltrexone to reduce alcohol intake in animal models of dependence and in alcohol-dependent patients. Abundant evidence indicates that the activation of cannabinoid receptors stimulates the release of opioid peptides, therefore the cannabinoid receptor antagonists may presumably alter opioid peptide release, thus facilitating the reduction of ethanol consumption. However, little is known about the effects of ethanol on the endogenous cannabinoid system, the vulnerability of cannabinoid receptors to alcohol intake or their neurochemical implications in reducing consumption of alcohol. In this paper, we review the role of opioid and cannabinoid receptor systems, their vulnerability to alcohol intake and the development of dependence, and the targeting of these systems in the treatment of alcoholism.     

Macrophagic myofasciitis: a summary of Dr. Gherardi's presentations

Dr. R.K. Gherardi presented two papers at the symposium, detailing his researches into a proposed new clinical entity which he has entitled Macrophagic Myofasciitis (MMF). In his first paper he described the histopathologic and immunologic characteristics of the condition, and in the second, the clinical and serologic features. Dr. Gherardi believes that MMF, a syndrome of ascending myalgias, fatigue and diffuse musculoskeletal pain, may be related to a chronic immune response to aluminum granulomas persisting at the sites of prior immunization with aluminum adjuvated vaccines.     

Improving the old, embracing the new: implications of alcohol research for future practice.

Alcohol research has two important goals. The first of these is to evaluate existing therapies for treating alcoholism. The second, more long term goal is to increase understanding of the biology of alcoholism. The second, more long term goal is to increase understanding of the biology of alcoholism and to use this understanding to develop new targeted medications to prevent alcohol use problems and to improve treatment outcome. Considerable research progress has been made over the past three decades toward achieving each goal. The careful study of existing therapies and the development of both behavioral strategies and medications, such as naltrexone, have helped improve treatment success. New neuroscience techniques have led to an increased understanding of how alcohol's actions in the brain are related to the phenomenon of addiction, and new imaging techniques have permitted scientists to study alcohol's effects on the brain and to link these effects to behavior in ways not even possible just a few years ago. Finally, genetics researchers are using both animal and human genetics techniques to identify the genes that confer vulnerability to alcoholism and developing ways to apply this information to clinical populations. As a result of increased understanding of the biology of alcohol dependence, future clinicians will need to understand not just the traditional behavioral nuances of alcoholism treatment, but the biology of alcohol dependence as well.     

Older alcoholics: professional, family education programs aid treatment

The identification and treatment of older alcoholics often are complicated by negative stereotypes and inaccurate information about the aging process. these misconceptions may result from incomplete statistical data, lack of attention to the subjects of alcoholism and aging in medical and gerontological journals, disagreement concerning the disease's origin and treatment, and conflict over whether to differentiate between alcoholism and alcohol abuse. In recent professional literature, however, some of these concerns are being addressed. A wider dissemination of information is essential for health professionals as well as for alcoholics and their families. Both groups must understand the changes associated with aging so that existing programs for alcoholism treatment can be adapted to serve the elderly. Results of an informed, enlightened attitude toward older alcoholics would be: Awareness that alcoholism--at any age--is a treatable disease; Increased attention to the special communication and mobility needs of the elderly; Availability of printed and audiovisual materials about aging and alcoholism in locations where older adults gather; and The training of family members and health care workers in alcoholism identification and intervention.     

Disordered sleep, nocturnal cytokines, and immunity: interactions between alcohol dependence and African-American ethnicity.

Sleep disturbance is one of the most prominent complaints of alcohol-dependent patients. In view of recent evidence that the immune system is integrated with other homeostatic processes ultimately regulated by the brain, the influence of sleep on host defense mechanisms and the expression of proinflammatory and T helper cell cytokines deserves attention in alcohol dependence. Although not all immune alterations found in alcohol-dependent persons are related to disordered sleep, it is exceedingly important to know whether sleep influences immunity in alcoholism because of the recognized impact of disordered sleep on infectious disease risk. Conversely, feedback systems are also operating between the brain and the immune system, and abnormalities in the expression of cytokines might contribute to sleep disturbances in alcohol-dependent persons. In this review, we identify the immune alterations found in association with alcohol dependence and discuss the implications of these findings for infectious disease risk, with particular attention to the interaction between African-American ethnicity and alcoholism in contributing to this risk. We provide evidence that sleep disruption occurs in association with alcohol dependence and that African-American alcohol-dependent persons show greater abnormalities in sleep and sleep regulatory processes than shown by Euro-American alcohol-dependent persons. The relations among alcoholism, sleep, and immunity are discussed, with an emphasis on understanding how the cytokine network is altered during sleep in the African-American alcohol-dependent populations. The potential is to use cytokine agonists or antagonists to determine whether physiologic changes in cytokines have a role in the homeostatic regulation of sleep in human beings, which has tremendous implications for the development of novel treatments of alcohol-related sleep disorders.     

Plasma homocysteine concentrations do not influence craving in alcohol withdrawal.

Results of a number of studies indicate that the glutamate system, especially the N-methyl-D-aspartate (NMDA) receptor, has a major function in chronic alcoholism, including craving. Homocysteine and other excitatory amino acids, such as glutamate and aspartate, lead to an overstimulation of NMDA receptors. Because alcoholism is associated with elevated plasma homocysteine concentrations, we designed the current study to determine whether elevated plasma homocysteine concentrations have an influence on craving in alcohol withdrawal. Two groups of patients with an established diagnosis of alcohol dependence were compared. Group A comprised 50 consecutively admitted alcohol-dependent individuals who had been abstinent from alcohol between 24 and 72 h before hospitalization. Group B comprised 146 consecutively recruited alcohol-dependent individuals who were admitted, acutely intoxicated, for withdrawal treatment. All patients were assessed with the Obsessive Compulsive Drinking Scale (OCDS) on the day of admission and after 7 days of treatment. The mean (27.1, S.D. 18.4) plasma homocysteine concentration for group B was significantly higher than the mean (12.5, S.D. 5.3) plasma homocysteine concentration for group A (Mann-Whitney U test: P < .001). No significant influence of homocysteine concentration on the extent of craving was found for either group with the use of the Spearman correlation (day 0: group A, r = -.076, P = .601; group B, r = .120, P = .148) and logistic regression analysis. Although homocysteine is a potent modulator of glutamatergic neurotransmission, results of the current study provide no evidence for a pathophysiologic role of homocysteine in withdrawal craving. Therefore, further research about alcohol craving should focus on neurobiologic factors other than homocysteine.     

The role of neuroactive steroids in ethanol/stress interactions: proceedings of symposium VII at the Volterra conference on alcohol and stress, May 2008

This report summarizes the proceedings of the symposium VII on the role of neuroactive steroids in stress/alcohol interactions. The production of GABAergic neuroactive steroids, including (3α,5α)-3-hydroxypregnan-20-one and (3α,5α)-3,21-dihydroxypregnan-20-one is a consequence of both acute stress and acute ethanol exposure. Acute, but not chronic ethanol administration elevates brain levels of these steroids and enhances GABA_A receptor activity. Neuroactive steroids modulate acute anticonvulsant effects, sedation, spatial memory impairment, anxiolytic-like, antidepressant-like, and reinforcing properties of ethanol in rodents. Furthermore, these steroids participate in the homeostatic regulation of the hypothalamic-pituitary-adrenal axis. Therefore, it is not surprising that neuroactive steroids are involved in ethanol/stress interactions. Nevertheless, the interactions are complex and not well understood. This symposium addressed the role of neuroactive steroids in both stress and alcohol responses and their interactions. Professor Giovanni Biggio of the University of Cagliari, Italy presented the effects of juvenile isolation stress on neuroactive steroids, GABA_A receptor expression, and ethanol sensitivity. Professor Howard Becker of the Medical University of South Carolina, USA presented evidence for neuroactive steroid involvement in ethanol dependence and drinking behavior. Professor Patrizia Porcu of the University of North Carolina, USA described a potential neuroactive steroid biomarker that may predict heavy drinking in monkeys and mice. These presentations provide a framework for new theories on the nature of ethanol/stress interactions that may be amenable to therapeutic interventions.     

Association of polymorphisms in nicotinic acetylcholine receptor alpha 4 subunit gene (CHRNA4), mu-opioid receptor gene (OPRM1), and ethanol-metabolizing enzyme genes with alcoholism in Korean patients.

Findings obtained from several studies indicate that ethanol enhances the activity of alpha4beta2 neuronal nicotinic acetylcholine receptor and support the possibility that a polymorphism of the nicotinic acetylcholine receptor alpha4 subunit gene (CHRNA4) modulates enhancement of nicotinic receptor function by ethanol. To identify the association between the CfoI polymorphism of the CHRNA4 and alcoholism, we examined distribution of genotypes and allele frequencies in Korean patients diagnosed with alcoholism (n = 127) and Korean control subjects without alcoholism (n = 185) with polymerase chain reaction-restriction fragment length polymorphism methods. We were able to detect the association between the CfoI polymorphism of the CHRNA4 and alcoholism in Korean patients (genotype P = .023; allele frequency P = .047). The genotypes and allele frequencies of known polymorphisms in other alcoholism candidate genes, such as alcohol metabolism-related genes [alcohol dehydrogenase 2 (ADH2), aldehyde dehydrogenase 2 (ALDH2), alcohol dehydrogenase 3 (ADH3), and cytochrome P450 2E1 (CYP2E1)] and mu-opioid receptor gene (OPRM1), were studied. The polymorphisms of ADH2, ALDH2, and CYP2E1 were significantly different in Korean patients with alcoholism and Korean control subjects without alcoholism, but ADH3 and OPRM1 did not differ between the two groups.     

Treatment of alcoholism as a chronic disorder

Alcoholism is a common disorder that tends to be chronic and relapsing. Although there is clear evidence that treatment can be expected to induce a period of remission or at least decreased symptoms, treatment of alcoholism is generally regarded as unsuccessful. Alcoholism should be approached as a chronic medical disorder such as diabetes or arthritis. Complete abstinence is the preferred goal, but “cures” or permanent abstinence from alcohol are rare. In this model, treatment benefits may be measured by length of remission, reduction in alcohol use, improvement in health and enhancement of social functioning. Treatment continues over a period of years, mainly on an outpatient basis with increasing intensity if symptoms recur. Medications that reduce craving for alcohol or diminish the euphoric effects of alcohol would be very helpful in the management of this chronic disorder. Preclinical studies have produced evidence for involvement of the endogenous opioid system in the reinforcing effects of alcohol. Recent controlled clinical trials of the opiate receptor antagonist naltrexone suggest that medications of this type may improve the results of treatment for alcoholism.     

Impulsive-aggressive traits and suicidal adolescents and young adults with alcoholism

Suicidal behavior and alcohol use disorders among adolescents and young adults are serious public health problems. In the study of suicidal behavior among young people with alcoholism, it has been shown that aggression and impulsivity are higher among those who attempted suicide. Impulsivity has been related to suicidal and self-destructive behaviors within different psychiatric conditions, i.e. alcohol and substance use disorders, mood disorders, conduct disorder, impulse control disorders, antisocial personality disorder, and borderline personality disorder. The term impulsivity has been used to define different constructs such as (1) personality trait or cognitive style in which disinhibition is the core characteristic, (2) a tendency to act immediately in response to external or internal stimuli, and (3) a group of psychiatric disorders with behavioral dyscontrol. Among adolescents suicidal behavior is transmitted in families independently of psychiatric conditions, but not independently of impulsivity/aggression. Two causal links between impulsiveness and alcoholism have been proposed: (1) adolescents who develop alcoholism possess higher premorbid levels of impulsiveness than those who do not develop alcoholism, and (2) levels of impulsiveness differentiate both populations only after the development of alcoholism, with higher levels of impulsiveness among those adolescents who developed alcoholism. Cognitive behavioral techniques have shown promising results in the treatment of adolescents with alcohol and substance use disorder and suicidality. The relative frequency of suicidal behavior among adolescents and young adults suffering from alcoholism and its subsequent devastating effects on individuals, families and society merits further research and development of prevention strategies.     

Governing images and the prevention of alcohol problems

Discussions of the prevention of alcohol problems are commonly organized around particular “governing images,” which characterize alcohol problems in terms of a coherent perspective. Three such governing images in current discussions of prevention are described. The image of alcohol as an irresistibly attractive but dangerous substance, suggesting restrictions on availability, fits easily into a public health epidemiological perspective. The image of alcohol problems as problems of disruptive or compulsive behaviors ascribed to a cultural ambivalence towards alcohol, pointing to general educational campaigns, is attractive to social psychiatrists and sociologists. The image of alcoholism as a specific disease of unknown but pre-existing etiology, calling for casefinding of “hidden alcoholics,” has been a fundamental tenet of the “alcoholism movement,” aimed at securing more humane treatment for the alcoholic. Though the three images focus on different aspects of alcohol problems, each involves a disease conceptualization. Yet the assumptions of a disease conceptualization often do not fit the empirical data on drinking patterns and problems in the general population, which show continua of severity, modest overlaps between drinking problems, and only a moderate persistence of problems in time. A disease conceptualization of behavior also presumes the abnormality and undesirability of the behavior, a presumption not shared by many heavy drinkers. The ethics of prevention needs detailed discussion; some possible ethical considerations are listed. Overall, governing images have distorted and limited discussions of the prevention of alcohol problems. Some strategies of prevention which do not fit present governing images are suggested, including measures encouraging nondrinking behaviors, modifications of popular images of and reaction to drinking, and insulating drinking behavior from social damage.     

The effects of alcohol abuse among the new chronically mentally ill

In recent years, there has been a growing recognition of the high incidence of alcohol abuse among the new generation of chronically mentally ill. This article reports on a study that tracked a subgroup of the chronically mentally ill, those discharged from state psychiatric hospitals, through an entire community mental health aftercare system and its major auxiliary human service agencies. Those who were assessed by hospital discharge social workers as having a need for alcoholism services were found to be less likely to be referred for aftercare and to make contact with aftercare agencies post discharge; and for those with an alcoholism problem who do make contact, they generally received less service than those who did not have a need for alcoholism services. The professionals in both the mental health and alcoholism fields need to work together to better meet the needs of the chronically mentally ill with an alcohol problem.