2010 New Grant Project Profiles
ABMRF/The Foundation for Alcohol Research has played a major role in shaping the early careers of the most prominent alcohol researchers across North America. Since our founding in 1982, we have maximized our impact as a relatively small foundation by centering the grant program on novel research proposals put forth by the most promising investigators. Recently funded research projects which are described below offer an exciting opportunity to view the future through the studies currently underway by Foundation grantees.
Behavioral and Social Advisory Council
Beth M. Anderson, Ph.D., Hartford Hospital, “Alcohol cue reactivity as a predictor of future alcohol-use disorders.”
Adolescence is a high-risk period for initiating alcohol use and problem drinking. The biological mechanisms underlying the transition from occasional use to problem drinking remain unclear. Current research suggests an interaction of family history/genetics and environmental exposure may lead to substance use disorders. This hypothesis can be tested by examining the brain mechanisms underlying responses to environmental exposure (e.g., pictures of alcoholic beverages in social drinkers) and family history of alcoholism/genetics. Understanding the interaction of family history/genetics and environmental exposure is a critical step in testing whether a pre-existing imbalance in neural function (through family history) leads to an increased risk of alcohol use (current dysfunctional drinking) which then moderates further dysfunction resulting in an alcohol-use disorder. This proposal uses functional magnetic resonance imaging (fMRI) to examine the effect of family history of alcoholism on alcohol cue reactivity in social drinkers. We hypothesize that individuals with a positive family history of alcoholism will be more responsive to alcohol cues, as evidenced by increased signal changes in brain reward areas. After two years, participants will return for a follow-up assessment to see if an alcohol-use disorder has developed. Participants will be divided based on presence/absence of an alcohol-use disorder at follow-up. Comparisons of baseline cue reactivity will be made for these groups. It is hypothesized those individuals that go on to develop an alcohol-use disorder will show increased alcohol cue reactivity at baseline, irrespective of family history status.
Lindsay S. Ham, Ph.D., University of Arkansas, “Alcohol’s effects on emotional facial cue processing as a mechanism for social stress response dampening.”
The costs of problem alcohol use are substantial, highlighting the need to address factors contributing to alcohol-use disorders. Social anxiety appears to increase risk for alcohol-use disorders. Alarmingly, nearly half of people with social anxiety disorder also have an alcohol -use disorder. When an individual is diagnosed with both conditions, the person experiences worse symptoms of each disorder, greater impairment, and poorer prognosis than those with just one of these disorders. Understanding how social anxiety leads to drinking to cope is critical in order to identify factors to target in treatment. Unfortunately, little is known about how social anxiety might lead to problematic drinking to cope behaviors. The objective of this project is to examine a mechanism that could explain the relationship between social anxiety disorder and alcohol-use disorders: the interpretation of social cues. Specifically, the project examines responses to facial expressions, as these are considered to be a social cue of critical importance in human interactions. In the present project, socially anxious and non-anxious drinkers will complete a laboratory-based experiment investigating the short-term effects of alcohol on how one recognizes several types of facial expressions. It is expected that alcohol will alter recognition of faces more so for those with social anxiety disorder than non-anxious control individuals. Further, facial recognition is expected to correspond with one’s anxiety and reported drinking behavior outside the laboratory. The results will provide information about how alcohol is appealing for social anxious individuals in particular, which could lead to a better understanding of the factors driving drinking to cope. This project is important because the results will inform the development of effective intervention strategies for co-occurring social anxiety disorder and alcohol-use disorder. Such efforts may be expanded to other conditions in which drinking to cope is prominent as well.
James Henson, Ph.D., Old Dominion University, “A daily process examination of unintended drinking among college students.”
Many institutions of higher learning continue to commit substantial resources toward the prevention of and intervention on alcohol abuse and negative consequences among college students. Unfortunately, typical alcohol intervention effects tend to be moderate and short-lived. The primary objective of this project is to investigate one potential mechanism that may explain the underwhelming effects of most college-drinking interventions. Specifically, most models of alcohol use, and thus most interventions, assume that drinking stems from conscious deliberation, and thus they focus on assessing and altering intentional behavior. However, the present study posits a model of unintentional drinking, or a Model of Unplanned Behavior. This model assumes that unintentional drinking is particularly problematic (i.e., particularly likely to lead to more negative alcohol-related consequences); therefore, interventions that focus solely on intentional drinking ignore the substantial problems associated with unintended drinking. Whereas an individual who intends to binge-drink is more likely to be prepared to do so in a relatively safe manner (e.g., plan a designated driver, drink with responsible friends), an individual who drinks beyond what one intends to drink is more likely to be unprepared to handle the consequences from drinking (e.g., driving home from a bar). Using state-of-the-art Ecological Momentary Assessment techniques via hand-held assessment devices, this research will examine if the gap between daily drinking intentions and daily drinking behavior predicts alcohol-related problems beyond typical intention-based predictors. We predict that this new Model of Unplanned Behavior may better account for alcohol-related problems, which may in turn be used to develop more effective preventions and interventions that are directly focused on harm reduction and decreasing alcohol-related problems.
Andrew S. Kayser, M.D., Ph.D., Ernest Gallo Clinic and Research Center, University of California, San Francisco, “Frontal cortical networks and cognitive control in subjects with alcohol-use disorders.”
Cognitive control refers to our ability to make decisions in a flexible way, based on our own goals and not necessarily on immediate circumstances. Interestingly, declines in cognitive control, reflected in complaints related to attention and memory, have been noted in people suffering from alcohol-use disorders, as well as those at risk for them; and it has been shown that these declines make treatment more difficult. The goal of our work is to understand the corresponding changes in brain function in our subjects, and to use this information to guide therapies for alcohol-use disorders. Recent research has indicated that there are two distinct sets of regions in the frontal lobes of the brain that are responsible for cognitive control: one set that addresses more transient forms of control, and one that is relevant to more sustained forms important for maintaining goals for longer periods. Based on these and other findings, we hypothesize that changes in the brain regions important for sustained control contribute to the cognitive dysfunction in people with alcohol-use disorders. We plan to investigate this possibility by acquiring functional MRI scans of patients with alcohol-use disorders and analyzing the connections between brain areas important for cognitive control. By linking these MRI-based findings to measures of the symptoms and severity of alcohol-use disorders, we hope to ultimately identify brain targets for effective treatments.
Shannon R. Kenney, Ph.D., Loyola Marymount University, “Increasing protective strategies with students of poorer mental health to reduce alcohol risk.”
Escalating rates of mental health issues among college students are a growing concern for college Student Affairs professionals and administrators interested in reducing alcohol harm as these students are at increased risk for alcohol misuse and negative consequences. However, to date, few alcohol harm reduction initiatives have targeted this population. Employing protective behavioral strategies (PBS; e.g., avoiding shots of liquor or having a friend let you know when you have had enough to drink) has been associated with lower consumption levels and fewer alcohol-related consequences in college students. Although education about PBS is routinely incorporated into multi-component alcohol interventions, no research has examined facilitator led skills training of PBS as a stand-alone intervention. Further, preliminary findings demonstrating that the natural use of PBS appear particularly beneficial in reducing drinking and consequences among students with poorer (as opposed to stronger) mental health points to the promise of PBS interventions targeting this at-risk group of students. The proposal seeks to examine a PBS-specific group cognitive-behavioral skills training (CBST) intervention aimed at increasing use of PBS and decreasing heavy drinking and consequences in college women with poorer mental health during their transitions into college. Over a two year period, 250 incoming first-year females will be randomized into either a group PBS intervention that will follow a CBST model and focus on raising awareness of risky drinking situations and building skills for using PBS or a study skills-based control condition. One-month and six-month post-intervention follow-up assessments will track PBS use as well as drinking, consequences, and mental health. It is expected that students receiving the intervention will report greater use of PBS and lower levels of consumption and negative consequences than control participants. Further, severity of mental distress (general mental health, depressed mood, anxiety, and stress) is expected to moderate intervention effectiveness.
Sherry Lipsky, Ph.D., University of Washington, “Trajectories of alcohol misuse and traumatic intimate partner violence: Implications for alcohol prevention and intervention.”
Alcohol misuse, such as binge drinking, and alcohol-use disorders are important risk factors associated with intimate partner violence victimization. Studies of the temporal relationship between alcohol use and traumatic experiences of partner violence in particular are limited, with the majority of studies focused on traumatic experiences overall. Further, the current literature suggests that gender may differentially impact the relationship between alcohol use and partner violence. Other factors may affect this relationship, such as childhood traumatic experiences. Although childhood trauma, mainly family violence and dysfunction, has been associated with alcohol misuse and with partner violence, the role of childhood trauma in the alcohol-partner violence relationship has not been well-studied. In addition, much less is known about how race/ethnicity might affect these complex relationships. This study will analyze two waves of a national household survey, The National Epidemiologic Surveys on Alcohol and Related Conditions. The surveys, conducted in 2000-2001 and 2004-2005, included the U.S. non-institutionalized population 18 years of age and older. The main goal of this study is to examine whether alcohol misuse or alcohol-use disorders lead to adult traumatic partner violence experiences or if those experiences lead to alcohol misuse and alcohol-use disorders. This study will also examine the effect of childhood trauma and race/ethnicity on these relationships among the three major racial/ethnic groups in the U.S., non-Hispanic Whites, Blacks/African Americans, and Hispanics/Latinos. These questions are of major public health importance given the substantial occurrence of partner violence and alcohol problems in the U.S. and the devastating effects they can have on the lives of individuals and families. Increasing our understanding of alcohol misuse in the milieu of violence and trauma, and identifying potential gender and racial/ethnic-specific factors related to these experiences, will help to inform the development of early and targeted prevention and intervention efforts.
Tara White, Ph.D., Brown University, “Imaging biphasic alcohol effects in heavy drinkers.”
Dr. White’s ABMRF project investigates the impact of alcohol on brain processing over the time course of its effects. When consumed at moderate to high doses, alcohol has a unique, time-delimited impact on mood. Approximately 10-30 minutes after consumption people report that alcohol improves mood, making them feel “up”, positive and activated. This effect lasts a short time, and is then be followed by a quieter, more negative, “descending phase”, in which people report feeling tired, negative, or sluggish, particularly if the original dose of alcohol was moderate to high and if no additional alcohol has been consumed. Differences in the degree to which people experience either the positive or the negative effects of alcohol could pose either a vulnerability to, or a resilience from, alcohol misuse, particularly in heavy drinkers who may be uniquely at-risk for both responses. There are also significant gaps in our knowledge base related to the negative phase, which has not yet been well studied using brain imaging techniques – such as fMRI -- in humans. The present study begins to fill these gaps, investigating the acute effects of consumed alcohol on fMRI brain responses during 3 separate points in time in each heavy drinker studied – during the positive phase, during the negative phase, and during a non-alcohol control period. The present ABMRF project thus permits “within-subject” collection of fMRI data in healthy volunteers who are heavy drinkers, who are not yet dependent on alcohol but who are at risk for alcohol misuse because of their personal drinking histories. The results of the project will provide proof-of-concept data for a new program of alcohol research using fMRI. The project is important because it increases our understanding of the brain mechanisms through which chronic alcohol use may affect functional brain responses after consumption of alcohol, using a moderate alcohol dose (0.6) that is routinely consumed by heavy drinkers in the real-world.
Medical Advisory Council
Eleni Anni, Ph.D., Thomas Jefferson University, “Alcohol regulates self-renewal and differentiation capacity of embryonic stem cells.”
Fetal Alcohol Spectrum Disorders (FASD) result from exposure of the developing fetus to alcohol and characterized by varying degrees of dysfunction of the central nervous system (CNS), and other growth and facial abnormalities. The action of alcohol on the developing brain during embryogenesis is not well understood at the molecular level. We have used mouse embryonic stem (ES) cells, derived from preimplantation blastocysts, as a model system to study the effect of alcohol on the transcription factors controlling (via activation or repression of target genes) the coordinated loss of self-renewal and cell lineage commitment to neuronal fate. Our approach is based on experimental single-cell multiplex datasets and modeling of discrete alcohol-altered transcriptional networks at various differentiation stages (from the stage of the primitive germ layers), across different cell subpopulations. We have found that alcohol modulates selectively the expression of core transcription factors Sox2 and Nanog at the onset of ES cell differentiation, changes the level of their corresponding target genes, and modifies the interactions among transcription factors in the regulatory network. The goal of this proposal is to define the malfunctioning transcriptional networks leading to abnormal CNS in FASD. Results from these studies will clarify the molecular causes of FASD, provide objective methods for early diagnosis and guide targeted treatments.
Jerome W. Breslin, Ph.D., Louisiana State University Health Sciences Center School of Medicine, “Impact of alcohol intoxication on hemorrhagic shock-induced microvascular dysfunction.”
Trauma victims who arrive at the emergency room are often intoxicated, which complicates resuscitation and post-resuscitation management strategies. Trauma patients with alcohol intoxication have a lower chance of survival than their non-intoxicated counterparts. The worse outcomes for alcohol-intoxicated patients are associated with low blood pressure and formation of edema (an excessive loss of fluid from the blood into the tissues). This proposal explores how acute alcohol intoxication affects blood pressure and edema during hemorrhagic shock injury and fluid resuscitation. Our focus is on two subsets of small blood vessels, arterioles and venules, which are both important for maintenance of blood pressure and fluid balance. We hypothesize that alcohol intoxication amplifies the low blood pressure and edema following hemorrhagic shock and resuscitation by decreasing the normal function of arterioles to finely tune blood pressure and the ability of venules to limit movement of fluid out of the blood. We will use an established rat model of combined alcohol intoxication and hemorrhagic shock to test this hypothesis. Our specific aims will be to test whether alcohol, either alone or in combination with hemorrhagic shock, 1) diminishes the ability of arterioles to constrict in response to stretch by impairing calcium-dependent contraction of smooth muscle cells, and 2) disrupts the structural proteins within the endothelial cells that constitute the walls of venules, resulting in reduced venule wall integrity and increased leakage. The results from this study will provide new insights about the mechanisms by which alcohol intoxication exacerbates hemorrhagic shock-induced injury. The new information will also serve as groundwork for development of therapies to restore normal function of arterioles and venules during alcohol intoxication, leading to more effective management of alcohol-intoxicated trauma victims.
Cedrick Dotson, Ph.D, University of Florida College of Medicine, “Hormonal modulation of alcohol taste.”
Excessive consumption of alcohol affects grave social, psychological, and physiological problems within human societies. A substantial body of evidence from human and animal studies has supported the existence of a relationship between the ingestion of alcohol and the consumption of sweet substances. Collectively, these findings suggest that sweet taste perception plays a significant role in alcohol consumption. Findings from our laboratory, as well as those from other researchers, have shown that various hormonal signaling systems (e.g., glucagon-like peptide-1 (GLP-1), glucagon and leptin), which contribute to the bodies ability to maintain stable glucose levels, and/or, through actions in various places throughout the body (e.g., brain, stomach), promote the state of feeling full or “sated,” can each act to modulate sweet taste function through actions on taste buds in the tongue. However, whether or not these hormones can modulate the taste of alcohol, and its subsequent consumption, remains unclear. We intend to determine if these hormones play a significant role in modulating the taste of alcohol. The proposed studies will address the interaction between these hormones and the taste receptors in the tongue that convey “taste” information to the brain. Understanding the relationship between taste function, hormonal regulation and alcohol consumption will facilitate the development of new therapeutic targets that can help address the problem of alcohol over-consumption in society. Indeed, an understanding of the factors that can influence or modulate alcohol ingestion is crucial to finding the most effective ways to prevent and treat alcohol misuse and alcoholism.
Shizhong Han, Ph.D., Yale University, “Investigating the genetic components of alcohol dependence by second-wave analysis of the GWAS datasets.”
Alcohol dependence (AD) is extremely costly to individuals and to societies in the United States and throughout the world. A genetic contribution to AD is well established, and important progress has been achieved in identifying AD susceptible genes. However, it is clear that only a small proportion of genes that influence risk for AD have been identified, and more effort is still needed to fully characterize the genetic basis for AD. Genome-wide association studies (GWAS) may identify more AD risk loci. The database of Genotypes and Phenotypes (dbGaP) has distributed three GWAS datasets investigating the genetic components of AD and other substance dependence disorders. These GWAS datasets include alcohol research using Australian twins and their families (OZ-ALC), Collaborative Study on the Genetics of Alcoholism (COGA) and Study of Addiction: Genetics and Environment (SAGE). Further analysis of these datasets using advanced analytical strategies may lead to further insights into the genetic mechanisms underlying AD. In this proposal, we hypothesize that common variants, rare variants and epistasis may play important roles in AD risk. To test this hypothesis, we propose the following analytical strategies. First, we will conduct imputation-driven meta-analysis of GWAS datasets to uncover the genetic effects of both common variants and rare variants. Second, we will perform population-based linkage analysis and genome-wide rare haplotype scans to identify genomic regions or genes which could potentially contain multiple rare risk variants. Third, we will execute genome-wide two-locus exhaustive search, pathway and network based analysis to detect SNP-SNP interactions and to identify groups of related genes acting synergistically to confer AD risk. The findings of our current proposal would further dissect the genetic components underlying AD risk, improve our understanding of the mechanisms that underlie this disorder, and ultimately enable effective AD prevention or treatment.
Isabel Quadros, Ph.D., Federal University of Sao Paulo, “Alcohol-heightened aggression in mice: Modulation by CRF-serotonin interactions in the dorsal raphe nucleus.”
Violence and aggression are among the most harmful and damaging consequences associated with alcohol drinking. Epidemiological data show that more than 50% of violent crimes are linked to alcohol. Under certain conditions some individuals present aggression-heightening effects after consuming alcohol, an observation that is consistent across humans, non-human primates and rodents. The present proposal will increase our understanding of the neurobiological mechanisms through which alcohol escalates aggressive behavior. The focus is the modulation of serotonin function by Corticotropin-Releasing Factor (CRF) as a critical neurobiological mechanism in the transition to escalated aggression under the influence of alcohol. We propose that the dysregulation of CRF-serotonin interactions, particularly in the dorsal raphé nucleus, may characterize the emergence of escalated aggressive behavior after alcohol consumption in rodents. Preliminary results show that blockade of CRF1 receptors in the dorsal raphé nucleus selectively attenuates alcohol-heightened aggression in mice, while blocking CRF2 receptors in the dorsal raphé further escalates aggressive behavior. We hypothesize that the apparent contrasting roles of CRF1 and CRF2 receptors on alcohol-related aggression reflect differential modulation of serotonin function in the dorsal raphé. Specifically, experiments in mice are designed to: 1) Characterize the role of CRF and its receptors in alcohol-heightened aggression. 2) Determine if the dorsal raphé nucleus is a critical site for CRF effects on alcohol-heightened aggression. 3) Investigate the extent to which CRF modulation of serotonergic projections to the prefrontal cortex is a critical determinant of escalated aggressive behavior promoted by alcohol. The proposal will increase the knowledge on mechanisms that promote alcohol-heightened aggression, and further identify targets for therapeutic interventions.
Richard M. van Rijn, Ph.D., Ernest Gallo Clinic and Research Center, University of California, San Francisco, “Identification of delta opioid receptor subtypes as novel targets to treat alcoholism.”
Alcoholism and anxiety disorders have a huge impact on society, afflicting 17.6 and 40 million people in the USA, respectively. A strong correlation exists between alcohol abuse and anxiety disorders, where withdrawal-induced anxiety often drives patients to relapse. In fact, drugs commonly used to treat anxiety are often prescribed for treatment-seeking alcoholics. However, many of the treatments that currently exist to combat anxiety disorders and alcoholism are not universally effective, which has prompted the search for improved treatment. A promising treatment lies in targeting the delta opioid receptors, which play a role in both alcohol consumption and anxiety. Currently, two DOR subtypes exist, which have been shown to have opposing effects on alcohol consumption. The lack of universal efficacy exhibited by Food and Drug Administration (FDA) approved drugs to combat alcoholism, such as the opioid antagonist Revia, may be attributed to their non- selective targeting of receptors. A key goal of this study is to determine whether targeting selective DOR subtypes can simultaneously treat anxiety and prevent alcohol abuse in hopes of improving currently available drug treatments.
Jun Wang, M.D., Ph.D., Ernest Gallo Clinic and Research Center, University of California, San Francisco, “Ethanol-mediated facilitation of dorsostriatal NMDAR activity and alcohol drinking behavior.”
Addiction is a maladaptive form of learning and memory. I recently observed that excessive alcohol consumption in rodents causes a sustained increase in the activity of the NMDA receptor (NMDAR), an important channel controlling learning and memory processes, in a part of brain called the dorsal striatum. Additional behavioral findings suggest that this increase may contribute to the development and maintanance of alcohol-drinking behaviors. In this proposal I aim to identify the mechanism by which the long-lasting activation of the NMDAR induces maladaptive memory processes that ultimately results in the development and maintancence of alcohol-drinking behaviors. The cellular model of learning and memory is long-term potentiation (LTP) of another ion channel called the AMPA receptor (AMPAR)-mediated synaptic transmission, a process whereby neural information transfers from one nerve cell to another. The induction of LTP of AMPAR-mediated synaptic transmission in striatal nerve cells requires the activation of NMDARs. I, therefore, plan to investigate whether facilitated NMDAR activity in the dorsal striatum, induced by repeated exposure of rodents to alcohol, leads to potentiated AMPAR activity. In addition, nerve cells in the dorsal striatum alternate between two resting-voltage states: the DOWN-state and the UP-state. Striatal nerve cells excite only during the UP-state allowing information flow through the striatum in the brain network. Importantly, NMDAR activity controls resting-voltage during the UP-state, thereby directly governing the excitability of striatal nerve cells. I will, therefore, examine whether repeated exposure of rodents to alcohol increases the amplitude of UP-state voltages in the dorsal striatum. I predict that through one or both of these mechanisms, repeated exposure of the brain to alcohol will abnormally strengthen striatal-dependent learning, thereby enhancing alcohol-seeking and consumption. Results generated from this proposal will greatly expand our knowledge of the mechanisms that contribute to the development and maintanance of alcohol-drinking behaviors.
Please refer to the links below for grants project profiles from previous years: