Mark T. Fillmore - US grants

Binge drinking is prevalent among college students and contributes to serious social and personal problems. A continued pattern of binge drinking poses immediate health risks (e.g., alcohol poisoning, acute alcoholic hepatitis), as well as long- term consequences (alcohol dependence, liver cirrhosis). The proposed research addresses the longstanding question of why some binge drinkers continue to binge drink, despite their attempts to restrain from excessive drinking. The proposed research examines how cognitive impairment produced by a moderate dose of alcohol can compromise a drinker's ability to stop ongoing drinking behavior and contribute to a binge. The study examines young healthy social drinkers between 21 and 30 years old. The research uses a cognitive paradigm to test the degree to which social drinkers can control and inhibit their behavior under a moderate dose of alcohol administered in the laboratory. Individual differences in the degree to which alcohol impairs this ability are examined in relation to drinker's self-reports of binge drinking, and other risk factors, such as their level of subjective reinforcement from alcohol, and their level of preoccupation with controlling drinking. The research will determine whether the propensity to binge drink is greater is greater among individuals who suffer more impairment of behavioral control from a dose of alcohol. The research also will show how alcohol impairment of self-control can represent an abuse liability factor that differs from traditional abuse liability measures that are based on self-reported levels of subjective intoxication and reinforcement. The long-term objective of this research is to determine how individual differences in alcohol impairment of cognitive functioning can represent an early-onset risk factor for later alcohol dependence by promoting a continued pattern of abusive binge drinking.

DESCRIPTION (provided by applicant): Excessive alcohol use during a drinking episode (i.e., a binge) contributes to many adverse health and social consequences. Binge drinkers are more likely to drive while intoxicated and to suffer blackouts and hangover. A continued pattern of binge drinking poses immediate health risks (e.g., alcohol poisoning, acute alcoholic hepatitis), and long-term consequences, such as alcohol dependence and liver cirrhosis. Given that even mild doses of alcohol impair cognitive processes that control behavior, it is important to understand how such disturbances also can reduce control over alcohol intake once a drinking episode has begun. The proposed project aims to determine how the inability to curtail alcohol consumption during a drinking episode is linked to alcohol-induced impairment of cognitive processes involved in the self-control and regulation of behavior. The research will examine acute alcohol impairment of cognitive functions in young non-dependent drinkers. The project combines measures of alcohol effects on cognitive inhibitory processes with traditional abuse liability indices based on subjective rewarding effects of the drug and its ability to reinforce self-administration. Studies will determine the degree to which alcohol abuse potential is influenced by two mechanisms of drug action: 1) reward-enhancing effects (i.e., elevation of an approach "go" mechanism); and 2) impairment of cognitive inhibitory processes (i.e., suppression of an avoidance "stop" mechanism). Multiple strategies will test the role of acute cognitive impairment in the abuse liability of alcohol. A drug-reinforcement model will test the degree to which preload alcohol doses "prime" subsequent drug self-administration by impairing inhibitory control processes that regulate behavior. The research also will test an indirect alcohol antagonist drug. caffeine, and an approved medication for alcohol abuse, naltrexone, for their ability to reduce alcohol self-administration by blocking its impairing effects on inhibitory control. The research has several long-term objectives. The findings will provide an understanding of how drinkers' susceptibility to alcohol's acute cognitive-impairing effects can pose an early-onset risk factor for later alcohol dependence by promoting a continued pattern of abusive binge drinking. The research strategies also will provide methods for testing the role of cognitive mechanisms in the treatment efficacy of existing pharmacotherapies. such as naltrexone, as well as some investigational medications that might operate via cognitive mechanisms (e.g., acamprosate). Finally, the proposed experiments will provide initial methods and protocols for studying alcohol use in combination with other drugs of abuse that also disrupt cognitive functions, such as cocaine, for which binge use is also a common pattern of drug-taking.

DESCRIPTION (provided by applicant): The effects of adolescent drug use on cognitive functioning is a significant public health concern. Adolescence marks a time of considerable neural development, particularly in brain regions that control attention and behavioral impulses. Drug use during these critical periods of brain development could impede or alter the normal course of neural maturation, resulting in long-term cognitive deficits in these areas. There is also considerable interest in the possibility that stimulant medications, such as methylphenidate, used in the treatment of attention deficit hyperactivity disorder (ADHD), could sensitize adolescents to the rewarding and disinhibiting effects of other stimulants, thus increasing their risk of abuse as this population enters young adulthood. Despite growing concern about the consequences of adolescent drug use, little is known about the specific behavioral and cognitive deficits that might result from a history of adolescent drug use. The proposed R21 project is designed to identify specific inhibitory-based, neurocognitive deficits associated with a history of adolescent drug use and to examine how this association is mediated by two established adolescent risk factors for substance abuse, ADHD and conduct disorder (CD). Inhibitory deficits will be examined in two domains of functioning: control of behavioral impulses and the ability to select attention to relevant stimuli. Studies will use behavioral and psychophysiological techniques (EEG) to identify specific inhibitory deficits prior to, and following, a history of adolescent drug use. Drug challenge tests are also proposed to identify potential differences in the acute sensitivity to the neurocognitive and rewarding effects of abused drugs as a function of adolescent drug use history and adolescent history of ADHD and CD. The long-term objective of this research is to distinguish antecedent inhibitory deficits that contribute to risk of early-onset adolescent drug use, from resultant inhibitory deficits that represent the underlying neurological insult following a protracted history of adolescent drug use.

DESCRIPTION (provided by applicant): Excessive alcohol use (i.e., a binge) contributes to many adverse health consequences (e.g., alcohol poisoning, acute alcoholic hepatitis and live cirrhosis). Alcohol is well-known for its acute impairing effects on neurocognitive processes involved in the regulation of behavior and attention. Yet, little research has examined how such disturbances might reduce self-control over actual alcohol use, leading to patterns of abusive drinking (e.g., binge drinking). Given that even mild doses of alcohol impair control of behavior and attention, it is important to understand how acute intoxication can reduce control over alcohol intake once a drinking episode has begun. The proposed project is based on the hypothesis that abuse potential of alcohol is determined by its reward-enhancing effects and its disruptive effects on control mechanisms. Experiments will examine non-dependent adults and will test the disruptive effects of alcohol on neurocognitive control mechanisms in relation to two characteristics associated with increased alcohol abuse: 1) alcohol-induced priming of self-administration;2) the development of alcohol tolerance. Studies examine the effects of controlled doses of alcohol on neurocognitive performance tasks that measure inhibitory and activational aspects of control. The measures will be studied in relation to alcohol-induced priming of self-administration and in the development of learned alcohol tolerance. The findings will provide an understanding of how drinkers'susceptibility to alcohol's acute behavioral-impairing effects can pose an early-onset risk factor for later alcohol dependence by promoting a continued pattern of abusive binge drinking. The research strategies also will provide methods for testing the role of neurocognitive mechanisms in the treatment efficacy of existing pharmacotherapies, such as naltrexone and acamprosate, as well as some investigational medications that might operate via neurocognitive control mechanisms:

DESCRIPTION (provided by applicant): Alcohol tolerance refers to a diminished intensity of response as doses are repeated. Tolerance has long been implicated as a factor contributing to alcohol abuse and dependence by encouraging the use of escalating doses to reinstate initial effects of the drug. Alcohol is also well-known for its acute impairing effects on neurocognitive processes involved in the regulation of behavior and attention. Yet, little research has examined how such disturbances might reduce self-control over actual alcohol use, leading to patterns of abusive drinking (e.g., binge drinking). Moreover, despite interest in tolerance as a phenotypic marker for alcohol use disorders, little research has sought to determine how differences in alcohol sensitivity and tolerance might characterize populations at-risk for alcohol abuse, such as those with externalizing disorders (e.g., ADHD). The proposal is based on the working hypothesis that abuse potential of alcohol is determined by sensitivity to its reward-enhancing effects and to its disinhibiting effects. The proposed studies examine the contribution of tolerance to abuse potential as measured by changes in alcohol effects on basic mechanisms involved in the control and regulation of behavior. Studies will investigate: 1) the sensitivity of control mechanisms to the impairing effects of alcohol and their contribution to abuse potential;2) tolerance development to the impairing effects on mechanisms that control behavior and attention;3) the contribution of such tolerance to the abuse potential of alcohol;4) the degree to which the inhibitory and attentional deficits associated with ADHD influence alcohol sensitivity and the development of tolerance;and 5) the degree to which the developmental course of tolerance is affected by concomitant use of stimulant drugs commonly used in the management of ADHD. PUBLIC HEALTH RELEVANCE: Excessive alcohol use contributes to many adverse health consequences (e.g., alcohol poisoning, acute alcoholic hepatitis and liver cirrhosis). Tolerance has long been implicated as a factor contributing to alcohol abuse and dependence by encouraging the use of escalating doses to reinstate initial effects of the drug. Yet, little research has examined how tolerance might increase the risk for alcohol abuse. The proposed studies examine the contribution of tolerance to abuse potential as measured by changes in the ability of the drug to alter basic mechanisms involved in the control and regulation of behavior. The findings of this research will provide an understanding of how drinkers'susceptibility to alcohol's acute behavioral-impairing effects can pose an early-onset risk factor for later alcohol dependence by promoting a continued pattern of abusive binge drinking. The research strategies also will provide methods for testing the role of neurocognitive mechanisms in the treatment efficacy of existing pharmacotherapies, such as naltrexone and acamprosate, as well as some investigational medications that might operate via neurocognitive control mechanisms.

DESCRIPTION (provided by applicant): Alcohol-related traffic fatality and injury continue to be a major public health problem, prompting the need for research aimed at identifying characteristics of DUI drivers in efforts to improve treatment and prevention. Although DUI offenders report traits of impulsivity, suggesting poor inhibitory control and heightened reward sensitivity, the specific cognitive characteristics underlying such behavioral dysregulation have not been systematically studied in the laboratory. The over-arching hypothesis of this application is that deficient inhibitory control and increased sensitivity to the disinhibiting effects of alcool contribute to the risk of DUI, and possibly to its recidivism. The proposed project views DUI offenders from a cognitive dysfunction perspective that targets deficits in specific mechanisms of behavioral regulation. The research will directly evaluate driving performance and mechanisms of self-regulation (e.g., inhibitory control, reward-seeking) in recidivist DUI offenders and will test hypotheses that these high-risk drivers respond differently to alcohol, wit increased disinhibition and risk-taking, and that these factors contribute to their decisions to drive after drinking. The application represents an innovative application of state-of-the-art assessments and techniques to identify the specific neurocognitive characteristics that underlie risky driving behavior, and which could be candidate mechanisms for treatment and prevention. The project aims fit well with the recent NIH Funding Opportunity Announcement (PA-10-255), Behavioral Regulation Mechanisms of Alcohol Dependence and Related Phenotypes aimed at promoting research on the effects of alcohol on neurocognitive mechanisms implicated in impulse control.

ABSTRACT/SUMMARY The aim of this training program is to provide graduate students with the research skills to identify alcohol-related risk factors by investigating their expression in response to acute and chronic exposure to alcohol at the cellular level, behaving laboratory animal, and the human subject. The training program will emphasize training in cellular and behavioral pharmacology of alcohol with the broad objective to understand how such acute and chronic reactions combine or interact with personal and environmental factors to confer risk for alcohol use disorders. The training is designed to achieve three objectives: 1) deliver intensive training in alcohol research; 2) foster interdisciplinary and translational perspectives on alcohol research; and 3) develop professional skills to support career development in alcohol research fields. The proposal requests support for five pre-doctoral appointments. The appointments will be for a two-year period. Training will be primarily delivered within the research programs of the faculty and the core facilities at UK. This includes a training faculty team of 20 researchers drawn from six academic and research units of the University of Kentucky. The rich environment provides opportunities for translational and multidisciplinary bio-behavioral research training in facilities such as the: 1) Center on Drug and Alcohol Research; 2) Center for Clinical and Translational Science; and 3) The Substance-abuse Prevention in Emerging Adults Research Center (SPEAR). The alcohol-specific expertise and broad research foci of our faculty, coupled with their interdisciplinary research provides a solid foundation by which implementation of the proposed T32 training program will bolster the research skills of our students for the ultimate goal of producing bright, productive scientists capable of significant developments and discovery in the etiology, prevention, and treatment of alcohol use disorders.