Kristen G. Anderson, Ph.D., Reed College, “Social information processing in college drinking situations.”

Hazardous drinking among college students is associated with a host of costs to students, colleges and universities,and their surrounding communities. While research has been able to identify many of the personal, environmental and social predictors of hazardous alcohol use for this group, little research has examined how late adolescents make in-the-moment decisions to use alcohol. The purpose of this project is to design an effective laboratory method to understand the cognitive processes underlying student decisions to drink alcohol in social situations commonly associated with heavy episodic drinking on campus. Using information from the research literature and focus groups of college students, audio taped vignettes will be developed that mimic common situations associated with heavy drinking (e.g., drinking games, pregaming,
etc.). In pilot testing, college students at three institutions of higher learning (2 small liberal arts and a large university) will be asked to provide open-ended responses to these vignettes as well as completing a structured interview to better understand the sequence and content of their decisionmaking at the beginning of their first year. In addition, they will be asked to complete a number of questionnaires targeting common risk factors associated with heavy episodic drinking. Students will be reassessed at the end of their first year. We will use this data to examine the potential usefulness of this novel assessment procedure to predict student drinking behaviors across their first year of college with specific emphasis on heavy episodic drinking. The long term goal of this stream of research is to design more effective prevention programs for youth entering college in order to reduce harms associated with hazardous drinking.

Joyce Besheer, Ph.D., University of North Carolina at Chapel Hill, “Regulation of the subjective properties of ethanol by stress-related pathways.”

Drugs of abuse, such as alcohol, produce distinct subjective effects in humans, such as the feeling of “drunkenness” or relaxation that accompanies alcohol drinking. The primary goal of this application is to investigate how activation of “stress”-related systems can alter the subjective properties of alcohol using an alcohol discrimination procedure in rats. Further, we will assess how these changes can affect alcohol self-administration (drinking). In humans, exposure to a social stressor has been shown to blunt the subjective properties of consumed alcohol. Thus, changing the subjective properties of alcohol may produce a change in alcohol drinking, such as stress-induced increases in alcohol consumption reported in both the clinical and preclinical literature. Preliminary data show that activation of stress systems by exposure to corticosterone in the drinking water blunts the subjective properties of ethanol in rats. Studies in Aim 1 of this application will characterize the role of corticosterone in the blunting of ethanol’s subjective properties by manipulating length of exposure to corticosterone and exogenous levels of corticosterone. Further, these results will be extended to self-administration studies to examine the effects of corticosterone-induced blunting of alcohol’s subjective properties on self-administration. Experiments in Aim 2 will focus on type 1 corticotrophin-releasing factor (CRF1) receptors as a potential mechanism for the corticosteroneinduced blunting of alcohol’s subjective properties. Lastly, examination of CRF1 receptor regulation of corticosteroneinduced increases in alcohol self-administration will be examined. To date, the complex nature of the mechanisms mediating stress and alcohol drinking are not well understood. Given that the subjective properties of drugs can be important determinants of drug abuse liability, understanding the mechanisms by which stress can influence the subjective properties of alcohol is a novel approach and may be a possible mechanism to better understand stress-induced increases in alcohol consumption.

Bethany C. Bray, Ph.D., Pennsylvania State University, “Alcohol use and gambling in college: examining unique aspects, shared aspects, and event-level co-occurrence of behaviors.”

Gambling is being recognized as a major public health concern as the availability of legalized opportunities continues to expand in the United States. Alcohol use is one of the most important behaviors associated with gambling and problems with gambling, and the positive relation between problem alcohol use and problem gambling appears to be particularly pronounced for college students. Despite the potential for serious, long-term negative consequences for young adults who participate in both behaviors, the way in which an individual’s alcohol use during college is related to his or her specific gambling behavior is not well understood. For example, although it is often thought that drinking alcohol while gambling causes individuals to bet more, play longer, and play less skillfully than they would otherwise, research studies have shown mixed results. Understanding when and why college students drink alcohol while they gamble, and what happens when they do, is essential to preventing cooccurring alcohol and gambling problems. This project uses a series of web-based surveys to interview a sample of 670 sophomore college students about their alcohol use, gambling, and other related behaviors. Information about daily alcohol use and gambling is collected from the students for fourteen consecutive days to look at daily variation in the two behaviors. There are three main goals of this project. The first is to identify individual and environmental characteristics like gender, personality and local events that are related to an individual drinking alcohol and gambling. The second is to describe why college students drink alcohol and why they gamble, and to see whether their reasons are similar. The third is to determine whether college students are more likely to gamble when drinking alcohol than when they are not. The extent to which individual and environmental characteristics and reasons to drink alcohol and gamble are related to drinking alcohol and gambling on the same day is investigated.
    

Suzhen Chen, M.D., Ph.D., Harvard Medical School, “Molecular mechanisms of alcohol-induced brain damage.”

The goal of our research is to explore the molecular mechanisms underlying alcohol-induced brain damage. Specifically, this study will focus on the effects of alcohol on neural network formation in the cerebellum. Fetal alcohol spectrum disorders (FASD) encompasses a range of birth defects caused by maternal consumption of alcohol during pregnancy and is the leading preventable cause of mental retardation in the United States. Children with FASD suffer significant cognitive, behavioral, and neurological problems; however, the mechanisms by which alcohol causes FASD remain unclear. The cerebellum, a brain region involved in balance, motor coordination, and learning, is particularly susceptible to alcohol-induced injury, both during development and in adults. In children with FASD, cerebellar injury is associated with motor and behavioral abnormalities. One feature of alcohol toxicity in the cerebellum is the failure of neurons to migrate to their correct destination and make appropriate contacts with other neurons. Neurons make complex connections with other neurons through the elaboration of a network of long processes, known as axons and dendrites. Defects in the development of this neural network may contribute significantly to alcohol-induced brain damage. Activity-dependent neuroprotective protein (ADNP) plays a critical role in brain development and is abundant in the developing cerebellum. We have shown that levels of alcohol attained after just a few drinks block ADNP-mediated axon outgrowth by interrupting a specific signaling pathway in neurons. We will use multidisciplinary approaches to study the effects of alcohol on ADNP-mediated neural network development using intact cerebellar cortex from 6- to 8-day old rats, a developmental stage equivalent to the third trimester of human pregnancy. We will also study the relevant signaling pathways involved in the actions of ADNP and alcohol. This study will explore new mechanisms responsible for alcohol-induced brain damage and may help identify potential targets for the prevention and treatment of alcoholinduced damage in the developing brain.

Laura H. Corbit, Ph.D., Ernest Gallo Clinic and Research Center, University of California San Francisco, “Alcohol self-administration in the rat: transition from goal-directed to habitual behavior.”

It has long been hypothesized that alcohol- and drug-seeking becomes habitual over time; this is apparent in our colloquial use of the term ‘drug habit.’ An important aspect of the hypothesis of habit formation is that alcohol seeking is initially flexible and under conscious control but that with more extensive practice this behavior becomes more automatic and no longer requires an explicit representation of the goal. Rather, it is argued that this type of performance is elicited by environmental stimuli that have previously been paired with reward. The exact time course of this transition, and the neural systems controlling it, have not been defined for alcohol self-administration. The current proposal seeks to test this hypothesis as it applies to alcohol self-administration. Hence, I hypothesize that alcohol self-administration by rats that have undergone limited training will remain a flexible, goal-directed behavior whereas alcohol self-administration by rats that have longterm experience with this behavior will become an automatic, habitual behavior. I will first define the time course of the development of habitual responding for ethanol. Next, I will probe the contribution of alcohol-paired stimuli in triggering alcohol seeking following different amounts of experience with alcohol self-administration. I predict that the stimuluscontrol of responding will increase as animals develop habitual responding for alcohol. Finally, I will examine the role of different striatal regions in the control of alcohol-seeking following limited and extended training with the prediction that initial goal-directed responding should depend on the integrity of the nucleus accumbens or ventral striatum but that the dorsal striatum should play an increasing role as responding becomes more habitual in nature.

Kyung-An Han, Ph.D., Pennsylvania State University, “Genetic dissection of ethanol-induced behavioral disinhibition and sensitization.”

Alcohol consumption enhances impulsivity leading to various disinhibited behaviors such as binge drinking, risky sexual behavior, sexual assaults and increased aggression, which have detrimental impact in society. However, the underlying mechanisms are poorly understood. To systematically study the mechanisms, it is beneficial to employ a simple system where one can readily manipulate genetic or environmental components and measure the effects on behavior. To this end, we use the fruit fly, a powerful genetic model organism, to unravel the neurobiological basis of alcohol-induced disinhibition and addiction. We have found that male flies, upon recurring exposure to ethanol (the active ingredient in alcohol beverages), display disinhibited intermale courtship. Moreover, the intermale courtship activity increases with recurrent experience of ethanol. This phenomenon is known as sensitization, an adaptive change associated with addiction. These ethanol-induced disinhibition and sensitization require dopamine, a neuromolecule regulating diverse brain functions such as cognition, attention, motivation, rewards and motor control. Individual functions of dopamine are initiated upon its binding to cell surface receptors in a particular neural structure and triggering intracellular signalling and biochemical changes. These changes, in turn, modify cellular output to generate a relevant behavioral response. The proposed study is directed at identifying the molecular, cellular and neural mechanisms by which dopamine mediates courtship disinhibition and sensitization. We will accomplish this by investigating flies with genetically manipulated, molecular and cellular components of dopamine neurotransmission. Behavioral disinhibition is associated not only with alcohol drinking but also with attention deficit hyperactivity disorder and Parkinson’s disease. Likewise, anomalous dopamine functions underlie attention deficit hyperactivity disorder, Parkinson’s disease and drug addiction. Since flies and mammals share numerous neural components and functions, knowledge obtained from this research will provide significant insights into the mechanisms underlying disinhibition and sensitization associated with alcohol and other disorders.

Li He, M.D., Ernest Gallo Clinic and Research Center, University of California San Francisco, “Ethanol and the trafficking of G proteincoupled receptors.”

Alcoholism represents one of the most widespread addictions and has huge negative impacts on our society both socially and economically.
It is now believed that alcoholism is a chronic disease and involves multiple neurotransmitter systems, among them is the opioid. Opioids are possibly best known for their use in pain management clinically as well as recreational abuse. Opioids exert their biological functions by binding to a cellular membrane protein called opioid receptor. Evidence indicated that opioid receptors play a major role in the activating/reinforcing effects of ethanol consumption. For example, genetic study found that the individual with polymorphism of the opioid receptor gene is several times more likely to report a positive family history of alcohol use disorders. On the other hand, animal experiments have shown that the animals will not drink ethanol if their opioid receptor is deleted. Furthermore, naltrexone, an antagonist of opioid receptors, is one of the few drugs for treating alcoholism in clinic. Opioids consist of endogenous peptides and natural alkaloids. One of the fundamental questions in the opioid addiction is why endogenous peptides don’t cause addiction? Research found that the endogenous opioid peptides promote opioid receptors internalization following their activation and recycle back to the cellular membrane to re-function; on the other hand, the natural alkaloids, such as morphine, are failed to promote this process. The consequence of this failure is that the opioid receptors constantly stay on cell membrane, are overstimulated and become dysfunctional, leading to physical dependence and addiction. Here we hypothesize that one of the mechanisms for alcoholism is that alcohol consumption impairs the ability of endogenous opioids to promote the receptor internalization-recycling process and opioid receptors become dysfunctional, which contributes to the alcoholism. We believe that by identifying the mechanisms, we will be able to develop more effective therapeutic means to treat alcoholism.

Gregory O. Hjelmstad, Ph.D., Ernest Gallo Clinic and Research Center, University of California San Francisco, “Substance P and ethanol reward.”

Alcoholism is a major medical and social problem that impacts millions of lives. While some treatment approaches are successful, most alcoholics either continue to drink, or relapse after a period of abstinence. The ultimate purpose of our research is to develop new and more effective pharmacological therapies for the treatment of alcoholism. We are interested in understanding the changes in the brain that produce the increased motivation to drink alcohol and how that motivation to drink is influenced by factors such as stress or exposure to alcohol or cues in our environment that predict the availability of alcohol. Midbrain dopamine neurons are of particular interest as they have been implicated in both the motivational and reinforcing aspects of ethanol. Thus, agents that alter dopamine neuron activity provide plausible targets for the pharmacological treatment of alcoholism. In the current research, we are interested in how the neuropeptide substance P influences the activity of dopamine neurons. Microinjection of a substance P analog into the VTA has been shown to trigger drug relapse and drugs that block the signaling of this neuropeptide reduce craving in alcoholics.  Importantly, substance P has been shown to be released into the midbrain by stress. Thus, substance P may influence the desire to drink alcohol in stressful conditions. The goal of our research is to understand how substance P interacts with other neurotransmitter systems in the midbrain to modulate the activity of dopamine neurons. By understanding how this neuropeptide interacts with other neurotransmitter systems, we may be able to develop therapies that have synergistic actions, thus improving treatment efficacy while producing fewer unwanted side effects.
  

Gregory G. Homish, Ph.D., University of Buffalo, “Alcohol, health, and relationships.” 

Research on alcohol use, drug use, and health outcomes has traditionally focused only on personal risk factors. Thus, risk that comes about from social network members (i.e., family, friends, coworkers, etc.) is often not considered. Among adults involved in romantic relationships, intimate partners can play a significant role in affecting change in each others’ substance use and health behaviors. This grant will examine the association between a problem drinking or alcoholic intimate partner and his/her partner’s substance use and health. To address this issue, a secondary data analysis will be conducted on the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC), a nationally representative sample of over 43,000 non-institutionalized U.S. citizens and non-citizens. Using two assessments from NESARC, this project will examine patterns of alcohol use and alcohol problems among four groups of individuals who are married or living as if married to: a stable problem drinker (i.e., problem drinker at both assessments), a new onset problem drinker, recovered problem drinker, or a stable non-problem drinker. The impact of divorce from a problem drinker on an individual’s substance use and health will also be examined. Ten percent of U.S. adults have married, or have lived as if married, to an alcoholic or problem drinking partner (National Institute on Alcohol Abuse and Alcoholism, 2006); however, the true impact of this is not clear. The proposed work will provide the much needed empirical evidence about the relation between one spouse’s drinking status and his/her partner’s substance use and health outcomes.

Terri L. Messman-Moore, Ph.D., Miami University, “The impact of emotion dysregulaton and negative mood on college women’s alcohol use and drinking motives.”

The primary objective of the proposed research is to examine the hypothesis that high levels of negative emotion (e.g., anxiety), in the context of emotion dysregulation, will increase the likelihood of coping drinking motives and risky behavior in college women. Approximately 400 college women will participate in a 10-week prospective study to clarify the temporal relationship between emotion regulation strategies, negative emotion,
coping motives, risky alcohol use and sexual behavior, and sexual assault. Participants will complete brief, online measures to assess negative emotion, emotion regulation strategies, risky alcohol use and risky sexual behavior during each week; if the target behavior occurred, additional information regarding motives for such behavior will be assessed. A cross-lagged panel design will examine the relative impact of negative emotion and emotion regulation strategies on risky behavior. It is expected that women who report high levels of negative emotion and poor emotion regulation strategies will be most likely to endorse coping drinking motives. Those who drink to cope with negative emotion are expected to engage in more problematic drinking and experience more negative drinking outcomes, including unplanned and unwanted sexual behavior. Individuals who report high levels of negative emotion but who possess strong emotion regulation skills are expected to have fewer drinking and sex-related problems. The prospective design of the study should clarify whether negative emotion and emotion dysregulation impact risky behavior. Findings of this study can be used to further refine theories regarding the role of emotion dysregulation in alcohol consumption, as well as the impact of coping motives on risky alcohol use and sexual behavior. Furthermore, the study should provide essential information for empirically-based prevention and education programs concerning the influence of emotion dysregulation on alcohol use and risky sexual behavior, and those programs seeking to reduce women’s risk for sexual assault.

Yoko Nomura, Ph.D., M.P.H., Mount Sinai School of Medicine, “Consequences of in utero cigarette exposure pertaining to later alcohol use.”

Research in child psychiatry has shown that exposure to smoking in utero is associated with increased behavioral problems such as attention deficit, hyperactivity, and lack of self-regulation in childhood, and a 2- to 4-fold increased risk of delinquency and early-onset alcohol experimentation. To date, however, few studies have examined the long-term consequences of in utero exposure to maternal smoking on their offspring beyond adolescence, while taking the effects of mediating conditions that emerged earlier in life into consideration, such as cognitive functioning and neurobiological and behavioral problems. Maternal smoking during pregnancy is one of the most modifiable behavioral risk factors for substance use problems, especially alcohol experimentation and use during late childhood and adolescence. Early initiation of alcohol experimentation is known to be a risk factor for regular alcohol use and dependence later in life. Elucidation of the pathway to alcohol abuse and dependence could inform more effective interventions. Funded by ABMRF/The Foundation for Alcohol Research, this study will attempt to examine the longterm influence of prenatal exposure to maternal smoking in offspring at different stages in life, with the ultimate goal of prevention of alcohol abuse and dependence. The study utilizes existing data from a well-known developmental study, the National Collaborative Perinatal Project that followed mothers throughout pregnancy prospectively and their offspring for over 30 years. By exploiting available prospective measures of maternal smoking during pregnancy and examining various mediating problems from birth to adulthood, we will gain a greater understanding of the mechanisms by which exposure to smoking in utero leads to a sequence of problems. The results will be used to map out a developmental model of risk for early alcohol use and dependence, exploring whether different nodal points in development have distinct relationships to alcohol abuse and dependence. 

Nicole Prause, Ph.D., Idaho State University, “Effects of alcohol on behavioral activation tendencies during states of reproductive relevance.”

When a person decides to participate in a sexually risky behavior, such as having intercourse with a new partner after consuming alcohol, it often is assumed that the decision was due to some general disinhibition induced by alcohol. However, research suggests that alcohol’s ability to increase feelings of sexual arousal, rather than a direct pharmacological effect of alcohol itself, may influence decision-making. Sexual arousal is a a pleasant, high motivation state that can be quantified physiologically. This study uses a novel application of psychophysiological and cognitive methods to discriminate amongst different models of the way in which alcohol consumption, sexual arousal, and sexual risk-taking may be related. Both male and female participants will be recruited for this laboratory study. Alcohol consumption and sexual arousal level are manipulated in each of three sessions. Alcoholic beverages are provided to participants in each session to reach a low-dose, a high-dose, or simulated (placebo) low dose of breath alcohol. Sexual arousal is manipulated using sexual films and monitored using genital physiological sensors and self-reported sexual arousal. Results are expected to contribute to the development of empirically-based approaches. Understanding the true impact of alcohol on sexual decision-making should lead to more effective interventions to curb sexual risk-taking.

Lara A. Ray, Ph.D., UCLA, “Integrating human laboratory paradigms to refine alcoholism phenotypes.”

Drinking alcohol often makes people feel energized, gregarious, and relaxed. Not everyone has the same response to alcohol and some people seem to enjoy it more. The effects of alcohol are a combination of its pharmacology and learnedassociations that people have developed over time for alcohol cues. For example, a person with alcohol problems may experience an urge to drink when they see or smell their favorite alcoholic beverage. It is difficult to separate the pharmacology of alcohol from alcohol cues. In this study we will do so by administering the alcohol through an IV and then presenting alcohol cues to 40 individuals with alcohol problems. Each participant will complete two sessions, one in which they receive alcohol and one in which they receive saline solution through the IV. After the alcohol, or saline solution administration, participants will be exposed to either their favorite alcoholic beverage or a non-alcoholic beverage. In this study, we hope to better understand the difference between pharmacological effects of alcohol and the learned ones that are triggered by alcohol cues. In addition, we will study a gene that may predict who has a more positive response to the effects of alcohol. Although people do not typically drink through an IV, this study is important because in the future it can be used to help us understand medication effects since some medications for alcoholism may change the pharmacological effects of alcohol but not the urge to drink when people are exposed to alcohol cues or vice versa.

Garret Stuber, Ph.D., Ernest Gallo Clinic and Research Center, University of California San Francisco, “Afferent specific excitatory plasticity in the nucleus accumbens following voluntary ethanol intake.”

Excessive consumption of alcohol is thought to lead to longterm changes in brain reward circuitry that may contribute to relapse following periods of abstinence. The nucleus accumbens, a crucial brain area for reward-related behaviors, is likely to undergo neuroplastic changes following prolonged alcohol consumption. The nucleus accumbens is part of the larger brain reward circuit, and receives a wide variety in inputs from other brain regions such as the amygdala and prefrontal cortex, both of which also play important roles in mediating alcohol intake. While it is hypothesized that the projections from the prefrontal cortex and amygdala to the nucleus accumbens play an important role in modulated alcohol seeking behaviors, little is known about whether persistent longterm changes occur in these pathways following excessive alcohol consumption. The experiments I have proposed will directly test this hypothesis by determining whether excessive alcohol consumption leads to enhance activity of synapses in the nucleus accumbens from the prefrontal cortex and amygdala. To accomplish this, neurons from these areas that project to the nucleus accumbens will be transfected with a virus coding the light-activated channel, channel rhodopsin-2. This will allow selective stimulation of these two pathways in brain slices via light pulses. These experiments will further our understanding of the alterations in neural circuitry induced by excessive alcohol intake, and may contribute to the development of new strategies to treat addiction.  

John T. Weber, Ph.D., Memorial University of Newfoundland, “Effects of adolescent ethanol exposure on physiology and synaptic plasticity in the cerebellum.”

‘Binge drinking’ (excessive drinking over short periods of time) is common among adolescent-aged youths. At this age, the brain is still in an important stage of development. Currently, there is some initial evidence that adolescents exposed to excessive levels of ethanol may experience long-lasting adverse effects on motor coordination and areas of the brain associated with motor function. However, the mechanisms contributing to these effects at the cellular level are not understood. Motor coordination is largely controlled in an area of the brain known as the cerebellum. Purkinje neurons are a particular type of cell in the cerebellum that are intricately involved with fine-tuning movements. In addition, Purkinje neurons undergo certain forms of synaptic plasticity, which are changes in the physiology of the cells associated with the information they receive. Some types of plasticity, such as long-term depression (LTD) and long-term potentiation (LTP), are believed to be the cellular correlates of motor learning. In our research project, adolescent-aged rats are subjected to a protocol of binge ethanol ingestion. Following the binge-drinking paradigm, animals are sacrificed and electrophysiology recordings are conducted from Purkinje neurons in slices prepared from the cerebellum. Several physiological parameters are monitored in cells from control animals that have not been exposed to ethanol, as well as those treated with ethanol. In addition, LTD and LTP are evaluated in tissue from both control and ethanol-treated animals. Any alteration in the physiology of Purkinje neurons suggests that adolescent ethanol exposure may affect cellular mechanisms which contribute to long-term motor dysfunction. In addition, if LTD or LTP were inhibited, this would suggest that adolescent binge drinking might lead to problems with how we learn new movements in adulthood.