2009 Grant Project Profiles
Behavioral and Social Advisory Council
Increasing evidence indicates that the majority of children adversely affected by fetal alcohol exposure do not present with birth defects. In the absence of physical features, accurate information about maternal drinking is required to confirm a diagnosis of Fetal Alcohol Spectrum Disorder (FASD) and to consider earlier interventions. Neither maternal self-report nor traditional ethanol biomarkers are sensitive enough to detect moderate drinking in pregnancy. These results will validate the use of direct ethanol metabolites in identification of moderate alcohol consumption among pregnant women.
Alcohol and tobacco are frequently used together and their combined use is associated with greater adverse health consequences than the use of either substance alone. Although previous research has found that alcohol use increases tobacco use and cravings, relatively little is known about why this is the case. It has been frequently proposed that alcohol's effects on smoking and craving involve interactions with nicotine, the putative primary addictive component of tobacco; yet there is there is little direct evidence to support this view. An alternative possibility that has received less attention is that alcohol affects smoking through an interaction that does not involve nicotine, since tobacco contains several constituents apart from nicotine that may significantly interact with alcohol. It is also possible that alcohol may affect tobacco use and craving through interactions involving nicotine and non-nicotine tobacco constituents when they are combined but not when they are administered separately. Finally, it is possible that there are individual differences among smokers in the extent to which alcohol's effects on smoking are associated with interactions involving nicotine vs. non-nicotine tobacco constituents. This project examines how alcohol affects the subjective (e.g., satisfaction and craving) and behavioral responses (self-administration) in a combination of nicotine and non-nicotine tobacco constituents across two distinct samples of smokers that drink. This research is expected to help clarify the reasons for high rates of tobacco use among consumers of alcohol, and to eventually lead to new targets for prevention and treatment for the greatest cause of death and illness among consumers of alcohol—smoking.
A large number of studies document the prevalence of heavy drinking and alcohol use disorders (AUDs) on college campuses; however, very few studies have examined patterns of alcohol use among African-American undergraduates. Studies comparing black and white college student drinking are important because (1) there are substantial racial differences in the epidemiology of alcohol use (2) rates of AUDs among African-American young adults are rising (3) African-Americans are at particularly high risk for alcohol-related consequences, such as risky sexual behavior and college attrition and (4) aspects of the college environment appear to differentially affect black and white students. To date, however, there have been no prospective, longitudinal studies of alcohol use among African American undergraduates; a critical gap in the literature. The current study aims to fill this gap by identifying predictors of alcohol use, among African-American and Caucasian students, over the transition to college and into the sophomore year. All first time freshmen at a large, urban university will be given a survey during their pre-college orientation which assesses potential predictors of alcohol use, alcohol use disorders and alcohol-related consequences. Three and fifteen months later, all African-American freshmen and an equal number of Caucasian freshmen will be e-mailed follow-up surveys. This study will allow us to identify prospective predictors of alcohol use, alcohol use disorders and alcohol-related consequences and to determine whether these predictors operate differently among African-American and Caucasian college students.
Posttraumatic stress disorder (PTSD) commonly co-occurs with problem drinking, potentially because individuals use alcohol to help cope with PTSD symptoms. This overlap is concerning given that individuals with both PTSD and alcohol abuse or dependence are more likely to relapse to alcohol use following treatment. Evoking key emotional experiences related to the traumatic event is often thought crucial in treating PTSD symptoms; however, trauma-related emotions are often not addressed in alcohol focused treatments. This may result in a cycle where unresolved PTSD symptoms maintain alcohol cravings and use even after treatment for alcohol use problems. Thus, understanding how PTSD symptoms may contribute to alcohol relapse and how we may best intervene to help individuals with both PTSD and alcohol abuse/dependence is of great importance. This study will examine the relationships between emotions associated with the trauma memory, beliefs about coping with PTSD symptoms, and rates of relapse to alcohol following alcohol focused treatment. This study will enroll 100 women currently in treatment for alcohol abuse/dependence who also report symptoms of PTSD. Assessments will be conducted at pre-treatment, post-treatment, and at 3-months following alcohol treatment. Half the participants will be instructed to write detailed, emotional accounts of their traumatic event during structured writing sessions. The other half will write about neutral events. Level of emotion during the writing will be assessed using both self-report and coding of narratives. We will compare individuals with the trauma focused versus neutral writing on alcohol cravings and rates of relapse to alcohol use following treatment. In addition, coping beliefs and motives for alcohol use will be examined. Overall, this study seeks to better understand the relationship between relapse to alcohol use and PTSD symptoms in women, and has the potential to identify important intervention targets for this difficult to treat population.
The prevalence of both alcohol use and disorder peaks during late adolescence (Kessler, 2002), coincident with the transition to college. Identifying which adolescents are most vulnerable to developing problems and disorders related to their alcohol use remains a priority of research. Both theory and research has suggested that higher levels of impulsivity underlie the development of alcohol use disorders in adolescence and young adulthood. However, recent developments in the conceptualization of impulsivity, guided by both personality theory and neurodevelopmental research, have demonstrated that impulsivity seems to be comprised of several relatively distinct facets comprising aspects of emotional drive and cognitive control, each of which may be differentially related to alcohol use and problems. Yet little is known about how these specific dimensions influence the development of alcohol use and the transition into alcohol problems, which itself has been shown to have antecedents that differ from those of alcohol use. Using a combination of survey and laboratory task measures, the project will test the influences of four unique dimensions of impulsivity on the development of alcohol use and problems in a three-wave prospective study across the first year of college. The study will use an innovative design that will analyze the associations between multiple dimensions of self control and levels and change in substance use and abuse across the first year of college.
The high co-morbidity between alcohol and nicotine dependence represents an important research priority. Alcohol-dependent smokers show an increased risk of tobacco-related mortality and morbidity. Indeed, smoking-related illnesses are the leading cause of death among alcoholics. Spontaneous smoking cessation is infrequent among alcoholics, and up to 75% of dually-dependent individuals require simultaneous treatment for both dependencies. An effective medication for treating both alcoholism and smoking would be of greater scientific and clinical value than a medication treating alcoholism alone. However, there is presently no approved single treatment for dual alcohol and nicotine dependence. Baclofen is a medication that acts on a brain neurotransmitter system, named GABAB. Some studies found that baclofen (30 mg/day) is effective in reducing alcohol drinking and craving in alcohol-dependent patients. Moreover, a recent study indicated that baclofen (80 mg/d) reduced the number of cigarettes smoked per day and cigarette craving in nicotine-dependent patients. These results lead one to conclude that baclofen could represent a new and unique medication for the treatment of alcohol dependent patients who smoke; however, this has never been formally investigated. This project proposes a double-blind, placebo-controlled treatment study to investigate the dual roles of baclofen (80 mg/d) in reducing alcohol and cigarette consumption in alcohol-dependent nicotine-dependent individuals. This research will add to our knowledge about the potential benefits of baclofen on alcohol dependence by examining its simultaneous effects on both alcohol and nicotine consumption. Furthermore, this study firstly will test a higher dose of baclofen (80 mg/day), in treating alcohol-dependent patients. The results of this study will inform future studies, which may compare different doses of baclofen and different subgroups (e.g.: alcohol-dependent smokers vs. alcohol-dependent non-smokers).
Positive expectancy among youth about outcomes of alcohol use has been identified as a cognitive predictor of underage drinking. However, an increasing body of research evidence suggests that the path from cognition to behavior within a specific situation often bypasses conscious awareness and controlled decision-making. Youth may hold implicit attitudes about alcohol. Our study examines the impact of situational primes on self-reported alcohol beliefs versus spontaneous, implicit associations. We will test the hypothesis that, prior to drinking onset, youth’s self-reported alcohol beliefs are related to longer-term intentions to use alcohol while situational cues uniquely impact implicit responses to alcohol as well as immediate approach tendencies. We will test the impact of priming a social interaction goal on positivity of implicit attitudes toward alcohol among 200 adolescents aged 12 to 14 (just prior to the average age of drinking onset). After presenting youth with a randomly assigned vignette priming either a social interaction or task-related goal, we will measure youth’s implicit cognitive associations related to alcohol, their explicit, self-reported alcohol expectancies, their intentions to use alcohol in the next 12 months, and the strength of their immediate approach/avoidance tendencies toward alcohol. We expect that youth primed with a social interaction goal will display greater implicit positivity toward alcohol than youth in the task-prime condition. Further, we predict that positivity of explicit expectancies will be associated with greater intentions to use alcohol in the next 12 months, while positivity of implicit associations will predict immediate approach tendencies toward alcohol. Our overarching research goal is to advance scientific understanding of underage alcohol use and its psychological antecedents by integrating theory and methods from developmental and social psychology.
Childhood maltreatment increases an individual’s risk for alcohol problems in young adulthood. However, we currently have minimal understanding of how childhood maltreatment influences hazardous drinking in young adulthood, which may limit the success of prevention efforts for the highly vulnerable population of young adults with a child maltreatment history. The study is designed to elucidate the relationship between exposure to childhood maltreatment and hazardous drinking in young adulthood. The primary factor postulated to link this relationship is individual self-regulation capacities (e.g., impulsiveness, planfulness). Since young people have much greater freedom from social control and parental monitoring during young adulthood than they ever did in the past, clarity about the role of self-regulation is central to our understanding of escalated alcohol use and abuse in young adulthood. The study uses 200 medically healthy young adults (ages 18-25), half with exposure to childhood maltreatment and half without exposure to child maltreatment. We will examine whether the presence of childhood maltreatment is associated with poor self-regulation processes, and investigate whether poor self-regulation processes are associated with hazardous drinking in young adulthood. The results of this study will help determine intervention targets to prevent hazardous drinking in young adulthood by enhancing maltreated individuals’ self-regulation processes.
Medical Advisory Council
M. Scott Bowers, Ph.D., Virginia Commonwealth University, “Role of rat nucleus accumbens astrocytes in alcoholism.”
The mammalian brain is predominantly composed of non-neuronal cells; the astrocytes. Abnormal astrocyte shape and abundance are frequently observed in postmortem brains from alcoholics. Traditionally, astrocytic responses were solely thought to reflect injury or toxic insult. A growing literature is now revealing that astrocytes actively shape neuronal communication. Importantly, rat strains with a smaller cortical astrocyte population exhibit increased alcohol consumption and preference. Further, poisoning astrocytes or interfering with astrocyte-to-astrocyte communication in the cortex also increased alcohol consumption and preference. My data revealed a decreased astrocyte population (fewer, smaller cells) in another brain region (the nucleus accumbens core, which is critical for cocaine, heroin, and alcohol craving and relapse). Significantly, this reduced astrocyte population appears to depend upon the repeated choice to consume cocaine or alcohol. Specifically, following repeated injection of a rat with cocaine or alcohol, astrocytes proliferate and grow, but if the rat repeatedly chooses to consume either of these drugs, the astrocyte population decreases. Thus, these data suggest that astrocyte stimulation may reduce the drive to consume alcohol. In partial support of this hypothesis, I have recently poisoned rat nucleus accumbens astrocytes and observed a significantly increased motivation to consume alcohol. Thus, I sought ABMRF support to characterize the biochemical and structural changes of rat nucleus accumbens astrocytes following repeated alcohol consumption. Further, I proposed to optically stimulate the astrocytes while the motivation to consume alcohol is measured. This AMBRF supported research will elucidate if astrocytes contribute to the etiology of alcoholism and will facilitate future funding for astrocyte transplantation that are derived from human embryonic stem cell lines. This should reduce the motivation to consume alcohol. To this end, I have already secured a highly interested and local expert in human embryonic stem cell line-derived astrocyte transplantations into the rat brain.
Anna N. Bukiya, Ph.D., University of Tennessee Health Science Center, “Alcohol-induced smooth muscle BK current inhibition and followed vasoconstriction is controlled by membrane cholesterol.”
Ethanol at levels reached in circulation after moderate-heavy episodic drinking (50 mM) inhibits the activity of cerebral artery smooth muscle cell BK channels, leading to cerebrovascular constriction. High cholesterol levels in the membrane of smooth muscle cells of arterial wall also inhibit BK channels, favoring vasoconstriction. Synergistic inhibition of BK channels by cholesterol and ethanol is expected to have a profound negative impact on vascular compliance and dilation. Preliminary data with BK channels cloned from rat resistance-size cerebral arteries and reconstituted into artificial lipid bilayers show that the presence of 33 mol% cholesterol in the bilayer robustly amplifies ethanol-induced inhibition of BK channels. These data are matched by preliminary results from native BK channels in their smooth muscle cell membrane environment: cholesterol enrichment of membranes from freshly isolated rat cerebral artery smooth muscle cells multiplies ethanol-induced BK channel inhibition. In contrast, cholesterol depletion from these membranes attenuates ethanol-induced decrease in BK channel activity. Ethanol-cholesterol interactions on arterial smooth muscle BK channels were also probed at the organ level: cholesterol depletion of rat cerebral de-endothelized arteries attenuated alcohol-induced vasoconstriction. Based on these findings, the project will use lipid bilayer recombinant channel reconstitution, patch-clamp on native channels in freshly isolated rat cerebral artery smooth muscle cells, and in vitro artery pressurization to determine whether cholesterol in arterial smooth muscle membranes play critical role in the final degree of ethanol-induced BK channel inhibition and, thus, cerebral artery constriction. While both alcohol and hypercholesterolemia are considered independent risks for cerebrovascular disease (including stroke), their co-existence will pose amplification of these modulators’ inhibitory effect on BK channels and will add an extra risk for cerebral artery constriction.
Cues such as the sight, smell or sip of an alcoholic beverage can trigger strong cravings for alcohol in abstinent drinkers, which in turn may facilitate behaviors that lead to relapse. Being able to diminish the salience of alcohol-predictive cues could therefore prove beneficial for the treatment of alcoholism. This hypothesis forms the basis of exposure-based therapy, wherein patients are repeatedly presented with alcohol-associated cues but are not given the opportunity to drink. This procedure causes a gradual reduction or ‘extinction’ of cravings and other responses elicited by alcohol-predictive cues. However, it has not proved efficacious in preventing relapse. One explanation for this lack of efficacy is that patients learn that the cue no longer predicts alcohol, but only in the treatment setting. The same or similar cues may therefore still prove capable of eliciting cravings outside the clinic. My research aims to examine behavioral and pharmacological strategies that enable this new relationship about cues and the absence of alcohol to prevail outside the treatment setting. Studies will utilize a behavioral animal model of alcohol self-administration in rats to test the hypothesis that relapse to alcohol-seeking will be reduced by presentations of an extinction-reminder cue. In addition, we will determine if drugs that enhance learning will facilitate the recall of extinction, and thereby reduce relapse to alcohol-seeking. The long-term goal of these experiments is to develop behavioral and pharmacological tools that might be employed clinically to produce long-lasting decreases in reactivity to alcohol-associated cues.
The broad objective of the proposed research is to investigate age-related differences in behavioral responses to alcohol. In humans, exposure to alcohol during adolescence is a relatively common occurrence and is a strong predictor of alcohol dependence later in life. While early use of alcohol may be related to another trait that elevates risk of abuse and dependence and may simply serve as a marker for later alcohol dependence, it is also possible that ongoing brain development during adolescence is impacted by alcohol exposure in ways that increase the likelihood of dependence in adulthood. Thus, understanding the influence of alcohol on the adolescent brain carries both short-term and long-term importance. The proposed studies will be conducted using a mouse model. Previous research suggests that adolescent rodents are relatively insensitive to several effects of alcohol compared to adults, including the aversive effects associated with withdrawal states. To the extent that the aversive effects of alcohol normally curb intake, a decrease in these effects could pave the way to increased consumption in adolescents, which could contribute to higher rates of dependence and increased risk of biomedical consequences. Using a place conditioning model to assess the aversive effects of the transition to intoxication our experiments will examine the effects of repeated alcohol exposure on its motivational effects in adolescent and adult mice. This will enable us to determine whether there are age-related differences in the development of tolerance to these effects.
Fetal Alcohol Syndrome (FAS) is a debilitating disease that has numerous defects, including variable craniofacial (skull) defects. Maternal alcohol consumption causes FAS, but FAS is also clearly genetically modulated. These genetic modifiers likely regulate the extent and severity of craniofacial disease in FAS. However, we know virtually nothing about the gene/alcohol interactions that underlie craniofacial defects in FAS. Because the genes mediating craniofacial development are highly conserved between all vertebrate species, we have used the zebrafish as a genetically tractable model system to study gene and alcohol interactions. We have found that at least two different genes interact with alcohol to cause craniofacial defects: platelet-derived growth factor receptor a (PDGFA) and ethanol-induced jaw hypoplasia. The interaction between PDGFA and alcohol causes severe palate and upper jaw defects, while ethanol-induced jaw hypoplasia and alcohol interactions cause defects of the lower jaw. The goal of this proposal is to understand the cellular causes of these gene/alcohol interactions and to discover additional genes that interact with alcohol. Results from these studies will elucidate the genetic risk factors and cellular causes of craniofacial defects in FAS, to aid in genetic counseling of prospective parents and potential therapies for FAS.
One of the most troubling, and difficult to treat, aspects of alcoholism, is relapse. Relapse occurs when an individual who has stopped consuming alcohol begins drinking again. There are numerous reasons for relapse to occur, yet one of the most commonly cited causes is stress. It has been hypothesized that chronic exposure to alcohol leads to the emergence of a negative emotional state. This negative emotional state is thought to contribute to relapse behavior, as individuals ingest alcohol as a means of relief. This altered behavior is believed to be caused by persistent adaptations in discrete brain regions that underlie stress responsivity. One brain structure that is thought to be a site of important adaptations underlying this behavior is the Bed Nucleus of the Stria Terminalis (BNST). This structure is a critical regulator of behavioral and physiological activation associated with anxiety. Recent reports suggest that activation of serotonin receptors in the BNST can govern emotional state, specifically anxiety. Our preliminary data indicate that serotonin signaling is altered in the BNST following a chronic exposure to alcohol. The experiments in this ABMRF proposal will utilize molecular and electrophysiological approaches to identify specific alterations in serotonin signaling in the BNST that may contribute to increased anxiety-like behavior following chronic ethanol exposure. Given the critical role that these long lasting behavioral deficits are believed to play in alcohol abuse and relapse, understanding molecular mechanisms that underlie this process could lead to more effective therapeutic interventions.
Exposure to ethanol during fetal development leads to a wide range of neurological deficits collectively termed fetal alcohol spectrum disorders (FASD). Impaired cognitive ability in individuals affected by FASD is associated with risk for several forms of adverse outcome later in life. Studies of the FASD population indicate that existing therapeutic intervention is effective, and that efficacy improves when therapy is initiated early in life. However, behavioral symptoms of FASD are not detectable until several years after birth, and therefore FASD is difficult to detect at early ages. Animal behavioral studies have established that rodents provide a powerful model of the impaired behavioral control characteristics of FASD. Additionally, anatomical studies of ethanol-treated animals have demonstrated specific morphological effects of ethanol exposure on developing neurons. A challenge remains to determine whether anatomical observations made at early stages of development relate to subsequent behavioral impairments. The first goal of the proposed research is to utilize a magnetic resonance imaging technique termed diffusion tensor imaging (DTI) to detect the effects of fetal ethanol exposure on morphological development of neurons in the cerebral cortex. By combining DTI with a Golgi-staining-based anatomical technique for quantifying morphological abnormalities, the hypothesis will be tested that perturbed cerebral cortical development may be detected through elevated anisotropy in water diffusion. The second goal is to leverage the non-invasive nature of the DTI technique to determine the behavioral consequences of altered cerebral cortical development. In an additional set of experiments, DTI measurements will be performed on immature rats to assay for anatomical evidence of ethanol-induced damage, and then the same rats will be behaviorally characterized as mature animals. Impaired motor control and cognitive impulsivity will be behaviorally characterized in ethanol-exposed and control rats. This approach will potentially provide an objective strategy for early FASD detection.
Previously, we have found the BK potassium channel represents a key target of ethanol important for behavioral responses to alcohol in a wide variety of species including model invertebrate organisms (C. elegans and Drosophila) and higher animals (mouse and human). The project seeks to take advantage of the powerful genetic tools available in C. elegans to discover the molecular basis for how ethanol activates this ion channel to cause acute intoxication. Then it will be determined whether these molecular mechanisms are conserved in mammalian BK channels. Therefore, we expect that our proposal has the potential to significantly increase our understanding of the molecular mechanisms for how ethanol acts on a single ion channel to contribute to acute intoxication.
Chronic alcohol abuse is the major cause of cirrhosis and liver failure in adult patients in the United States. Alcoholic liver disease in patients progresses from steatosis to hepatitis, fibrosis, and cirrhosis. A decade ago, Ronald Thurman’s group established the concept that excessive alcoholic intake damages the intestinal epithelial barrier which leads to an increase in intestinal permeability. This results in an elevation of the levels of endotoxin, Gram negative bacterial cell wall components, also known as lipopolysaccharide (LPS), in the portal vein. Increased endotoxin reaches the liver through the portal vein, which stimulates hepatic resident macrophages, Kupffer cells, by the activation of Toll-like receptor (TLR) 4, a receptor for LPS. Then, activated Kupffer cells produce a large amount of inflammatory cytokines and reactive oxygen species, resulting in alcoholic liver injury and inflammation. We have recently demonstrated that TLR4 signaling contribute to the activation of hepatic stellate cells, the central cellular components of extra cellular matrix protein production, including collagen, during liver fibrosis. However, the role of TLR4 on hepatic stellate cells in alcoholic liver disease is largely unknown. The study aims to investigate whether TLR4 signaling activates hepatic stellate cells and further investigate whether TLR4-activated hepatic stellate cells contribute not only to alcoholic liver fibrosis, but to alcoholic liver injury and inflammation as well in vivo by using intragastric alcohol feeding models (Tsukamoto-French Model). The project will use an in vitro study using hepatic stellate cells isolated from alcohol-treated mice, which is a new method we have recently developed. The results from this proposed study will provide insight into the potential targeting of TLR4 on hepatic stellate cells for developing new therapies for alcoholic liver disease.
Please refer to the links below for grants awarded in previous years: