Alcohol Research: Promise for the Decade. INSTITUTION National Inst

DOCUMENT RESUME

ED 398 506 CG 027 281

AUTHOR Gordis, Enoch TITLE Alcohol Research: Promise for the Decade. INSTITUTION National Inst. on Alcohol Abuse and Alcoholism (DHHS), Rockville, Md. REPORT NO ADM-92-1990 PUB DATE Aug 91 NOTE 83p. PUB TYPE Reports Descriptive (141)

EDRS PRICE MF01/PC04 Plus Postage. DESCRIPTORS *Alcohol Abuse; Alcohol Education; *Alcoholism; Fetal Alcohol Syndrome; Health Education; *Medical Research; Physical Health; *Scientific Research; Special Health Problems

ABSTRACT Over the past 20 years, alcohol researchers have made intensive efforts to understand alcohol use and its outcomes. To date, researchers have made much progress toward understanding the causes and consequences of alcoholism and its related problems. This publication attempts to convey the great spirit and promise of alcohol research. Established findings that serve as foundations for future research are presented, and compelling areas for the coming decade that promise to advance understanding of the nature of alcoholism and promote efforts to prevent and treat the disease are highlighted. Extensive illustrations and photographs supplement the text. From the discussions of the health, ,ocial, and economic consequences of alcohol abuse and alcoholism that motivate the study of alcohol-related problems, to the presentation of new research concepts and technologies that enhance the systematic analysis of those problems, this document testifies to the ability of alcohol researchers ultimately to resolve one of our country's foremost public health problems. Chapters are:(1) Alcohol Abuse and Alcoholism;(2) Alcohol and the Brain;(3) Genetics and Environment; (4)Why DoPeopleDrink?;(5) The Medical Consequences of Alcoholism; (6)FetalAlcoholSyndrome; (7) Prevention and Treatment. An additionalchaptercontains information on developing new medications for alcoholism. (JBJ)

*********************************************************************** Reproductions supplied by EDRS are the best that can be made from the original document. *********************************************************************** . ' £

... II . II .. Mk

U S DEPARTMENT OF EDUCATION Office of Educational Research end Improvement EDUCATIONAL RESOURCES INFORMATION CENTER (ERIC) This document has been reproduced as received from the person or organization originating it 2 Minor changes have been made to improve reproduction quality a . II 111 Points of view or opinions stated in this document do not necessarily represent it official OERI position or policy 'i

AlTheBrain:

The brain governs manyexter of drinking---outcomesthat re hol's actions on manyinternal tures andfunctions. The brain the cranial cavitywithin the s primarily as acommunicatior highly organizedsystems tha thought, guide movement, an Scale Model

:'ones functions. In an adult, the brain hasan aver- of highly branched filaments, called den- alco- age weight of 3 pounds. A cross-sectional drites, that receive information from other ;truc- slice of the brain (2) reveals itsmany internal neurons (4). Each neuron has a cell mem- used in structures. The brain has an estimated 100 brane (5) that provides structure andserves ictions billion nerve cells, or neurons (3) of various as a physical barrier between the inside and with sizes and shapes. Most neurons havea long the outside of the cell. These membranesare filament, called an axon, that carries infor- composed primarily of lipids (fatsor fat-like ite body mation away from the cell body, anda series substances) and proteins. DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service Alcohol, Drug Abuse, and Mental Health Administration National Institute on Alcohol Abuse and Alcoholism

ALCOHOL RESEARCH: PROMISE FOR THE DECADE

Enoch Gordis, M.D. Director National Institute on Alcohol Abuse and Alcoholism August 1991

5 DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service Alcohol, Drug Abuse, and Mental Health Administration National Institute on Alcohol Abuse and Alcoholism

ALCOHOL RESEARCH: PROMISE FOR THE DECADE

TABLE OF CONTENTS

Foreword v

Acknowledgments viii

Chapter I. Alcohol Abuse and Alcoholism 1

Chapter II. Alcohol and the Brain 5

Focus on Brain Imaging Tools 15

Chapter III. Genetics and Environment 23

Chapter IV. Why Do People Drink? 33

Chapter V. The Medical Consequences

of Alcoholism 41

Chapter VI. Fetal Alcohol Syndrome 51

Chapter VII. Prevention and Treatment 57

Focus on Developing New Medications for Alcoholism 67

Epilog 72 6

ill FOREWORD

The importance of research on alcohol date, alcohol researchers have made abuse and alcoholism is unmistakable much progress toward understanding in light of the substantial harm and the causes and consequences of alco- costs that result from these disorders. holism and its related problems. The debilitating effects of alcohol on As we move toward the beginning the physical and social well-being of of a new century, alcohol research has problem drinkers, the far-reaching a preeminent goal:to gather knowl- harm that drinking causes in our com- edge that will enhance the develop- munities, the related costs borne by .:..=!nt of methods to prevent and to individuals and society alikeeach of treat ale- iol use disorders. these consequences affirms the need Developing new medications to for greater knowledge about what advance alcoholism treatment is criti- causes alcoholism, how it can be pre- cal to this process. As part of the con- vented, andonce a drinking prob- tinuing pursuit of enhanced treat- lem developshow it can be treated ment measures, researchers now are effectively. Such knowledge will come extending the search to include new only from research. pharmacotherapies that target the Over the past 20 years, alcohol mechanisms of the addiction itself. researchers have made intensive Scientists are armed in this quest efforts to understand alcohol use and with increasing knowledge about the its outcomes. During this time, the brain processes underlying addiction. alcohol research field has developed The discovery of new medications from relatively modest beginnings to will offer fresh hope to those who become one of the most rapidly grow- struggle to achieve and maintain ing areas of scientific investigation. To long-term sobriety. Some of these Alcohol Research: Promise for the Decade new drugs may ease the intense crav- care among alcoholic patients. Yet, sci- these features. In turn, the animal ing for alcohol experienced by many entists have observed that these models can serve as fundamental recently abstinent alcoholics or pathologies are not distributed equally tools for developing and assessing improve alcohol-induced cognitive throughout the alcoholic population. treatment measures for the various impairments that can affect a patient's Recent studies suggest that different elements of alcoholism. potential to benefit from traditional underlying genetic factors in people As one of the first steps in medica- therapies. exposed to high levels of alcohol may tions development, animal studies can It is unlikely that a single agent be responsible for the development of ensure that further tests can be con- will be developed to treat this com- such disorders as fetal alcohol syn- ducted in humans without danger. plex disease. However, coupling drome, liver cirrhosis, and Wernicke- Nonetheless, animal studies alone pharmacotherapies that control spe- Korsakoff s syndrome. cannot confirm the efficacy of poten- cific clinical events in the disease Future studies potentially can tial pharmacological therapies in alco- course with traditional behavioral identify the physiological bases for holism treatment. Clinical trials of and verbal therapies will enhance genetic susceptibility to alcohol-related new pharmacotherapies are indis- treatment outcome immeasurably. pathologies. Such knowledge can pensable for determining dose, effica- Refined therapies will benefit help scientists to develop specific cy, and safety of medications in many people. For alcohol dependent techniques to prevent the onset of humans. Such trials will serve as inte- individuals, who face the realistic fear alcohol-related illnesses. In addition, gral tools for developing new medica- of relapse to drinking, improved inter- this knowledge can enable clinicians tions for alcoholism treatment. ventions can abateand, optimally, to identify individuals at risk for Advances in technology also will preventrelapse occurrences and halt developing these disorders, allowing enhance the research efforts in the continuing disease that ultimately can for early identification of alcohol- next 10 years. During the past decade, lead to death. For society, which car- related pathologies. Finally, knowl- a number of noninvasive imaging ries the weight of the enormous eco- edge of the etiologies of genetically- techniquescomputerized tomogra- nomic and social costs of problem influenced consequences can aug- phy, magnetic resonance imaging, drinking, improved treatment strate- ment efforts to generate more effec- positron emission tomography, elec- gies that heighten the potential for tive therapies for such disorders. troencephalographywere enhanced. long-term abstinence can lessen this Ultimately, these advances can effect These techniques offer scientists the burden and enhance overall quality of large reductions in health care costs unprecedented and exciting opportu- life. New therapies promise to reduce and save countless lives. nity to look inside the living brain the billions of dollars lost annually Two primary prerequisites must be without invading the brain. In the from reduced workplace productivity, met to accomplish the fundamental coming decade, alcohol researchers alcohol-related injuries and illnesses, goals of alcohol research. First and will be able to apply these powerful and alcohol-related premature deaths. foremost, the alcohol field needs the resources to probe the actions of alco- Furthermore, more effective treatment abiding efforts of talented clinicians hol on the biochemistry and physiolo- can reduce the frequency of the vari- and researchers who, through comple- gy of the living brain. ous social tragediesmotor vehicle mentary endeavors, link research Imaging studies are likely to reveal crashes, falls, drownings, fires and advances and treatment practice. critical knowledge about the brain burns, crime and family violence Second, the production of techniques mechanisms involved in the funda- that are associated with alcohol and technologies that allow for the mental components of alcohol addic- misuse. observation and evaluation of rele- tion. In addition, by allowing the While studies of the causes, pre- vant phenomena are vital to research opportunity to view the possible vention, and treatment of alcohol progress. changes in the brain that precede the addiction are critical, investigations of Animal models are a principal onset of symptoms, imaging technolo- the medical consequences of alco- example of techniques needed in the gy will contribute much to the holism continue to be key components coming decade of alcohol research. development of successful prevention in the research agenda. The severe dis- Developing models with correlate fea- measures. These tools eventually may orders that develop from alcohol's tures of the human disease, such as be used in conjunction with treatment damage to the body are responsible craving or tolerance, will enable scien- research and practice, enabling for great suffering and contribute sub- tists to probe the biochemical and researchers to observe the alterations stantially to the high cost of health physiological mechanisms underlying in brain physiology that occur in

vi Foreword response to various behavioral and pharmacological treatments. At present, the scarcity of imaging technology frequently restricts its use in many laboratory and clinical alcohol studies. Given the potential value of this technology in alcohol research, the alcohol research community increasingly will turn to these new tools and apply strategies that will foster their efficient use. The research areas highlighted here are just a few of the many exciting components of alcohol research. Alcohol Research: Promise for the Decade presents the established findings that serve as foundations for future research and highlights the compelling areas for the coming decade that promise to advance understanding of the nature of alcoholism and promote efforts to prevent and treat the disease. This document attempts to convey the great spirit and promise of alcohol research. From the discus- sion of the health, social, and economic consequences of alcohol abuse and alcoholism that motivate the study of alcohol-related problems, to the presentation of new research concepts and technologies that enhance the systematic analysis of those problems, this document testifies to the ability of alcohol researchers ultimately to resolve one of our country's foremost public health problems.

Enoch Gordis, M.D. Director National Institute on Alcohol Abuse and Alcoholism

vii Alcohol Research: Promise for the Decade

ACKNOWLEDGMENTS

It is always easier to look backward Distinguished Professor of Medicine, and Director, Alcohol Research and record what has happened than IndianaUniversitySchoolof Center, University of Connecticut to look forward and authoritatively Medicine, Indianapolis, Indiana; Medical School,Farmington, describe what can be. In this regard, Barbara S. McCrady, Ph.D., Professor Connecticut. Samuel B. Guze, M.D., we were most fortunate to have the and Clinical Director, Rutgers Center Professor and Chairman, Department help of a group of truly farsighted of Alcohol Studies, Piscataway, New of Psychiatry, Washington University individuals whose expert knowledge Jersey; and Robin Room, Ph.D., School of Medicine, St.Louis, of science and keen insights about the Scientific Director, Alcohol Research Missouri, served as liaison from the future potential of alcohol research Group, Berkeley, California. National Institute of Mental Health were instrumental in shaping this Permanent liaison members to the Extramural Science Advisory Board. report. ESAB representing the National Five additional distinguished sci- Guiding the Institute's response to Advisory Council on Alcohol Abuse entists served as consultants to aid the Congress were members of the and Alcoholism included Martha B. NIAAA's ESAB in this project: Henri NIAAA Extramural Science Advisory Alexander, Executive Director, Beg leiter,Ph.D.,Professorof Board (ESAB), who determined Charlotte Council on Alcoholism and Psychiatry, State University of New NIAAA's approach to the task, invit- Chemical Dependency, Charlotte, York Health Science Center at ed the scientific papers that formed North Carolina, and member of the Brooklyn, New York, New York; the basis for the document, and Board of Directors for the National FloydBloom,M.D.,Director, reviewed the work as it progressed. Council on Alcoholism and Other Research Institute, Division of Core members of the ESAB who were Drug Dependencies; Bernell N. PreclinicalNeuroscienceand involved in this process included Boswell, Executive Director, The Endocrinology, Scripps Clinic, La James D. Beard, Ph.D., Professor of Cottage Program International, Inc., Jolla, California; Harold Holder, Psychiatry and Director, Alcohol Salt Lake City, Utah; and Roger Ph.D., Director, The Prevention Research Center, Memphis, Meyer,M.D.,Professorand Research Center, Berkeley, California; Tennessee; Ting-KaiLi,M.D., Chairman, Department of Psychiatry Marcus A. Rothschild, M.D., Chief,

viii I0 Acknowledgments

Radioisotope Service,Veterans final version of the report that you are Administration Medical Center, New about to read. Without her diligence, York, New York; and G. Terence Alcohol Research: Promise for the Decade Wilson, Ph.D., Graduate School of would be a lesser document. Applied Professional Psychology, Rutgers University, Piscataway, New Jersey. Altogether, more than 30 biomedical and psychosocial scholars contributed their thoughts and insights through papers that aided the ESAB and our writers in developing the perspectives that are the foundations of this report. To each of these individuals, members of the ESAB, and special consultants, go our thanks for their expert knowledge and guidance, and our gratitude for their patience as we sought their counsel time and again throughout the development of this document. Finally, special thanks are due to the NIAAA staff who have worked so diligently to produce Alcohol Research: Promise for the Decade:Kenneth Warren, Ph.D., Director of the NIAAA Office of Scientific Affairs, whose leadership sustained this effort from its conceptual stages to its publication; Michael Lewis, Ph.D., Executive Secretary of NIAAA's Extramural Science Advisory Board, who coordi- nated the initial efforts in the development of the document; Barbara Smothers, Ph.D., in NIAAA's Office of Scientific Affairs, whose conceptual- izations, writing, and editing helped to ensure the document's accuracy and readability; Ann M. Bradley, also in the Office of Scientific Affairs, who contributed substantively and editori- ally to the final document; Brenda G. Hewitt, Special Assistant to the Director, who, from inception to com- pletion, imbued the report with excitement about the potential of alcohol research to better individual lives and societal conditions; and Jane C. Lockmuller, M.S., Office of Scientific Affairs, who, with exceptional forti- tude and skill, wrote and crafted the Ii

ALCOHOL ABUSE IAND ALCOHOLISM

What are alcohol abuse and alcoholism? Physicians long have witnessed the Although many adults drink with few, if reality of craving in recovering patients any, problems, others experience a num- for whom the notion of having a drink ber of adverse consequences from drink- becomes overwhelming and preoccupy- ing. Even isolated episodes of alcohol ing, impossible to ignore. This craving misuse may result in such tragic conse- for alcohola drug hungeroften quences as alcohol poisoning and injury occurs in recently abstinent alcoholics or death from alcohol-impaired driving and is an important determinant of and other accidents. When alcohol prob- relapse to drinking. The basis of this crit- lems persist over time, however, they ical element of alcoholism has not been are classified as one of two clinical disor- determined. Some researchers suggest ders: alcohol abuse or alcoholism. that it is an appetitive urge, similar to Today, alcoholism is recognized as hunger, with a physiological founda- a disease characterized by abnormal tion. Others submit that the desire to alcohol-seeking behavior that results drink is a behavioral response to envi- in impaired control over drinking. ronmental triggers. Recent research Variously termed "alcohol depen- demonstrating that alcoholics display dence," "alcohol addiction," and numerous physical responses when "alcoholism" over the years, this dis- exposed to alcohol suggests that crav- ease has four main clinical features: ing, indeed, has a physical basis. Alcohol abuse and alcoholism are clini- craving, impaired control over drink- Whereas craving refers to the cal disorders that affect millions of ing, physical dependence, and toler- hunger for alcohol before drinking Americans of every age, race, and sex. ance. These are the key elements of begins, impaired control over drinking Although these disorders cost our society billions of dollars annually, the what has been termed the "alcohol refers to the difficulty that an alcoholic human costs are immeasurable. dependence syndrome." experiences in stopping once drinking Photographs courtesy of Lloyd Wolfe. 13

1 Alcohol Research: Promise for the Decade

has started. Unlike nonproblem icated; yet, many aspects of brain func- THE EXTENT OF THE PROBLEM drinkers, alcoholics may lack internal tioning are impaired and vital organs signals that would allow them to regu- may be damaged. More Americans use alcohol than any late alcohol intake. Any drinking that produces a prob- other drug, including cigarette tobacco. Physical dependence is an adaptive lem, whether social or medical, mild or According to national surveys, approxi- state manifested by intense physical severe, is important. "Alcohol abuse" mately two-thirds of all adults in the disturbances that occur when drinking refers to problem drinkingshort of the United States drink alcoholic beverages. is discontinued. A consequence of alcohol dependence syndromethat Of individuals who drink, one-half are chronic alcohol use, physical depen- results in health consequences, social light drinkers and one-half are moderate dence results from the adaptation of problems, or both. "Problem drinking" to heavy drinkers. However, some indi- central nervous system structures and viduals drink far more than others; the and "nondependent alcohol abuse" are functions (and probably those of other 10 percent of those who drink most additional terms that have been used to organs) to the presence of alcohol. heavily account for fully one-half of all describe this problematic use of alcohol. Dependence necessitates continued alcohol consumed in this country. While alcohol abusers are not depen- drinking to prevent alcohol withdrawal More men than women drink, and dent on alcohol, they nonetheless may syndrome, a host of symptoms ranging more men than women are heavy from profound anxiety, tremulousness experience social and medical problems drinkers. White Americans are more ("the shakes"), intense hyperactivity, as a result of poor judgment or uncon- likely to use alcohol than African- and sleep disturbances, to hallucina- cern about the adverse consequences of Americans, American Indians, and tions and seizures. The intensity of such their drinking. Asian Americans. Nonetheless, with the symptoms reflects the level of physio- Problems caused by even occasional exception of Asian Americans, members logical dependence on alcohol. drinking episodes (such as an isolated of U.S. minority groups suffer to a During withdrawal, some alcoholics alcohol-related traffic crash or a fall greater extent from alcohol-related prob- experience only mild symptoms, where- while intoxicated) can be serious or lems than do white Americans. For as others endure extremely severe reac- fatal. Continuous heavy drinking can example, among men and women, non- tions that can be life-threatening. provoke more severe social problems, white individuals experience higher Whether mild or severe, these symp- such as divorce and other family prob- death rates than white individuals from toms can prompt a return to drinking to lems, and economic problems, such as alcoholic cirrhosis. Among the homeless relieve the discomfort. Thus, it is impor- job loss. In addition, such serious med- population, it is estimated that 20 to 45 tant to control the more severe with- ical consequences as liver cirrhosis, percent suffer from alcohol problems. drawal reactions in alcoholics who are memory loss, stroke, heart damage, During the 1980s, alcohol use by high beginning abstinence. Recent evidence and cancer may occur. school seniors began a welcome, though suggests that repeated untreated with- Although alcohol abusers and alco- gradual, downward trend. Yet, alcohol drawals from alcohol may have a cumu- holics suffer from many of the same use among young people is still alarm- lative brain-damaging effect, possibly health, social, and economic problems, ingly high. In 1990, 32 percent of high leading to more serious withdrawal dependence on alcohol and the school seniors reported having five or episodes in the future. more consecutive drinks on a single impaired ability to control alcohol intake An individual who drinks heavily occasion during the 2-week period prior that characterize alcoholism distinguish over a period of months or years gradu- to the survey. the two disorders. Social use does not ally develops an ability to consume inevitably progress to alcohol abuse or increasing amounts of alcohol without to alcoholism. Rather, over the course of showing gross signs of intoxication. This CONSEQUENCES OF phenomenon, called tolerance, often is time, persons who abuse alcohol can ALCOHOL USE mistaken to be a sign of resistance to the become social users or abstainers later in adverse consequences of heavy drink- life; those who abstain in their youth or Alcohol use may lead to social conse- ing. Actually, the tolerance to alcohol young adulthood may become alcohol quences that often affect not only the that occurs after chronic heavy drinking abusers as they age. Further, an individ- drinker but also family, friends, and is indicative of long-lasting changes pro- ual can be an alcohol abuser without strangers. For example, alcohol can play duced by alcohol. Tolerance allows indi- being alcoholic, or can be alcoholic an important role in accidents, including viduals to maintain higher blood alcohol before displaying alcohol-related social falls and motor vehicle crashes. The seri- concentrations without appearing intox- and medical problems. ousness of this issue is reflected in acci-

14 2 Chapter I

dent statistics: Accidents account for the every system (for example, gastrointesti- majority of deaths among people nal, reproductive, and endocrine) in the between the ages of 5 and 34 years in the human body can be damaged by chronic United States. Over one-half of these drinking. The damage can lead to a vari- deaths are due to traffic accidents, and ety of diseases and other health prob- alcohol has been implicated in recent lems. These medical consequences of years in about one-half of the estimated alcohol abuse and alcoholism are 46,000 annual traffic deaths. responsible for a significant amount of The percentage of teenagers who die illness in the United States and result in in traffic accidents continues to be a mat- at least 40,000 deaths annually. ter of public concern. Approximately 40 Alcohol abuse and alcoholism are percent of all teenage deaths each year costly. For 1985, the total economic cost result from traffic crashes. Yet, evidence of alcohol abuse and alcoholism was suggests that alcohol may be decreasing estimated at $70.3 billion; this estimate as a factor in teenage traffic crashes. was projected to $85.8 billion for 1988. From 1982 through 1988, the percentage Of the projected 1988 total, $33.0 billion of teenage drivers who were intoxicated (38.4 percent) was due to lost employ- in fatal crashes decreased by 36 percent. ment and reduced productivity (an Although this trend is encouraging, alco- indirect cost that is difficult to measure) hol is involved in a substantially greater and $28.5 billion (33.2 percent) was due number of fatal crashes among teenage to premature mortality. The projected drivers than among other age groups. cost of treatment and associated It is estimated that alcohol is a factor research, training, and other supportive in approximately 30 percent of all sui- activities was relatively low: $8.7 billion cides and, in particular, that alcohol use (10.2 percent). is prevalent among adolescents who On the average, health care costs for commitsuicide.Inonestudy, untreated alcoholics are at least 100 per- researchers found that, between 1978 cent greater than those for nonalco- and 1983, 46 percent of adolescents who holics. Alternatively, treating alco- took their own lives had been drinking holism reduces general health care costs. just before committing their final act. One study reported that the average Alcohol also appears to play a significant monthly health care costs for an alco- role in suicides that are impulsive rather holic's family were 50 to 90 percent than premeditated. The use of alcohol is lower following treatment of the alco- predominant among suicide victims holic family member. who used firearms to take their lives. Why study alcohol use? Because by In the United States, the social and studying alcohol use, we can learn how economic toll of alcohol abuse and alco- to prevent alcohol abuse and alcoholism far exceeds the toll of many other holism and how to minimize their contemporary medical and social prob- effects when they do occur. In turn, by lems. Alcohol abuse and alcohol depen- learning how to control alcohol abuse dence affect about 10 percent of adult Americans. Heavy alcohol use con- and alcoholism, we can decrease health care costs and reduce the incidence of tributes to medical problems; one study heart disease, cancer, liver disease, acci- found that an estimated 25 percent of all persons admitted to general hospital dental injuries, suicide, crime, and vio- beds screened positively for alcoholism. lence. In short, by studying alcohol use, Further, the social costs of alcohol prob- we can make a difference. lems match the high economic costs. Virtually every organ (for example, liver, pancreas, heart, and brain) and

15 3 Corpus Cerebral callosum hemisphere

Thalamus and hypothalamus (diencephalon) re' Midbrain

VI'It Mir 0

Pons Cerebellum

Spinal cord

Medulla ALCOHOL AND IITHE BRAIN

Clinicians long have been aware of area of investigation for alcohol the myriad medical consequences researchers. Alcoholism appears to that can develop from alcohol use. involve changes in mood, behavior, Liver disease, pancreatitis, and and possibly appetite, all of which degenerative changes in heart and aregovernedbythebrain. muscle are all examples of alcohol- Accordingly, neuroscience research induced damage. Yet, the effects of provides essential information in the alcohol that produce intoxication, search for why some people who reinforcement of continued drinking, drink become addicted to alcohol and the features of the disease and how alcohol damages normal process of alcoholism are based prin- brain functions. cipally in the brain. Researchers have identified many Neuroscience is the field of study that focuses on the structure and of the fundamental questions con- activities of the brain. Through cerning the effects of alcohol on the research in this field, we have come brain, and new research methods and to learn that the brain governs a host technologies are becoming available of basic responses such as fear and every day to advance our search for pain, hunger and thirst. Moreover, it answers. Neuroscience research is the seat of all that is human promises to propel us through the thinking, abstracting, emotions, plan- next decade to an excitingand in ning for the future, and memories of many ways unprecedentedage of The ways in which alcohol affects dif- the past. discovery about the activities and ferent types of nerve cells in different parts of the brain are just beginning to It is not surprising that neuro- functions of the brain and their role be understood. Illustration by Robert science is an especially important in alcohol abuse and alcoholism. Czechowski.

5 Alcohol Research: Promise for the Decade

THE BRAIN: NEURONS AND the muscles in body movement, and new ideas and to respond with emo- generate thoughts, feelings, and tions and opinions. NETWORKS actions. How do neurons actually commu- Throughout the brain, each of the nicate? Each nerve cell bears a large The brain is one of the most complex billions of neurons makes as many as number of highly branched filaments organs in the body. Functioning thousands of connections with its called dendrites and one long fila- basically as a communication center, neighbors. As the brain controls ment called an axon. The dendrite its highly organized systems control thoughts and behaviors, it must inte- receives a chemical message from an thinking and feeling, process infor- grate large amounts of diverse, rapidly adjacent neuron. The chemical mes- mation from the senses, guide mus- received information from many sage is converted into an impulse cular movement, and regulate body groups of these neurons in various that involves the movement of elec- functions. brain regions. This is an ever-changing trically charged elements (ions), such Nerve cells, or neurons, are the situation, involving vast numbers of as sodium and potassium, through basic units of the brain and nervous neurons that often function simultane- the cell membrane. This bioelectric system. Although their structure is ously within specific systems of the current travels along the length of the similar to that of other cells, neurons brain. The study of these systems of axon, where the message is picked up are specialized to communicate by neurons, or neural networks, has by dendrites of neurons farther away. transmitting messages. Some nerve emerged as a major area of research. For the most part, nerve cells actu- cells outside the brainin particular The actions of neurons and neural ally do not touch each other. Rather, the sensory neurons of the eyes, ears, networks control mental activity. a tiny gap known as a synapse sepa- nose, tongue, and skingenerate Even as you read this sentence, thou- rates the axon of the transmitting signals in response to such external sands of neurons are"firing," neuron from the dendrite of the stimuli as light and sound; others exchanging messages that enable you receiving neuron. As the nerve transmit signals that control muscle to see the symbols on the page, under- impulse reaches the end of the axon, activity. The neurons of the brain stand them, and incorporate the infor- chemical messengers, or neurotrans- receive information from the sensory mation into your memory. These basic mitters, carry the message across the organs, send messages that control actions also allow you to consider synapse.

Dendrite

Synapse

Nucleus Axon

CellBody

Each nerve cell bears highly branched filaments called dendrites and a single long filament called an axon. The synapse is the space between the axon of one nerve cell and the dendrite of another. 18 6 Chapter II

Approximately 100 neurotransmit- nization: the single neuron, cell-to- ters and neuromodulators (other cell communication, and integrated chemicals that modify the function or neuron activities within brain sys- effects of a neurotransmitter) have tems. Many studies focus on the most been identified. These chemical mes- basic levelthe individual neuron sengers are released from the terminal and the effects of alcohol on the neu- portion of the axon, cross the synapse, ron's ability to transmit electrical sig- and bind to specific receptors (pro- nals through its cell membrane. teins that serve as sites of attachment) Cellular studies also probe the effects on the surface of the dendrite. Just as of alcohol on neurotransmitters and the shape of a lock determines the fit neuromodulatorstheir production of a key, the shape of the receptor and release by certain neurons and allows it to bind a precise neurotrans- their binding to receptors on others. mitter. The binding of a neurotrans- Studies of higher organizational levels mitter to an appropriate receptor sets explore the effects of alcohol on the off a cascade of events within the physiology of an isolated single neu- receiving neuron. These events stimu- ron, on the composite activity of neu- late the receiving neuron to send an rons within neural systems, and on electric current down its own axon, the whole brain structure and func- inducing chemical changes associated tion as measured through electro- with the formation of thoughts, emo- physiology and behavior. tions, or memories. Complex machin- ery within the cellvarious enzymes, molecules known as second messen- THE EFFECTS OF ALCOHOL gers, minerals such as calcium, and ON CELLULAR so-called coupling proteins that link COMMUNICATION the various componentscarry out these processes. Clearly, alcohol has a profound effect on the brain. Nevertheless, scientists still do not understand how alcohol THE EFFECTS OF ALCOHOL can exert its effects to produce such ON THE BRAIN phenomena as intoxication, reinforcement, tolerance, and dependence. Why isit important for alcohol Because the brain exists principally researchers to study neurons and as a communication system, it is neural networks? We study the cellu- assumed that alcohol acts to alter lar events that underlie the brain's communication. Changes in commu- response to alcohol because this nication may result from alcohol's research will explain the basic chemi- actions on one or more levels of the cal and physiological processes that brain's functional organization. are the foundation of alcohol addic- Studies of alcohol's actions on neu- tion. Moreover, our studies provide ronsthe basic unit of the braincan invaluable information about the provide important information about basic functioning of the brain itself. how alcohol disrupts the communica- The functions of the brain are tion process. As a message, conveyed accomplished through an intricate as a bioelectric signal, travels down interplay of numerous brain systems. the membrane, it stimulates the To grasp a true picture of the sundry release of neurotransmitters from effects of alcohol on the brain, we nerve endings. In turn, neurotrans- must explore alcohol's actions at each mitters act as chemical messengers of the many levels of functional orga- that cross the gap (synapse) between Alcohol Research: Promise for the Decade cells to carry the message to neigh- various brain regions differ in their they must use a communication mech- boring neurons. Studies of alcohol's sensitivitytoalcohol. These anism that can bridge the synapse that actions on the communication process approaches also have shown that alco- lies between adjacent cells. examine alcohol's effects on each of hol can stimulate or hamper neuron Intercellularcommunication these stages: the communication of a functioning, depending on the type of involves the release of neurotransmit- signal within the neuron, the release neuron (that is, which receptors are ters, an event stimulated by a bioelec- of neurotransmitters from one neu- present on the membrane of the nerve tric signal within the cell. The neuro- ron, and the binding of neurotrans- cell) and the brain region in which the transmitter crosses the synapse and mitters to the neuron receiving a binds to a receptor in the membrane message. Further, because the critical of a neighboring cell. With the bind- events involved in the message Studies ing, the neighboring cell may become transmission occur in the membrane stimulated to fire or may become less of the neuron, scientists are examin- have demonstrated responsive to other neurotransmit- ing whether alcohol alters communi- ters.Accordingly, neurotransmitters cation by modifying the membrane's that various brain serve to excite or to inhibit the firing chemical and physical structure. of neighboring neurons. Because regions differ in Investigators use electrophysio- some neurotransmitters may act to logical techniques to uncover some their sensitivity modulate the message of other neuro- of the mysteries surrounding alco- transmitters, they are referred to as hol's effects on the brain's communi- to alcohol. neuromodulators. cations systems. These procedures Alcohol is a psychotropic druga enable scientists to study the capaci- pharmacologic agent that alters brain ty of the neural membrane to propa- neurons are found. In addition, alco- function. Many psychotropic drugs, gate its bioelectric signal. Recently, hol may affect more than one type of such as opiates, marijuana, and ben- the development of several new and ion channel and may increase or zodiazepine tranquilizers, affect the innovative techniques has enhanced decrease ion flow through these mem- brain by interacting with specific researchers' facility for examining brane pores. receptors on brain cell membranes. these electrophysiological events. Overthenextfewyears, Alcohol, however, differs from these One such procedure, known as researchers will attempt to define the psychotropic drugs because it does voltage clamp recording, is a detailed conductive mechanisms in different not bind to one specific receptor. and painstaking process in which a brain regions that are altered by alco- Rather, alcohol may act on distinctive scientist, while looking through a hol. Once these mechanisms are receptors in the brain, and its actions microscope, inserts the tip of a fine defined, changes in the processes of may be unique for each receptor or, microelectrode into a single cell. This message transmission that occur further, for each neurotransmitter technique allows researchers to mea- with chronic exposure to alcohol can system. sure varying current across the cell be measured. Findings from such Because alcohol may act on recep- membrane resulting from alcohol- studies can help to relate the electro- tors and generate specific effects induced changes in the flow of ions physiological effects of alcohol on depending upon thereceptor through the membrane. "Tear-off specific brain regions to the various involved, studying alcohol's actions patch clamping," a more recent tech- behavioral actions associated with on the brain is an extraordinarily nique, permits an even closer look at drinking. complex challenge for researchers. To the effect of alcohol on ion movement define and understand the specific across the membrane. This procedure behaviors that stem from the effects can measure electrical events associat- NEUROTRANSMITTERS AND of alcohol on the brain, scientists ed with ions moving through a single RECEPTORS must determine how alcohol exerts ion channel (a protein that both cre- its actions on the cell surface recep- ates a pore in the membrane and con- A neuron must be able to transmit a torswith whichitinteracts. trols the passage of ions into and out signal from one end of the cell to the Scientists, likewise, must ascertain of the cell). other as well as interact with a wide how many of the more than 100 Studies using these and similar array of other neurons. Because neu- knownneurotransmittersare techniques have demonstrated that rons do not actually touch each other, involved in the expression of alco-

8 Chapter II

Molecules of gamma-aminobutyric acid (GABA) released into a synapse bind to receptors embedded in the surface of a nerve cell.This binding tends Nerve to bring about an inhibition of the Terminal nerve cell's activity. Alcohol and benzodiazepines (such as the tranquilizer et Valium) exert some of their effects at GABA in this receptor. Synaptic Vesicles (10 Benzodiazepine Receptor GABA Receptor Complex Nfe-Arnrn%Mink1 Cell Membrane r11555555, 45555555

hol's actions. At present, researchers azepines, such as the tranquilizer have found evidence that a few neu- diazepam (Valium), further inhibit the rotransmitter systems appear to be ability of the neuron to fire. Other extremely sensitive to alcohol, benzodiazepines, however, produce including gamma-aminobutyric acid the opposite effect and may even (GABA), glutamate, and serotonin. cause seizures. Scientists have begun to question GABA how alcohol specifically affects the GABA is the major inhibitory neuro- GABA receptor. It appears that the transmitter within the central nervous influence of alcohol on the GABA system. As an inhibitory neurotrans- receptor is analogous to that of the mitter, the binding of GABA to its benzodiazepines that function as tran- receptor on a neuron will dampen, or quilizers. Alcohol seems to enhance decrease, the ability of that neuron to the movement of chloride ions across propagate its bioelectric signal, or to the cell membrane and reduce the fire. ability of the receiving neuron to fire. The GABA receptor is actually a Two effects attributed to alcohol complex of several protein subunits. the reduction of anxiety and the loss Within this protein complex, there is a specific binding site for the GABA of motor coordination associated with molecule. The binding of GABA to its intoxicationmay arise from the receptor causes chloride ions to enter actions of alcohol on the GABA sys- the cell. This process makes it more tem, specifically its actions at the difficult for the neuron to fire, render- GABA receptor.Atpresent, ing the neuron less sensitive to the researchers are focusing their efforts effects of other neurotransmitters. on studying alcohol's interactions The GABA receptor also possesses with GABA in the areas of the brain a site that can bind drugs of the ben- that appear sensitive to the effects of zodiazepine class. Some benzodi- alcohol. 21 9 Alcohol Research: Promise for the Decade

is exposed chronically to alcohol, NMDA receptor however, it begins to compensate for this effect: The number of NMDA- activated ion channels in the brain increases. This adaptive process (known as upregulation) could result in hyperexcitability of neurons, a major factor in physical dependence. In addition, this process may account for several of the chronic effects of heavy drinking, including alcohol- withdrawal seizures. Alcohol can impair memory and learning processes, as well as produce profoundcognitiveproblems. Recently, scientists have found evidence that glutamate and the NMDA The neurotransmitter glutamate, acting at the NMDA receptor, is involved in learning, receptor may play a significant role in memory formation, and nerve cell development. Alcohol interferes with the function of this receptor, possibly contributing to memory disorders, impaired nervous system these damaging alcohol-induced development, and alcohol withdrawal seizures. Courtesy of Dr. Boris Tabakoff. effects. This area of research is compelling, given the suggested role of In addition, scientists are focusing brain. When glutamate binds to its the glutamate and the NMDA recep- on identifying the characteristics of receptor on a neuron, it augments the tor in normal memory functions. the GABA receptor that render it sen- potential of that neuron to fire. A Knowledge of the interaction between sitive to alcohol. The configuration of number of distinct subtypes of gluta- alcohol and the NMDA receptor can different GABA subunits in select mate receptors are named for various brain areas may contribute to alco- chemical analogs (substances that help us to understand more fully the hol's varying effects on different brain also specifically bind to these recep- memory impairments that result from regions. Findings from these studies tors). Alcohol primarily affects the heavy drinking, including the phe- may pave the way for genetic research receptor subtype named after the syn- nomenon of blackouts. exploring why some people differ in thetic chemical N-methyl-D-aspar- Serotonin their response to alcohol. tate, abbreviated NMDA. The binding Tolerance to alcohol's sedative of glutamate or NMDA to this recep- Evidence suggests that serotonin, a effects may result from an adaptive tor heightens the neuron's respon- neurotransmitter involved in mood, response of ion channels controlled by siveness to stimuli. At this receptor, sleep, and consummatory behavior, GABA to the chronic presence of alco- glutamate has been implicated in also may be sensitive to alcohol. hol. Studies using neurons taken from such phenomena as learning and Researchers have used serotonin- animals made tolerant to the sedative memory formation and is involved in uptake blockerssubstances that effects of alcohol have shown that the neuronal development. block brain serotonin uptake and stimulatory effect of alcohol on Evidence suggests that the NMDA allow for greatly increased action of GABA-controlled chloride ion chan- receptor may be involved in the the neurotransmitterto analyze the nels in these cells is either reduced or development of physical dependence role of serotonin in alcohol consump- absent. on alcohol. Under normal conditions, tion. They have found that serotonin- activation of the NMDA receptor uptake blockers appear to diminish Glutamate and NMDA allows calcium ions to flow through somewhat the desire for alcohol in Whereas GABA is the major inhibito- ion channels into the cell, thereby some alcoholics, a possible indication ry neurotransmitter in the brain, glu- causing the cell to become excited. of the role of serotonin in alcohol con- tamate is the major excitatory brain Short-term exposure to alcohol sumption. These findings could have neurotransmitter, accounting for inhibits NMDA-stimulated calcium considerable importance in future approximately 40 percent of all the flow and, consequently, dampens the development of medications to con- nerve signals sent throughout the cell's responsiveness. When the brain trol craving for alcohol. 22

10 Chapter II

Much of our knowledge of neuro- molecules, such as water; certain transmitters and receptors has been nutrients; and selected ions to enter attained through studies using genetic the cell. Alcohol molecules also may animal models of alcoholism. Animal cross this barrier. models are important research tools Changes in the chemistry of the because they allow for controlled cell membrane are an important topic analysis of many biological charac- in alcohol research. Cell membranes teristics observed in human studies. are composed primarily of lipids (fat By selectively breeding animals that or fat-like substances) and proteins. exhibit distinct characteristics of To varying degrees, alcohol can dis- alcoholism, researchers can explore solve in the cell membrane and weak- theneurochemical differences en the bond between lipid molecules between the animals serving as mod- in the membrane, causing the lipids to els for alcoholism and control ani- become disordered. Thus, alcohol mals. For example, rats that display a may cause the membrane to lose some preference for drinking alcohol have rigidity and become more fluid. Such been selectively bred to .develop the fluidization may alter the function of alcohol-preferring (P) rat line. As control animals, rats exhibiting a strong aversion for alcohol have been bred Much of our selectively to produce the nonpreferring (NP) line. Neurochemical studies knowledge of of these animals have revealed that P rats consistently have lower serotonin neurotransmitters levels than NP rats in select regions of their brains. To date, a number of and receptors has been genetic animal models have been developed, providing knowledge of attained through studies using alcohol-seeking behavior as well as of neurochemical substrates of intoxica- genetic animal models tion, dependence, and withdrawal. of alcoholism.

ALCOHOL AND THE CELL proteins embedded in the membrane, MEMBRANE thereby impairing the ability of nerve cells to process information. It has been suggested that the effects Research has suggested that it is of alcohol may arise from its ability to disrupt the cell membrane: Alcohol unlikely that changes on a broad scale has some ability to dissolve in water as in membrane fluidity can account for well as in the fatty substances that most of the effects of alcohol. Yet, a comprise the cell membrane. change in the physical properties of a Regardless of the cell type, every particular "microdomain"a mem- cell has a membrane that provides a brane region that circumscribes an physical barrier between the inside important functional protein such as a and outside of the cell. The receptors receptor or ion channelcould be discussed previously are embedded in part of the explanation of the effects of the cell membrane. The cell mem- alcohol on brain function. Advanced brane also serves additional functions. techniques of physical chemistry and It gives the cell its shape and acts as a biophysics now permit this vital area gatekeeper, allowing only selected of investigation to be pursued.

2,3 11 Alcohol Research: Promise for the Decade

is unit of ACcontribute to the expression of AC activity. Some research findings suggest Phospholipid that the G receptor may be the site Bilayer for alcohol's effects on this system. For example, in the brain striatum (an area believed to be important in N motor and cognitive brain functions), Phospholipid head groups the neurotransmitter dopamine of different types appears to stimulate AC activity by Protein interacting with G protein and the AC catalytic unit. Alcohol appears to enhance the effects of dopamine on AC activity, possibly by activating the G regulatory protein. In turn, AC Alcohol Action activation increases cAMP levels in the cell. Researchers recently have shown, however, that brain cells Alcohol Action adapt to long-term exposure to alcohol by reducing AC-stimulated cAMP levels:Cells begin to require alcohol to achieve normal levels of AC-stimulated cAMP. This process may represent a form of cellular "dependence" on alcohol. Because The nerve cell membrane is composed mainly of lipids arranged in a bilayer, within the AC system is common to several which are inserted various proteins, including receptors for neurotransmitters. Alcohol neurotransmitter systems, future may distort the orderly arrangement of membrane lipids, thereby altering the function studies of alcohol's effects on AC of membrane proteins. The top figure illustrates normal membrane lipids; the bottom hold great promise for identifying figure illustrates membrane lipids distorted by alcohol. Courtesy of Dr. Boris Tabakoff. the mechanisms that underlie these SIGNAL TRANSDUCTION AND cules, known as second messengers, effects. SECOND MESSENGERS that act to relay the message within The effects of alcohol on second the cell. Recent research indicates that messenger systems can modify a alcohol's effect on second messenger neuron's electrical excitability and The binding of such chemical messen- systems may influence the biochem- chemical properties. These systems, gers as neurotransmitters or neuro- istry of neural transmission and signal which play key roles in signal trans- modulators to a receptor elicits an transduction. duction, appear to be involved in effect in the receiving neuron. For The membrane-bound enzyme, many of alcohol's actions on the example, the messenger may signal adenylate cyclase (AC), is linked to brain. Much of our knowledge about the neuron to fire, or it may direct the various neurotransmitter receptors alcohol's effects on second messen- neuron to ignore firing signals from and plays a role in synaptic transmis- ger systems is preliminary yet other receptors. In addition, the signal sion. Adenylate cyclase regulates lev- promisinga foundation for excit- of the chemical messenger may trigger els of the second messenger cyclic ing research advances in this area in a metabolic event in the receiving neu- AMP (cAMP) within the cell. cAMP the coming decade. ron. The process of the conversion of a affects protein activity and synthesis; signal to a chemical or physiological thus, its proper functioning is impor- action is known as signal transduc- tant to long-term cellular conse- ALCOHOL AND NEURAL tion. Signal transduction involves spe- quences for cellular well-being. Three NETWORKS cialized proteins (such as the G pro- linked componentsa receptor in the tein), as well as a family of enzymes membrane, a regulatory protein The brain functions by analyzing involved in the generation of mole- known as the G protein, and a catalyt- and transmitting many pieces of 24

12 Chapter II information simultaneously. Thou- groups of neurons to learn more sands of interconnecting neurons fire at about their role in the brain. Further, the same moment, communicating a we can use laboratory-generated host of distinct messages within the information about simple systems to brain. These interconnecting neurons build models of circuits in the may be thought of as the wiring for human brain. distinct nerve message tracks, known as neural networks. The brain must simultaneously process, integrate, and appropriately respond to all of the signals received from the many neural networks. Although the actual process is likely to be exceedingly complex, a simplified model of the brain events that may transpire with alcohol use illustrates how simultaneous processing from distinct neural networks might affect brain function. As an individual drinks alcohol, the brain simultaneously processes details about alcohol's taste, smell, rewarding and anxiolytic effects, and caloric value and even about previous drinking experiences. In some individuals, genetic or other factors might cause networks involved in a specific activity, such as the communication of euphoria, to prevail over circuits that convey other information on the effects of alcohol, creating an inaccurate and inappropriate assessment of the physiological events that have tran- spired. Such imbalances in neural information processing could be a significant factor in fostering drinking, in craving, and in developing alcohol abuse and alcoholism. During the next decade, our study of information processing will help us to identify the specific neural networks important in alcohol use and to determine their role in alcohol abuse and alcoholism. Innovative electrophysiological and computer technologies will enhance our efforts to define these networks, to record their physiological and electrical activity, and to experi- mentally manipulate multiple 25

13 , FocusON BRAIN IMAGING TOOLS

The most important sites of alcohol's With the development of noninva- actions undoubtedly lie within the sive imaging techniques, researchers brain. It is the actions of alcohol on the have the exciting opportunity to brain that produce intoxication, rein- explore inside the living brain and forcement of continued alcohol use, probe its biochemistry and physiolo- and important features of the disease gy. No longer restricted to autopsy process of alcoholism. studies, alcohol researchers now can Until recently, studies of alcohol's use imaging tools to follow alcohol- actions on the brain could be conduct- induced changes over time in the ed only after a patient's death, when brains of living people and to relate the brain could be examined physical- these changes to thinking and behavior. ly. Although autopsy studies permit- By providing an altogether new ted scientists to examine the brain approach to assessing alcoholism, lesions and cell loss that can result imaging techniques offer new promise from heavy drinking, these investiga- in the quest for answers to such fun- tions provided little knowledge about damental questions as: alcohol's interaction with the biochemical pathways in the living brain Do chemical changes in the brain that produce intoxication, craving, produce such features of alco- dependence, and tolerance. Moreover, holism as craving for alcohol and The MRI scanner uses magnetic fields researchers were unable to examine impaired control over drinking and radiofrequency waves to form the events in the living brain that behavior? What region(s) or bio- exquisitely detailed three-dimensional place some individuals at greater vul- pictures of anatomical structures in the chemical pathway(s) in the brain body. Photograph courtesy of Dr. nerability than others to alcoholism. are involved in these processes? Adolph Pfefferbaum. 27

15 Alcohol Research: Promise for the Decade

How does chronic alcohol abuse IMAGING TECHNIQUES can map brain activity by tracking damage brain tissue? Are some and measuring brain glucose metabo- regions of the brain more sensitive lism. Glucose is the sole source of than others to the deleterious Positron Emission Tomography energy for the brain. Thus, systems of effects of alcohol? Are some indi- Positron emission tomography (PET) the brain involved in various func- viduals more vulnerable to this is one of the most powerful of the new tions or tasks metabolize glucose to damage than others? Does absti- noninvasive scanning technologies. obtain energy to perform work. By nence reverse the damage? Is This technique employs short-lived using PET to trace the distribution of there a predictable relationship radioisotopes, linked to a key mole- radiolabeled glucose throughout the between the physical damage to cule such as sugar or oxygen, which brain, scientists can identify those sys- the brain and the loss of certain are introduced into the body. As the tems and regions involved in a specif- mental capabilities experienced by compounds enter the brain, they emit ic behavior or function. PET also can some alcoholics? radioactive energy (a positron) that is detect changes in glucose levels in detected by special cameras arranged localized brain regions, thereby Recognizing that genetic factors around an individual's head. With the revealing systems that use more ener- contribute to the risk of develop- aid of a computer, the emitted gy thanothers.Inthisway, ing alcoholism, are there inherent radioactivity is processed into a three- researchers can identify systems that differences in the central nervous dimensional image of the brain that become more active than others as an system that differentiate persons shows the distribution and concentra- individual exhibits a behavior or per- at higher risk and lower risk for tion of the radioactive compounds. forms a task. alcohol addiction? Do high-risk PET offers an exciting opportunity In addition, PET can be used to individuals respond differently to to view directly the brain networks examine specific brain neurotransmit- alcohol than low-risk individuals? and physiological and biochemical ter systems. To date, tracers devel- Is the vulnerability among high- processes involved in specific behav- oped for the study of dopamine and risk individuals specific to alcohol iors or functions. For example, PET serotoninneuroreceptorshave or do these individuals respond similarly to other drugs of abuse? Are early signs of withdrawal or physical dependence more apparent in high-risk individuals than in low-risk individuals after administration of alcohol? Which neural systems are involved?

Currently, a variety of imaging tools are available to researchers and clinicians. Some methods provide information about the size, shape, and physical integrity of the brain. Other approaches assess the brain at work by measuring electrical activity, blood flow, oxygen and glucose use, and neurotransmitter activity. Although each technique has distinctive strengths, the coupling of two or more approaches can provide multifaceted knowledge about the brain structures and functions involved in the vulnera- This color-coded, three-dimensional PET image of the brain, constructed from 16 two- bility to and expression of alcoholism. dimensional brain slices, depicts glucose utilization and thus, functional activity, in different brain areas. Orange, yellow, green, and blue correspond to a range of Some of these new techniques are activity levels, with orange representing the highest level and blue the lowest level. described in the sections that follow. Courtesy of Dr. Michael Eckardt.

16 enabled researchers to observe the binding of neurochemicals to receptors in living persons. Such studies hold great promise for identifying the role of various neurotransmitter systems in specific functions or behaviors.

Single Photon Emission Computed Tomography Like PET, single photon emission tomography (SPECT) uses short-lived radioisotopes to follow metabolic !t4 activity and neurotransmitter system functioning. Unlike PET, however, SPECT uses injected radioisotopes that emit a gamma particle, producing a single photon that is recorded with a SPECT camera. Recent improvements in SPECT instrumentation make it differentiated and specific anatomical Computer-colorized magnetic possible to rotate the cameras in dif- structures of the brain can be outlined. resonance images of the brain from a healthy 57-year-old man and a ferent planes. This technique, which This technique offers several 57-year-old man with a history of heavy can be employed to observe blood advantages over other structural alcohol consumption. Magnetic flow in the brain (to mirror closely imaging devices. MRI produces resonance images reveal detailed structural information, such as the brain metabolism), currently is enjoy- images with amazing clarity using neuroanatomical changes produced ing widespread clinical application. magnetic fieldsnot x-rays. Hence, by alcohol. These changes are evident an individual can have repeated MRIs in the enlarged ventricles in the Magnetic Resonance without the risk of exposure to ioniz- alcoholic's brain compared to the control's brain. Courtesy of Dr. Adolph Techniques ing radiation. MRI also offers great Pfefferbaum. Magnetic resonance imaging (MRI) is flexibility for viewing the brain from a new structural imaging technique many different directions. Finally, that provides exquisitely detailed pic- MRI allows scientists and clinicians to tures of the anatomical structure of distinguish gray matter (primarily any organ of the body, including the composed of nerve cells) from white brain. This technique does not use matter (primarily composed of the ionizing radiation, such as x-rays. long "wires," or axons, connecting Rather, an individual, lying inside a nerve cells) within the brain. large superconducting magnet, is Advances in magnetic resonance exposed to magnetic fields. Exposure technology have broadened the appli- to magnetic fields and radiofrequency cation of this technology to allow the waves causes certain atoms in the study of structure and of biochemistry brain to emit signals as the atoms of the living brain. Magnetic reso- align and realign within a field. The nance spectroscopy (MRS), a new signals vary in intensity, depending technique resulting from technologi- on the substance from which they cal.advances, uses the MRI scanner to originate. MRI scanners use the sig- examine the proton signals of mole- nals emitted from atoms with odd cules such as fat, amino acids (the numbers of protons, such as hydrogen building blocks of proteins), and (the most abundant element in tissue), metabolic products, which behave dif- to form three-dimensional images in ferently in a strong magnetic field. which different types of tissue can be The resulting images provide detailed

29 17 Alcohol Research: Promise for the Decade information about the metabolic state stroke) on brain electrical activity. the ERP is modeled as arising from of regions of brain tissue. MRS also Such factors can produce abnormal multiple intracranial electrical dipole may measure magnetic resonance sig- patterns, reduced wave amplitude, sources. This method offers great nals from phosphorus atoms, thus and a shift in wave frequency. promise as a means to partition ERP providing information about the con- Event-related potential (ERP), a waveforms emanating from concur- centrations of compounds critical to technologicallyadvanced EEG rently active brain regions into cellular energy. The concentrations of method, measures specific electrical subprocesses that are anatomically these compounds correspond to the responses to a sensory stimulus, such localized as biophysical sources of activity of the specific systems or net- as a sight or a sound. EEG electrodes electrical activity. works in the brain. are placed on the scalp to measure the Until recently, the use of MRS was electrical responses within a fraction limited to assessing the chemical of the second that follows the delivery IMAGING TECHNIQUES IN composition of a single volume of of the external stimulus. The ERP ALCOHOL RESEARCH material without constructing an waveforms, which result from the image. With new technological Heretofore, alcohol researchers have advances, however, it is possible to attempted to understand alcoholism produce three-dimensional images by examining the external manifesta- that detail the chemical events occur- Today's imaging technology tions of the disease. Today's imaging ring within the organ under study. technology will enable researchers to Currently, MRS produces images of will enable researchers to observe observe directly the dynamic mecha- coarser resolution than those of PET. nisms that are the disease. Yet, as MRS technology improves, it directly the dynamic mechanisms Each of the imaging tools dis- will offer researchers a unique oppor- cussed, with its distinctive strengths, that are the disease of tunity: Because, unlike PET, MRS can provide key information about does not use radiolabeled tracers, alcoholism. structural and functional brain injury MRS can be used repeatedly on the associated with alcohol use, about same individual, allowing researchers vulnerability to alcoholism, and about to examine specific metabolic and activity of the various brain processes the brain processes and anatomical physiologic events over time. that occur in response to outside stim- sites involved in elements of the dis- uli or endogenous brain activity, are ease (craving, impaired control, Electroencephalography embedded in background EEG noise. dependence, tolerance, and relapse The electroencephalogram (EEG),Thus, a computerized method, known and recovery). Collectively, this infor- measured with electrodes placed in as averaging, must be used to extract mation can provide a complete pic- standard positions on the scalp, is a the characteristic waveforms of the ture of the disease process. record of the spontaneous electrical evoked responses from the back- Any consumption of alcohol activity within the living brain. The ground EEG activity. The ERP tech- appears to affect numerous metabolic, normal human EEG usually is classi- nique has the unique value of measur- physiologic, and neurotransmitter fied into four major brain waves: ing mental activity that occurs on the systems in the brain. Additional beta, alpha, theta, and delta. Each order of milliseconds, providing an research is needed to identify the sys- wave has a distinctive amplitude and immediate record of brain activity tems involved, to determine how they frequency. Characteristic wave pat- associated with sensory and cognitive are affected, and to understand how terns occur in varying proportions processing. alcohol's actions on one system may with different behavioral states. For Recent advances in computer tech- influence other systems in the brain. example, as a person passes into sleep, nology and mathematical analyses of Imaging techniques can be vital to this the slower frequency delta wave signals have made it possible to assess research. Specifically, PET, SPECT, becomes predominant. These changes the spatial and temporal properties of and MRS have the potential to trace in frequency can be quantified with event-related brain potentials. One the regional brain distribution of alco- computer techniques. such method, known as dipole source hol and to characterize alcohol's EEG also reveals the effects of localization, has as its basis the dipole, effects on the biochemistry and physi- drugs, metabolic conditions, and the simplest current source in the ology of these various brain regions. injury (such as head trauma and brain. With dipole source localization, Because MRS does not expose people

18 to radioisotopes, it offers the distinct high-risk sons of alcoholic fathers opportunity to examine the same than among low-risk individuals. study subjects repeatedly and follow Using ERP, researchers have found alcohol's actions in the brain over that alcohol-naive sons of alcoholics time. Superimposing MRI images display reduced amplitude of the P3 over all of these maps of brain func- wave, a genetically determined wave tion will help to identify the brain that appears during the performance structures affected by alcohol's of cognitive tasks. This trait may be a actions. In addition, ERP mapping marker for genetic vulnerability. studies can show alcohol's effects on These early findings suggest that elec- electrical activity within various brain troencephalography will provide regions. When considered together, much knowledge about the function these findings will enable researchers of electrical activity in genetic suscep- to study the effects of alcohol on spe- tibility to alcoholism. cific brain systems and structures, Electroencephalography studies no potentially providing insight into how doubt will continue to broaden our drinking alcohol can produce pleasur- knowledge of the genetic factors able sensations, reduce anxiety, alter involved in the development of alco- mood, influence cognitive processing, holism; yet, other imaging approaches and cause sedation. also can contribute significantly to this Efforts to identify why some peo- understanding. Using MRS, PET, and ple seemingly possess a greater vul- SPECT, scientists can address a critical nerability for developing alcoholism question concerning the role of func- than others may be facilitated greatly tional processes in susceptibility to with imaging techniques. Already, alcoholism: Are there inherent func- electroencephalography studies have tional differences in some individuals provided fascinating information in that cause them to respond to alcohol this regard. Alcohol appears to affect differently than others? Imaging tech- EEG activity in high-risk persons dif- niques may reveal that some individ- ferently than in low-risk individuals: uals respond differently to alcohol After drinking, greater variations in because it may affect different systems fast EEG activity are observed among in them than it does in others. With

N-acetyl aspartate

60 min. postingestion alcohol

Using magnetic resonance spec- #s.14/kA/1-'440d, troscopy, alcohol, which produces a spectrum different from those of water and lipid, can be detected in the human brain. This spectrum illustrates an alcohol signal from a localized brain region, following consumption of wine. Adapted from Pfefferbaum et al. I I I I I I 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 Proceedings, Annual Meeting of ppm College of Neuropsychopharmacology, December 1990.

31 19 Alcohol Research: Promise for the Decade these techniques, researchers can gain ing that a physiological event in the define the neural processes involved new insight into the role of certain brain may account for the observed in the return to drinking. This knowl- functional processes in producing her- change in behavior. Until now, scien- edge, in turn, should lead to recogni- itable vulnerability to alcoholism. tists have not had the means to search tion of the means by which the brain Specific states and behaviors of for and identify the brain processes processes underlying relapse may be alcoholism, such as relapse, may be that underlie relapse. Noninvasive controlledgreatly enhancing the linked to physiologic processes in the imaging technology provides a win- potential for recovery. brain. Imaging tools can help dow through which scientists can Imaging tools also provide great researchers to identify and more fully study the biochemistry and physiolo- opportunity to examine the injury to understand these brain processes. For gy of the living brain. By using PET brain structures and processes that example, behavioral changes often are and MRS to examine brain biochem- results from chronic drinking. MRI observed in recovering individuals istry and physiology before, during, studies have shown that the percent- prior to a relapse to drinking, suggest- and after relapse, scientists well may age of gray brain matter declines with age, while the percentage of white matter remains relatively constant. Alcoholics, however, have significantly less gray and white brain matter than their nonalcoholic peers, suggesting that alcohol may accelerate the brain's aging process. Future studies using MRS, PET, SPECT, and ERP will enhance our understanding of this process, possibly characterizing functional disturbances associated with chronic drinking. Chronic drinking can impair a person's ability to reason and to process information. These tools will enable researchers to identify the underlying brain injury that produces this impairment. Further, imaging tools will allow scientists to examine whether abstinence leads to reversal of the damage. Similarly, these tools will enhance greatly our knowledge of alcohol's injurious effects on the developing brain. Children born to alcohol-abusing mothers may exhibit a number of characteristic alcohol-related defects, classified clinically as fetal alcohol syndrome (FAS) and fetal alcohol effects (FAE). Damage to the central nervous system is one of the most profound defects in FAS and FAE

Patterns of electrical activities, marked by the color shading, are different in individuals who are at risk for developing alcoholism (top) than in low-risk individuals (bottom). Courtesy of Dr. Henri Beg leiter.

20 children, resulting in neurologic useful information for defining sub- abnormalities, developmental delays, types of alcoholics. behavioral problems, and intellectual Imaging technologies also can con- deficits. A significant need exists to tribute significantly to research on correlate the behavioral and intellec- development of new medications for tual dysfunctions seen in the children alcoholism treatment. Although the with underlying brain abnormalities. potential for pharmacological treat- The use of noninvasive functional and ment is widely recognized, few med- structural techniques allows for icationsareavailabletoday. detailed study of brain anatomy and However, imaging tools will enable activity in these children. Coupling researchers to observe the actions of these tools with tests to assess neu- potential medications on specific ropsychological problems in children neural systems and to test their effica- will allow researchers to identify the cy in mitigating alcohol problems. extent and nature of fetal alcohol effects in individual children. These technologies also may pinpoint the specific brain areas that appear most vulnerable to alcohol's actions during development. In addition, noninvasive imaging tools can help to classify the severity of alcohol-related brain injury. Finally, imaging tools will enable researchers to follow the effects of treatment by observing the changes that may occur within the brain, not only as a result of medications but also as individuals experience traditional behavioral and verbal therapies. Although traditionaltherapy approaches benefit a large number of alcoholics trying to achieve and maintain sobriety, it remains to be determined how these approaches influence recovering individuals. The effect of successful therapy on brain processes and cognitive behavior of patients currently cannot be studied. Imaging toolsespecially ERP, PET, and MRSeventually may provide a means to observe adaptations in neural systems that occur over time in response to successful therapy. Moreover, such studies can provide insight into understanding why various treatment approaches are ineffective for some alcoholics and may help to distinguish the forms of treatment most suited to particular patients. Ultimately, these studies may provide

21 I GENETICS AND IIIENVIRONMENT

People vary considerably in their Nevertheless, the distribution of drinking behavior and in their sensi- alcoholism within any given popula- tivity to alcohol's effects. Some indi- tion indicates that genetic factors viduals drink only moderate amounts alone cannot account for the develop- of alcohol and experience few, if any, ment of the disease; environmental problems from their drinking. Others, factors also have an important effect however, become addicted to alcohol on drinking. Family dynamics, peer and may develop serious medical influences, cultural values, everyday consequences, encounter adverse stresses, and a host of other influences social difficulties, or experience both shape our thinking about alcohol and as a result. affect our drinking behavior. The vulnerability that some people In an attempt to understand why seemingly possess to developing alco- only some people who drink advance holism has prompted researchers to to problematic drinking, alcohol search for factors that may contribute researchers are exploring the age-old to heightened susceptibility. The lega- question of nature versus nurture. cy of alcoholism in families and This research, to date, has yielded a among certain ethnic groups suggests wealth of knowledge about the genet- that genetic factors can increase an ic determinants of alcoholism Computer drawn deoxyribonucleic individual's vulnerability for this dis- knowledge that has led to profound acid (DNA) illustrates the double- stranded helical conformation of this ease. On the other hand, researchers changes in society's view of alcohol important molecule. Outside strands also have observed that individuals abuse and alcoholism as matters of are composed of deoxyribose sugar within certain ethnic groups have pro- public health. and phosphate; linked pairs of bases that connect the strands of the helix tective genetic factors that make it The modern public health model of determine genetic coding. Courtesy doubtful they will ever abuse alcohol. disease holds that many human illnesses of NIH archives.

35 23 Alcohol Research: Promise for the Decade result from the interaction of environ- researchers may devise psychothera- the same home (such as adoptees and mental and genetic factors. The sus- peutic techniques to help genetically their nongenetic siblings); environmen- ceptibility to high cholesterol levels is vulnerable individuals deal more tal influences can be assessed by com- an example of this model: Although effectively with drinking-related stres- paring genetically related individuals genetic makeup may heighten an indi- sors and craving. (such as adoptees and their nonadopt- vidual's risk for high blood choles- However, little is known about the ed genetic siblings) who are raised in terol levels, regular exercise and a diet way that genes and environment different environments. low in saturated fat and cholesterol interact to produce different types of An adoption study in Denmark could counteract much of this genetic alcohol-related problems. Researchers revealed that the adopted-away sons of vulnerability. The awareness that acknowledge that such factors as per- alcoholics were more than three times alcohol-related problems follow this sonality, cognition, and sociocultural as likely to become alcoholic as the same gene-environment model has norms contribute profoundly to the adopted sons of nonalcoholics. A large- influenced greatly the course of alco- development of alcohol abuse and scale study in Sweden confirmed these hol research during the past decade. results, showing that the incidence of In addition, the results of several alcoholism among male adoptees born pivotal adoption and twin studies It is now recognized to severely alcoholic fathers was three- conducted over the past 25 years sug- and-one-half times greater than among gest that alcoholism is a heteroge- that alcoholism stems adopted sons of nonalcoholic men. In neous disorder, with some forms that addition, male adoptees of alcohol- are highly heritable and others that from a complex interplay abusing biological mothers were are less so. Alcoholism, like hyperten- almost twice as likely to become alco- between genetic sion, coronary artery disease, and dia- hol abusers themselves as male betes, appears to be a disorder in and environmental adoptees born to mothers who did not which environmental factors activate abuse alcohol. genetic components. In other words, factors. Analysis of the Swedish adoption genetic predisposition does not imply studies revealed the existence of two predestination: Environmental factors prototypic forms of alcoholism that are needed for alcoholism to develop alcoholism. In the next decade, studies differ in inheritance patterns, alcohol- in persons who have inherited a vul- focusing on gene-environment inter- related behaviors, personality traits, nerability for the disease. play will provide insight into the and environmental influences. Type Although much remains to be genetic mechanisms involved in the I alcoholism, also known as milieu- learned about the specific biological development of alcoholism. limited alcoholism, is a more common factors involved in the development form that occurs in both men and of alcoholism, it now is recognized women and is associated with adult- GENETIC SOURCES OF that alcoholism stems from a complex onset alcohol abuse in either biological interplay between genetic and envi- VULNERABILITY parent. This form is called milieu-limit- ronmental factors. This knowledge ed because its expression requires both opens avenues for developing medica- Studies of persons raised in adoptive genetic predisposition and environ- tions and other biological therapies homes from an early age provided the mental provocation. that compensate for genetic suscepti- earliest clues that genetic factors play a Type II alcoholism, also known as bility. Moreover, it lays the founda- role in alcoholism and that environ- male-limited alcoholism, is a severe tion for conceiving prevention, early mental factors influence whether a per- type of predisposition found only in intervention, and treatment methods son with genetic vulnerability for alco- men. Less common than Type I, Type that focus on changing environmental holism actually develops the disease. II is associated with severe, early- risk factors for alcohol abuse and Adoption studies help to untangle the onset alcoholism in the biological dependence. For example, neurophar- contributions of genes and family envi- father. Its transmission is highly macologists one day may develop a ronment, allowing these elements to be genetic and appears to be unaffected medication that can counterbalance a evaluated independently. The effects of by environment. genetic factor that enhances nerve genetic factors can be estimated by As with other genetically transmit- cells' vulnerability to the effects of comparing individuals with different ted diseases, the search for genetic alcohol. At the same time, behavioral genetic backgrounds who are raised in factors responsible for susceptibility 3b

24 Chapter III

aa 4i)

Female Female Deceased II Chronic Alcoholism Drug Abuse AP:Antisocial Personality SZ: Schizophrenia Male AiMale Deceased III Binge Drinking Marijuana Use SD: Somatization Disorder

to alcoholism has involved several Located in the nucleus of the cell, Studying family pedigrees enables stages. Studies in the primary stage genes carry information for hereditary researchers to assess familial frequency of alcoholism. Courtesy of Dr. David involved a close observation of famil- characteristics. Housed within genes Goldman. ial incidence. In the next phase, stud- are complex sets of instructions that ies focused on analyzing families to direct the development, organization, determine whether environment or and functioning of the human body. genes caused the family linkage. At The scores of instructions are con- present, genetic research on alco- tained not in one gene but, rather, are holism is moving into the area of mol- found in thousands of genes. Genes ecular biology to isolate and identify are organized and stored in structures the gene or genes that may confer known as chromosomes, each of vulnerability for this disease. which contains thousands of genes. By their chemical structure, genes control every detail about develop- MOLECULAR BIOLOGY: ment of the body: They specify the STUDYING THE CHEMISTRY OF body's size, shape, and color and pro- INHERITANCE vide directions for the functioning of bodily systems, such as the nervous Molecular biology is a relatively new and circulatory systems. Genetic infor- area of science in which knowledge of mation is coded in the deoxyribonu- normal physiology and of disease is cleic acid (DNA) molecule, the prima- gained through the study of genes. ry component of genes. DNA is a giant 37 25 Alcohol Research: Promise for the Decade double-stranded molecule that resem- acterize the genes involved in an indi- located, isolated, and cloned. The bles a ladder twisted into a helical vidual's heightened vulnerability to location of such markers can serve as shape. The sides of the DNA structure this alcoholism. a reference point on the genome, are composed of deoxyribose sugar providing the means for mapping and phosphate; the rungs consist of the gene or genes that may confer linked pairs of bases. It is the sequence IDENTIFYING GENETIC vulnerability to alcoholism. of these base pairs in the DNA chain VULNERABILITY Among the several types of bio- that constitutes the genetic code. chemical markers of genetic suscepti- Although genes specify the organi- Armed with strong and increasing bility to alcoholism currently being zation and functions of structures evidence for genetic transmission of studied, enzymes to date have within the human body, they do not alcoholism, researchers are concentrat- received the most attention. An actually construct these structures. ing on identifying the genetic mecha- enzyme is a protein that accelerates a Rather, the DNA that embodies a gene nisms responsible for predisposition chemical reaction but does not under- is "read" in a process known as tran- to this disease. Towards this aim, go a net change itself. Because scription. Through transcription, a researchers are studying families to enzymes are direct products of genes, copy of a gene is created in a form determine whether certain heritable variations in the properties of called ribonucleic acid (RNA). RNA traits are highly associated with the enzymes can be traced easily to varia- acts as a template and, through the occurrence of alcoholism. Traits tions in the corresponding genes. process of translation, directs the syn- cotransmitted with genetic predisposi- Moreover, certain enzymes are close- thesis of proteinsmolecules that tion to alcoholism can be used as ly associated with mechanisms and form structural components of cells markers to identify individuals at sites in the body known to be affected and tissues and perform physiological increased risk for developing alco- by alcohol. Both features make functions. holism. Although these cotransmitted enzymes valuable as markers of Thus, genes are the blueprint of the traits have not yet been identified, genetic involvement. human body, directing the synthesis of researchers are considering traits that The enzyme monoamine oxidase the body's proteins. If a gene is defec- (MAO) has been studied extensively tive, the corresponding protein will be as a potential biochemical marker of defective, resulting in a structural or Adenylate cyclase predisposition to alcoholism. Mono- functional abnormality. Such abnormal- amine oxidase is involved in the ities are the basis of genetic diseases. is another enzyme metabolism of several neurotransmit- The tools of molecular biology ters implicated in certain aspects of enable researchers to study the connec- that is receiving considerable alcoholism. Several studies have tion between genes and corresponding reported abnormally low MAO levels proteins. Various techniques can be research attention as a in blood platelets of alcoholics com- used to isolate specific DNA fragments pared with those of nonalcoholics. possible marker of for study. Numerous copies of a gene Moreover, because genetic factors con- subsequently can be reproduced with a predisposition to trol variations in MAO levels among technique known as molecular cloning. people, researchers believe that this Additional techniquespermit alcoholism. trait is not a secondary effect of alco- researchers to read the sequences of the holism. Recently, investigators have base pairs in the DNA fragment that associated low levels of platelet MAO comprises the gene. By so doing, they may be linked to genetic susceptibility with the highly heritable Type II alco- can determine whether a change in the to alcoholism within three promising holism but not with the more environ- base sequence accounts for a particular categories:Behavioral traits (impul- mentally influenced Type I. This find- genetic defect. sive and violent behavior), physio- ing demonstrates that biochemical dif- In alcohol research, molecular biol- logical traits (EEG abnormalities, ferences are likely to exist between the ogy has revolutionized the search for upper body sway), and biochemical two subtypes of alcoholism. genetic determinants of alcoholism. traits (enzymes involved in neuro- Adenylate cyclase (AC) is another By applying molecular cloning tech- transmitter metabolism). Once the enzyme that is receiving considerable niques, researchers now have tools associated markers are identified, the research attention as a possible mark- that potentially can identify and char- genes that produce them can be er of predisposition to alcoholism.

38 26 Chapter III

Found in the central nervous system, serve as "sign posts" that point to the this enzyme is involved in the forma- general location of the genes responsi- tion of second messengersintracel- ble for the development of alcoholism. lular chemicals that perform bio- Although the characteristics them- chemical functions that ultimately selves may not be responsible for the result in a physiological or a behav- development of alcoholism, they rep- ioral response. Adenylate cyclase resent identifiable factors that can be activity can be stimulated experimen- associated with alcoholics. For exam- tally by numerous substances, includ- ple, if three characteristic markers are ing the salt cesium fluoride and the always identified with alcoholism, hormone prostaglandin E.,. However, these markers are said to be linked to AC stimulation by either of these the development of alcoholism. Such agents appears to be significantly linkage suggests that the genes for the lower in alcoholics than in nonalco- markers lie on the same chromosome holics. The persistence of this effect in and are in close proximity to the gene alcoholics suggests that it may be a or genes responsible for alcoholism. marker of genetic risk for alcoholism, Using molecular biology tech- an interesting possibility currently niques, researchers can determine the being investigated. position of these markers on the Genetics researchers also are pur- human genome. It is anticipated that a suing research aimed at identifying sufficient number of markers will be electrophysiological markers of inher- identified within the next few years to ited predisposition. Communication allow researchers to produce highly within the brain involves bioelectric resolved genetic maps. Genetic maps impulses that begin in response to label the position of known genes chemical signals. One brain electrical (markers) on a chromosome. As the phenomenon that appears to be a locations of more and more markers strong indicator of genetic vulnerabili- are determined, the map becomes ty to alcoholism is the P3 signal, a highly resolved. High-resolution brain wave that normally appears genetic maps will enable researchers during the performance of various to detect, through linkage analysis cognitive or learning tasks. This wave with marker genes, those genes repeatedly has been shown to be responsible for susceptibility to alco- weaker in young boys who have holism. Identifying these genes is an never drunk alcohol but are at risk of important long-term goal in the study alcoholism because their fathers were of the human genetics of alcoholism alcoholic. Early studies had found the a goal that eventually can lead to a same reduced P3 wave amplitude in systemic approach to preventing and adult alcoholics who had become treating alcoholism. abstinent, raising the possibility that Through a large collaborative the reduced amplitude may be a con- study, presently ongoing at six sites sequence of and not an antecedent to across the United States, scientists alcoholism. However, the discovery have embarked upon a systematic that reduced P3 amplitude is present effort to identify the gene or genes in alcoholism-susceptible boys who responsible for predisposition to alco- have never consumed alcohol indi- holism. Scientists will study large cates that it precedes the development families of alcoholics by methodically of alcoholism and is a potential genet- collecting biological material and by ic marker of susceptibility. conducting neuropsychological and Heritable characteristics that may personality assessments. This multi- be associated with alcoholism can disciplinary, multisite project is

27 9 Alcohol Research: Promise for the Decade

expected to lay the groundwork for variant enzyme consume alcohol, the However, because many Asians who future genetic research on alcoholism noxious alcohol metabolite acetalde- experience the flushing reaction con- by yielding fundamental knowledge hyde increases in their systems, lead- tinue to drink, it appears that the pres- about possible biological markers and ing to the flushing reaction. Studies in ence of various isoenzymes is only genetic, psychological, and environ- Chinese and Japanese persons have one of the many genetic factors that mental risk factors associated with shown that the mutant gene occurs influencedrinking behavior. susceptibility to developing alco- five times less frequently in alcoholic Furthermore, environmental factors holism. patients than in the general popula- that influence alcohol consumption Genetic research on alcoholism is tion. This finding is important because may alter or override the effect of not limited to identifying and charac- the frequency of this abnormal gene in these genetic factors on drinking terizingtraitsassociatedwith the population may help to predict behavior. In fact, recent studies have increased vulnerability.Rather, susceptibility to alcohol abuse. reported that alcohol consumption is researchers also are interested in In contrast to most Asian popula- increasing among Asians as a result of defining the factors that appear to tions, Taiwanese aborigines have a social pressure to consume alcohol. In protect certain people from pathologic highincidenceofalcoholism. addition, the nature of the specific drinking, thereby protecting them Scientists have shown that, unlike ADH and ALDH genes in some indi- from the development of alcoholism. most Asians, members (85-90 percent) viduals may produce a less severe A notable and extensively studied of the aboriginal group possess a nor- aversive reaction that is less likely to protective phenomenon is the flushing mal gene for ALDH. Thus, the serve as a deterrent in the presence of reaction to alcohol observed in many absence of the abnormal ALDH gene new cultural and social pressures. people of Asian heritage. The flushing may be a contributing factor to the This new information suggests that reactionmanifested as a reddening high rate of alcoholism among future studies will require close obser- of the face and upper chest as a result Taiwanese aborigines. vation of both the biological and psy- of vasodilationproduces such Abnormal genes found in other chosocial factors that influence drink- unpleasant symptoms as hot skin, ethnic groups also may affect drinking ing behavior. increased heart rate, and lightheaded- behavior and contribute to alcohol ness. This response to alcohol long has abuse in these populations. For exam- been considered a deterrent to alcohol ple, scientists have discovered that ANIMAL MODELS IN consumption, and scientists have three variant forms (isoenzymes) of GENETIC RESEARCH hypothesized that the flushing reac- alcohol dehydrogenase (ADH)iden- tion may account for reduced alcohol tified as beta 1, beta 2, and beta 3are Animal models are an important tool consumption and lower incidence of found predominantly in white, Asian, in the study of genetic susceptibility alcoholism observed in the Asian pop- and African-American populations, to alcoholism because these models ulation compared to many other eth- respectively. Because alcohol dehy- enable scientists to control for various nic groups. drogenase (ADH) is the first enzyme biological characteristics observed in Molecular biology techniques were involved in metabolism of alcohol, humans. Use of these models in instrumental in identifying the biolog- differences in the properties of this experimentalstudiesenables ical factors that underlie the flushing enzyme could affect the rate at which researchers to analyze potential genet- reaction. Using these techniques, alcohol is metabolized in the body. ic determinants of alcoholism. The researchers showed that the inheri- Experimental studies have demon- findings gathered through animal tance of an abnormal gene for the strated that the isoenzymes metabo- research on alcohol, in turn, can be enzyme aldehyde dehydrogenase lize alcohol at different rates, and applied to the study of alcoholism in (ALDH) was primarily responsible for researchers are beginning to deter- humans. producing the flushing reaction to mine the relevance of this finding to Most experimental animals avoid alcohol consumption. ALDH is one of drinking behavior and complications drinking alcohol under normal condi- two enzymes involved in normal of alcohol abuse. tions. Thus, to develop an animal metabolism of alcohol. The variant The disparate distribution of these model that parallels the human dis- form of ALDH produced from this enzymes in Asian alcoholics com- ease, researchers have been faced with abnormal gene is inactive, thereby pared to Asian nonalcoholics supports finding animals who actively will seek preventing normal metabolism of the belief that alcoholism may have a alcohol. This problem was resolved alcohol. When individuals with this genetic basis in some persons. with the development of selectively 40

28 Chapter III bred animal lines that differ greatly in embryos, producing transgenic ani- their preference for alcohol. The mals. If the transgenic animal displays diversity of alcohol preference in such the drinking behavior found in the animals provided evidence that this original animal line, scientists have characteristic may be genetically influ- strong evidence that the transferred enced and suggested that animals gene is involved in the behavioral may be bred selectively for this response under study. attribute. Transgenic animals also may be As the next step in developing used to study the regulatory elements animal models for alcoholism, scien- of genes. Regulatory elements act as tists had to resolve whether alcohol- "switches" that turn a gene on or off. preferring animals drink alcohol for For example, by selectively modifying its nutritional or caloric value, or for portions of the regulatory elements in its pharmacological effects. Studies alcohol and aldehyde dehydrogenase with rats bred selectively for alcohol genes and introducing the altered preference demonstrated that these genes into mice or rats, scientists will animals not only will work to obtain alcoholpressing a bar more than 1,000 times a daybut also will self- To develop administer alcohol directly into their stomachs. Such actions indicate that an animal model the rats are consuming alcohol for its that parallels the pharmacological effects, rather than for the benefits of taste, smell, or calories. human disease, At present, researchers have bred several lines of animals that exhibit a researchers have been preference for alcohol. The use of such animals in alcohol research offers the faced with finding potential to identify the gene or genes responsible for the alcohol-preferring animals who actively behavior. For example, using a technique known as subtractive screening, will seek alcohol. scientists can identify differences in the genes between lines of alcohol- be able to observe the changes in preferring and nonpreferring animals. expression of the genes under study This research may provide a greater and the effect of over- or under- understanding of the underlying production of that enzyme on drink- mechanisms of alcohol consumption ing behavior. Such information also and alcoholism. will be valuable to understanding fac- Once the genes responsible for tors that control tissue-specific expres- alcohol preference are identified, sci- sion of each gene. entists will be able to apply innova- Genetic variations in an individ- tive techniques in molecular biology ual's response to the effects of alcohol to determine how the presence or may account for some differences in absence of a particular gene influences vulnerability to alcohol abuse and behavior toward alcohol consump- alcohol dependence. The development tion. At present, scientists can use of selectively bred animals that either recently developed technology to prefer or do not prefer alcohol has introduce the gene(s) for alcohol pref- enabled alcohol researchers to begin to erence (individually or in various unravel the complex brain mecha- combinations) into mouse or rat nisms that control the relationship

41 29 Alcohol Research: Promise for the Decade between genetic and environmental Animal research also contributes to to develop animal lines with either factors in alcohol addiction. our knowledge of the medical conse- heightened or diminished sensitivity Although many animal species quences of alcohol use, including our to prenatal alcohol. Ovum transplan- avoid all but the lowest concentrations understanding of alcohol-related fetal tation, in which a fertilized ovum of alcohol, alcohol-preferring rats vol- injury and fetal alcohol syndrome from one animal strain is placed into untarily administer alcohol (by oral, (FAS). For example, it is recognized the uterus of another strain, offers an intragastric, or intracranial routes) for that not all women are at equal risk important opportunity to localize the maternal and fetal factors that affect some rewarding effects and will per- for giving birth to a child with FAS. the risk for fetal injury. form various behavioral tasks to gain Evidence (including heightened sensi- access to even highly concentrated tivity among some racial groups and varying extent of injury in dizygotic, alcohol solutions. Yet, factors other THE INTERACTION OF or nonidentical twins) points to the than genetic susceptibility may con- possibility that genetic factors make GENETICS AND tribute to drinking behavior: Through some women or some fetuses more ENVIRONMENT the use of certain behavioral induce- susceptible and others more resistant ments, alcohol-nonpreferring rats can to the effects of alcohol. However, As more is learned about alcoholism, learn to drink increasing quantities of these genetic factors remain unidenti- researchers are beginning to question alcohol. Nevertheless, the nonprefer- fied. Also unknown is whether the whether it is a discrete disease with ring animals continue to consume far heightened sensitivity is defined by stable patterns of inheritance. If only less alcohol than the preferring ani- the genes of the mother or of the fetus. one type of familial alcoholism exists mals. Over the next few years, Answers to these important ques- and genetic factors are solely respon- researchers will use specially bred ani- tions can be approached in animal sible for its development, then the incidence of alcoholism in families mal lines to understand the role of models by coupling genetic breeding should remain relatively stable from rewarding, anxiety-reducing, and with the new technologies of ovum generation to generation, and changes aversive effects of alcohol in the con- transplantation. Sophisticated genetic in environment should have little trol of drinking. breeding studies offer the opportunity effect on that incidence. The incidence of sporadic, nonfamilial cases, however, would fluctuate with the presence of various environmental factors, such as increases or decreases in trends of alcohol consumption in the general population. In a recent study, researchers observed that heightened drinking in the general population leads to both an increase in sporadic cases of alcoholism and a marked increase in the proportion of relatives who abuse alcohol in families of alcoholics. The marked change in populations of individuals who seemingly are genetically vulnerable to alcoholism suggests that social and temporal trends in the use of alcohol influence the observed inheritance of alcoholism. In the coming decade, gene- environment studies will play a criti- With new techniques, researchers can isolate and extract a gene from one animal cal role in shedding new light on the and, as shown above, microinject it into the ovum of a pregnant animal. The developing "transgenic" animal begins to express the newly introduced gene. Photograph genetic and environmental causes of courtesy of Dr. Carol Readhead. (Magnification 400x) the onset and progression of alco- 42

30 Chapter III holism, adolescent drinking and other high-risk behaviors, and the impact of one person's alcoholism on other persons, such as children of alcoholics, especially with regard to factors that may protect those other individuals from developing alcoholism. From the population studies of the 1970s, which identified a heritable component to alcoholism, to the increasingly sophisticated biological and psychosocial studies of the 1980s, alcohol researchers have continued to refine our understanding of the course of alcohol abuse and dependence. This fine-tuning in our understanding of alcohol-related problems will continue at an increasingly rapid pace throughout the 1990s, spurred by new technological advances and heightened interest of researchers and the lay public alike in preventing and treating these major public health problems.

31 .abge.---

6._

lb I

I .

...

44 WHYDo IVPEOPLE DRINK?

It has long been recognized that REINFORCEMENT: A individuals tend to repeat behaviors DETERMINANT OF DRINKING that lead to pleasant outcomes. However, the factors that motivate The reinforcing properties of alco- people to perform an act again and hol may explain, in part, why some again to gain pleasure or to allevi- people drink. Many persons find ate discomfort are not yet fully the effects of alcohol to be pleasant: They experience mild stimulation understood. and a feeling of well-being or Scientists use the term "reinforce- reduced anxiety, usually soon after ment" to describe the process in drinking. These effects may rein- which an effect or outcome increas- force continued alcohol use. At this es the chance that a behavior will time, scientists do not understand recur. People learn to perform a fully the processes in the body that behavior, such as drinking alcohol, are involved in the reinforcement of to obtain a particular outcome, or alcohol use. During this last decade reinforcer, such as the pleasant of the 20th century, however, (euphoric) or the anxiety-reducing researchers hope to gain more knowledge about the nature of alco- (anxiolytic)effectof alcohol. holreinforcementandwhat Alcohol researchers are beginning to prompts some individuals to seek explore reinforcement in their repeated exposure toalcohol Why do people drink? Scientists are efforts to understand the processes despite adverse consequencesa using animals to study the processes responsible for alcohol-seeking responsible for alcohol-seeking behav- behavior that appears to contribute ior in humans. Photograph courtesy of behavior. significantly to the development of Dr. Kathleen Grant. 45

33 Alcohol Research: Promise for the Decade

Researchers use brain stimulation reward studies to examine the nerve circuits in the brain that control reward. Animals learn to press a lever to administer low levels of electric current to specific regions of the brain. This stimulation evokes a rewarding sensation. Drawing by Robert Czechowski and Clare Little. chronic drinking and dependence euphoria. Findings from a number of electrical current needed to produce and to craving and relapse in different experiments indicate that the reward decreases. Scientists have patients recovering from alcoholism. neurotransmitter dopamine and its interpreted these findings to indicate Alcohol researchers have used interactions with other neurotransmit- that alcohol increases the euphoria experimental animals and techniques ters are essential in reward. BSR stud- experienced by the animal. This effect, to study reinforcement and the prop- ies can be used to measure the effect however, is observed only as the erties of alcohol that encourage people of alcohol on the reward sensation in amount of alcohol present in the ani- to drink. One technique, known as the brain. Stimulating specific regions mal's blood is increasing. brain stimulation reward (BSR), has of the brain with electrical currents Studies with people who consume demonstrated that reinforcement of can produce euphoria. In BSR studies, alcohol in the laboratory have shown alcohol-seeking behavior can develop animals work to stimulate their own that humans also may experience a from the property of alcohol that gen- brains with low levels of electrical cur- mild euphoria as the amount of alco- erates a sense of pleasure. This tech- rent to evoke a rewarding sensation. hol in the blood increases toward its nique has provided valuable informa- When these animals are given alcohol, peak level. This knowledge may help tion on the nerve circuits in the brain the rate at which they stimulate their us to understand some of the mecha- that control reward and, perhaps, brains increases while the amount of nisms by which euphoria may act to 46

34 Chapter IV

reinforce alcohol-seeking behavior.If These observations appear to par- alcohol can produce euphoria only as allel reports of many individuals who levels of alcohol in the blood are describe diminished tension and anxi- increasing, people may continue to ety as desirable effects of drinking. drink more and more to sustain a pat- The desire to relieve anxiety may con- tern of increasing alcohol levels. tribute to increased drinking and alco- Researchers also have demonstrat- hol abuse and promote relapse in ed the anxiolytic effect of alcohol in abstinent alcoholics. studies using animal models and a Alcohol has a unique quality that plus maze technique. A plus maze is distinguishes it from other psychoac- a track for animals in the shape of a tive drugs and that also may contribute plus sign. The maze is divided into to the reinforcement of alcohol-seeking two sectionsone with sides, which behavior:It furnishes calories and, shields an animal from open areas; the thus, may serve as a source of food and other without sides, which exposes an energy to the drinker. Although the animal to the open environment. calories supplied by alcohol are Experimental animals placed in the "empty" calories, lacking such essen- maze usually try to remain within the tial nutrients as vitamins and protein, closed area, avoiding the sections they, nevertheless, may substitute as a without sides. source of energy and may affect body Following the administration of metabolism. Scientists now recognize alcohol, however, the experimental that chronic alcohol consumption can animals will run freely into the open affect the normal processes by which areas of the maze. Moreover, these our energy and other nutrient needs animals will spend more time in the are met. Accordingly, alcohol prob- open regions than the animals that are lems may be linked to appetite and to not given alcohol. Researchers believe appetitive processes. that this behavior demonstrates alco- Researchers have just begun to hol's anxiolytic effect:Alcohol explore the complex appetitive appears to lessen the anxiety that the processes that control hunger, nutri- animals experience in open spaces. tional demands, and thirst.In the

74,

A plus maze is used to study the anxi- 0 olytic effect of alcohol. Although rodents normally avoid open sections of the maze, they run freely into these regions after drinking alcohol. This behavior suggests that alcohol may lessen the anxiety that the animals experience in open spaces. Photograph courtesy of Dr. David Goldman.

47 35 Alcohol Research: Promise for the Decade coming decade, they will work vative techniques to explore two tent sets of expectancies about the toward determining how alcohol aspects of drinking behavior: (1) the effects of alcohol on behavior. These affects these processes and whether process by which people learn about expectancies, which are expressed by alcohol reinforcement is derived, in alcohol and (2) the ways in which peo- adolescents as young as 12 to 14 years part, from its food qualities. ple make decisions about drinking. of age and probably are formed at an Just as some of the effects of alco- even younger age, are predictive of hol may serve to reinforce continued Expectancies About Drinking drinking behavior among all age drinking, other physiological effects of Drinkingbehaviorcannotbe groups. For example, adolescent prob- alcohol may deter individuals from explained solely by the direct pharma- lem drinkers and adult alcoholics alcohol use, thus serving to protect cological effects of alcohol that pro- expect that alcohol will improve their individuals from alcohol abuse and duce euphoria or alleviate anxiety. mental and physical functioning; yet, dependence. Alcohol can produce dis- Other considerations, such as psy- their nonproblem-drinking peers do agreeable, or aversive, effects, such as chosocial factors, learning, and envi- not share this expectancy. Children of the extremely uncomfortable symp- ronment, may help to shape drinking alcoholics also hold this expectation of toms associated with a hangover. behavior. alcohol, whereas their peers, who do Some individuals experience aver- Scientists have found that an indi- not have family histories of alcohol sive effects after drinking even small vidual's beliefs and expectations abuse or dependence, do not. amounts of alcohol. As described ear- about the effects of alcohol on behav- Expectancy about alcohol use is lier, persons of certain Asian origins ior and social functioning play a piv- one factor that may contribute to an experience an unpleasant flushing otal role in alcohol use and abuse. adolescent's risk for developing alco- response (reddening of the face and Several studies have shown that peo- hol dependence. Learned expectancies upper chest, hot skin, and increased ple who think they are consuming may be one way in which risk for pulse rate) after drinking alcohol. This alcoholism (that is, family history of response can be sufficiently unpleas- alcohol involvement) is translated into ant to be a deterrent to excessive Expectancy problem drinking. Moreover, specific drinking. expectancies eventually may be useful Scientists are faced with the chal- about alcohol use for identifying those persons who are lenge of determining the importance vulnerable to developing alcoholism. of such aversive effects in controlling is one factor that may Not only can stimuli associated alcohol intake and in bringing about with the taste of alcohol and its phar- abstinence in alcoholics. In addition, contribute to an adolescent's macological effects (for example, future research may provide insight euphoria) serve as reinforcers of alco- risk for developing alcohol into the possibility that potential and hol use; expectancies about drinking established alcoholics may be defi- dependence. experiences also may lead to contin- cient in their ability to experience ued drinking. Expectancies may arise some of the unpleasant effects of alco- from thoughts of drinking, from hol. These deficits may play a role in alcohol drink more than those who pleasant social situations that involve the course of their illness. believe they are drinking a nonalco- alcohol, and from the anticipation of holic beverage. Further, both social the euphoria or the diminished anxi- drinkers and alcoholics who believe ety that can accompany drinking. PSYCHOLOGICAL AND they have consumed alcohol behave Research conducted in the next SOCIAL INFLUENCES ON differently from those who think decade will explore more fully the DRINKING they have not, even if alcohol has not mechanisms that underlie expectancy been consumed. as a reinforcer and the role that it How drinking develops, continues, Why is this? One explanation may plays in drinking and relapse. and is modified over time is of consid- be that expectancies, which are erable importance to understanding learned through social processes that Learning Factors the nature of alcoholism and, in turn, transmit information about behaviors It is believed commonly that ideas to developing both prevention and and their consequences, are powerful about alcohol and other drugs begin treatment activities. Researchers predictors of behavior. Indeed, both to develop during middle childhood studying these issues are using inno- adolescents and adults have consis- and blossom during adolescence. 48 36 Chapter IV

Thus, students in the late elementary, experimental, and clinical psychology middle or junior high school, and to discover what young children early high school years usually are the know about alcoholic beverages and target group for educational programs drinking behavior. One technique on the harmful effects of alcohol and involves showing young subjects pic- other drugs of abuse. In the past few tures of everyday situations in which years, however, alcohol researchers people are holding a glass or beverage have found evidence suggesting that can. The children then are asked to knowledge about alcohol use is describe what each person is drinking. formed much earlier than previously Results show that children as young thought. as three years of age know that adults Investigators have applied innova- consume alcoholic beverages; that tive techniques from developmental, children should not drink alcohol; and

MIrMINM.

Future research studies will examine the family factors that may protect individuals who are at risk for developing alcoholism from developing the disorder, 49 37 Alcohol Research: Promise for the Decade

that men drink alcoholic beverages ing effects on children of another paring labels, public service announce- more often than women. Young chil- ent's alcoholism; and (4) the condi- ments, formal educational programs, dren also can correctly identify differ- tions surrounding the onset of adoles- and legal restrictions on consuming ent alcoholic beverages, and this abili- cent alcohol abuse. and serving alcohol. ty improves with age. Not surprising- In addition tothese issues, Studies of decisionmaking process- ly, a significant association exists researchers will focus on unraveling es apply two basic approaches: between the ability to make correct the increasingly prevalent problems of empirical research and formal model- identifications and the level of drink- alcoholism in women. Over the past ing. Empirical research examines how ing in the child's home. Thus, educa- few years, research findings have sug- people actually make decisions. tional efforts focused on high-school gested that the family processes Formal models, sometimes called students may come too late. involved in transmitting and perpetu- decision trees, are used to structure Previous research efforts have pro- ating alcoholism differ for female and the problem-solving processthat is, vided evidence suggesting that atti- male alcoholics. A greater under- to identify and measure risk and to tudes about alcohol are formed early standing of these differences will pro- demonstrate how decisions are made. in life. During the 1990s, researchers vide new insight into preventing and Research on decisionmaking expect to build on this evidence to treating alcoholism in women. processes involved in alcohol-related make significant advances in charting choices among adolescents is exceed- how young children learn about alco- Decisionmaking Processes ingly important. As adolescents test hol and how this knowledge affects Should I drink alcohol? Should I cut the constraints of their physical and subsequent behavior, especially in back? Should I seek help? Should I social environments, they make con- preadolescent and adolescent children. have one more for the road? Should I scious and unconscious decisions to drive after drinking? Should I ride consume or abstain from alcohol. Family Influences home with my intoxicated date? Disruptive family events, parental Much of our social learning takes place Drinking alcohol entails many deci- behavior, peer pressure, and percep- within the family. Hence, scientists sions. Some decisions concern drink- tions about community approval may have begun to examine the role of fam- ing itself; others involve managing its affect their decisionmaking. ily in shaping patterns of alcohol use consequences. Some are made alone; Over the next decade, researchers and abuse. The course of alcoholism will continue to examine the decision- often depends on continuing patterns making process and the role of choice of family life; some family dynamics As adolescents in the emergence of alcohol problems. can reinforce and perpetuate abusive This new wave of research will drinking. Marriage or a marriage-like test the constraints address such questions as whether relationship, for instance, has been of their physical and processes involved in making deci- found to modify the genetic risk for sions about alcohol differ significantly heavier drinking in women. social environments, from those that involve other issues. Alcohol researchers have set as an With a better understanding of the important goal for the coming decade they make conscious and decisionmaking process, researchers developing an accurate picture of how can identify more effective methods to family dynamics affects the beginning, unconscious decisions help individuals make health- continuation, and modification of promoting decisions about drinking. alcohol abuse. The most important to consume or abstain Further, these studies can assess an advances in this area of study will individual's perceptions of the risks address four key issues: (1) the specif- from alcohol. and benefits of alcohol consumption. ic ways in which families are disrupt- An understanding of decisionmak- ed by an alcoholic member; (2) the others are made in social settings. ing processes also may enhance our family and other social factors that Some are made while sober; others are efforts to establish effective social protect persons who are at risk from made while under the influence of policies to reduce alcohol-related developing alcoholism and the mech- alcohol.Moreover, many social problems. Economists have theorized anisms by which these factors act; (3) responses to alcohol use involve that a model of "rational addiction" the pivotal role one parent may play attempts to influence decisionmaking can describe decisionmaking involved in moderating the potentially damag- through such efforts as health warn- in addictive behavior. This approach 50

38 Chapter IV emphasizes the effects of prices on drinking choices. The model postu- lates that even alcoholics may be influenced by the pattern of prices for alcoholic beverages. Moreover, the effect of price on drinking behavior is dynamic (that is, lower prices may contribute to increased drinking that strengthens an addiction and leads to increased drinking in the future). Temporary price increases may affect behavior differently than permanent increases. In addition, drinking behavior may change with an anticipated rise in prices. Although preliminary studies exploring this concept have provided promising results, more research is needed. The knowledge gained from these studies will be useful in the continuing search for effective policies to reduce the person- al and social costs of addiction.

39 52 VTHE MEDICAL CONSEQUENCES OF ALCOHOLISM

Liver disease, pancreatitis, cardiovas- lity to developing diseases associated cular disorders, and brain damage are with alcohol abuse. It appears that just several of the many disorders complex relationships exist between resulting from chronic drinking that the development of alcohol-induced clinicians often see in the patients they damage and the amount, duration, treat. Virtually no part of the body is and pattern of consumption. The fre- spared the harmful effects of excessive quency of drinking, the duration of alcohol consumption. drinking bouts, the blood alcohol con- When alcohol is consumed, it passes Although, at present, no proven centration attained in the drinker's through the esophagus (1) and into the mechanisms explain completely how body, and whether the pattern of stomach (2), where small amounts are absorbed. Most of the alcohol ingest- alcohol exerts its effects to produce drinking permits time for the body to ed, however, passes to the small intes- the multitude of diseases associated recover before drinking resumes are tine (3), and is readily absorbed into with heavy drinking, evidence sug- likely to be important risk determi- the bloodstream with other nutrients. Distributed throughout the body in the gests that a number of factors con- nants for the development of alcohol- blood, alcohol affects various organs tribute to the development of alcohol- relateddiseases.Alternatively, and systems, including the heart (4) induced disorders. Susceptibility for researchers may discover that the total and cardiovascular system. Although moderate drinking may have some developing alcohol-related diseases lifetime exposure to alcohol is more beneficial effects on the cardiovascu- seems to vary from individual to indi- important to defining risk than the lar system, heavy drinking eventually vidual. Although much of the evi- number of times an individual attains can cause the heart muscle to deterio- dence is preliminary, researchers now relatively high blood or organ alcohol rate. Digested food substances and alcohol are carried away from the are finding that genetic factors may concentrations. small intestine to the liver (5), the primary play a significant role in defining an Cofactors also may influence an site for alcohol metabolism. In the individual's vulnerability. individual's vulnerability for alcohol- liver, enzymes metabolize alcohol to carbon dioxide and water. Painting by Yet, genetic factors, alone, may not induced organ damage. Although Edward S. Gazsi. Reprinted from National fully account for varying susceptibi- alcohol is the primary cause of most Geographic Magazine 181(2), 1992.

5,3 41 Alcohol Research: Promise for the Decade alcohol-related diseases, the presence the portal vein. By acting selectively Healing usually occurs with absti- of other diseases or conditions, such upon the digested material, the liver nence, although there may be resid- as infections or nutritional deficien- can remove toxic substances from the ual scarring. cies, may increase an individual's circulating blood. Cirrhosis is an extremely grave and chance of developing one of the many Once alcohol reaches the liver, it is irreversible disease that accounts for diseases that result from alcohol's metabolized initially to acetaldehyde. over 26,000 deaths each year. In 1986 deleterious effects on the body's Acetaldehyde is broken down rapidly (the last year for which data are avail- organs and systems. to acetate which, in turn, is converted able), this disease was ranked as the It is still unknown why only certain to carbon dioxide and water. Because ninth leading cause of death in the people who drink develop alcohol- acetaldehyde is highly toxic to the United States. Characterized by a pro- related diseases. Despite decades of liver and to other organs, its conver- gressive replacement of healthy liver slow progress in studying and treat- sion to acetate is an extremely impor- tissue with diffuse scarring, cirrhosis ing alcohol-related diseases, however, tant metabolic step. It has been sug- can lead to death from liver failure if we now can approach these problems gested that the elevated levels of drinking continues. However, if a cir- with increasing optimism. Recent acetaldehyde often found in heavy rhosis patient becomes abstinent, the research, such as evidence for the pos- drinkers may cause the alcohol-medi- proliferation of scar tissue subsides, sible role of genetic factors in the ated injuries frequently seen in these and the individual's life can be pro- development of alcohol-related individuals. longed. pathologies, should produce rapid Chronic and heavy drinking can Impaired liver functioning also advances in treatment in the future. cause significant damage to cells in may have profound effects on other the liver. Cellular injury is presented organs and systems in the body. as fatty liver, alcoholic hepatitis, or Primary hepatic encephalopathy, a ALCOHOL AND THE LIVER cirrhosis. brain dysfunction associated with Fatty liver, a relatively benign and alcoholic hepatitis and cirrhosis, is an The largest organ of the body, the example of such an effect. This condi- liver performs many essential func- reversible condition that is common to alcoholics, usually indicates recent tion, which is marked by altered intel- tions:It filters circulating blood; it drinking. The condition is marked by lectual function and emotion, as well secretes bile into the gastrointestinal as by disturbed psychomotor and tract; and it synthesizes proteins and behavioral regulation, appears to other organic compounds vital to the As the primary site develop as a consequence of the body. Because the liver plays a critical liver's inability to perform its many role in many fundamental activities for alcohol metabolism, vital functions. within the body, injury to this organ can produce a wide range of serious the liver is particularly Immune Responses medical consequences. in Liver Damage As the primary site for alcohol vulnerable to injury from Alcohol can damage the liver directly metabolism, the liver is particularly or through a series of complex bio- chronic alcohol vulnerable to injury from chronic alco- chemical interactions that cause the hol consumption. Because liver dis- consumption. body literally to attack itself. The eases are prevalent among heavy metabolite acetaldehyde is a highly drinkers, efforts to understand the reactive compound that combines basic mechanisms responsible for the accumulation of fat in the liver chemically with various proteins and alcohol-induced liver damage are a that causes the organ to become cell membrane components to form priority for alcohol researchers. enlarged. Abstinence usually leads to products known as adducts. When When alcohol is consumed, it pass- complete reversal of this abnormality. naturally occurring proteins combine es through the esophagus and stom- Alcoholic hepatitis, a considerably with acetaldehyde, their physical and ach to the small intestine, where it is more serious condition, is marked by chemical properties become altered readily absorbed with other nutrients. widespread inflammation of the liver and they appear foreign to the body's Digested food substances and alcohol and increasing destruction of liver immune system. As a result, the then are carried from the small intes- tissue. In its most severe form, this immune system generates antibodies tine to the liver, entering by way of condition can be life-threatening. to attack and remove these proteins.

54 42 Chapter V

572 I7i

According to a recent study, 70 ence of alcoholic liver disease and (1) A healthy liver. (2) Cross-section of percent of alcoholics have antibodies may be involved in its development. a healthy liver. (3) A cirrhotic liver. Cirrhosis is characterized by diffuse to acetaldehyde adducts. Antibody Recent studies have shown that TNF scarring of the liver. (4) Cross-section levels are especially high in patients alpha production is abnormally high of a cirrhotic liver. Photographs cour- with alcoholic hepatitis, suggesting in alcoholic hepatitis patients, even tesy of Dr. Emmanuel Rubin. that immune response to acetalde- when they are not drinking. More- hyde adducts is involved in the devel- over, elevated TNF alpha levels in opment of alcoholic liver disease. alcoholic hepatitis patients appear to Moreover, acetaldehyde adducts be highly predictive of early death. appear to interfere with proper func- Whether TNF alpha plays a direct tioning of important liver proteins. role in the development of alcoholic Thus, the presence of these adducts, hepatitis remains unresolved. The alone, may contribute to the develop- production of this cytokine may be ment of alcoholic liver disease. the immune response triggered by the Scientists also are examining the acetaldehyde adducts present in role of cytokines in alcoholic liver dis- patients with alcoholic liver disease ease. Cytokines are a class of small and, further, may be the mechanism proteins, produced by white blood by which alcohol causes liver disease. cells, that serve as cell messengers and If cytokines, such as TNF alpha, are hormones. Elevated levels of a specif- identified as causative factors for ic cytokine, called tumor necrosis fac- alcohol-induced liver disease, med- tor alpha (TNF alpha), mark the pres- ications that selectively block this

43 Alcohol Research: Promise for the Decade

immune response may be developed, dehydrogenase, a primary metaboliz- question whether genetic factors may thereby lessening or eliminating at ing enzyme that converts alcohol to play a role in susceptibility to liver least one factor involved in liver dis- acetaldehyde, is more abundant in injury. Evidence that supports this ease. Ultimately, such medications regions of the liver far away from the idea, which includes studies of iden- could impede the progression of this entry point of oxygenated blood to the tical twins, has shown that if one serious alcohol-related disease. organ. Thus, the region where alcohol member of the pair has alcoholic cir- Research on the involvement of may provoke oxygen deficiencies also rhosis, the other member is more immune response in alcoholic liver is the site where acetaldehyde adducts likely to develop this disease than are disease is still new and requires more can form. other siblings. detailed study in the future. For exam- In addition, oxygen deprivation The disproportionate number of ple, it is not known whether genetic from alcohol metabolism may decrease deaths from alcoholic liver disease in factors that control immune response the rate at which fatty acids are broken women compared with men provides to acetaldehyde adducts play an down. This rate, normally reduced in more evidence for a genetic risk factor important role in explaining why only low-oxygen regions of the liver, would for alcohol-induced liver injury. a percentage of heavy drinkers devel- be much reduced in the presence of Findings suggest that the detrimental op alcoholic hepatitis. Gaining a fuller effects of alcohol on the liver are more understanding of the nature of genetic severe for women than for men: risk factors will enable alcohol Researchers are Women who drink heavily develop researchers and clinicians to more liver disease after a comparatively effectively prevent and treat alcoholic attempting to determine shorter drinking period and at a lower liver disease. level of daily drinking than men. whether mechanisms Although the reasons for varying Oxygen Availability susceptibility between the sexes are Researchers are attempting to deter- other than not known, gender specific variation mine whether mechanisms other than in alcohol metabolism may contribute immune response may be involved in immune response to the heightened vulnerability to the damaging effects of alcohol on the alcoholic liver disease in women. A liver and the subsequent development may be involved in the recent study found that alcohol dehy- of liver disease. At present, the role of damaging effects drogenase (ADH), a primary enzyme oxygen deprivation in the liver is in alcohol metabolism, is expressed in being explored as a causative factor of alcohol on the stomach in lower levels in women for liver disease. When an individual than in men. Diminished levels of drinks heavily, the liver requires the liver. ADH in women result in decreased increasing amounts of oxygen to metabolism of alcohol, and increased metabolize the alcohol. Thus, oxygen amounts of alcohol in the blood. The may be diverted from other functional alcohol. The effect of alcohol on this resulting elevated levels of blood alco- processes in the liver to allow the process may explain why low-oxygen hol may contribute to women'sseem- organ to carry out alcohol metabolism. regions are the sites of fat deposits in ingly heightened susceptibility to However, diverting the oxygen to heavy drinkers with fatty liver. All of alcoholic liver disease. alcohol metabolism may deplete liver these phenomena are consistent with The genetic mechanisms involved cells of critical oxygen supplies need- the observation that alcohol-induced in the production of collagena struc- ed for other vital functions. The result- injury most frequently occurs in liver tural protein and the major protein ing diminished oxygen quantities may regions with limited oxygen availability. found in liver scar tissuealso may provoke injury to the liver. Moreover, be a link to understanding disparate the presence of anemia or blood flow Genetic Susceptibility susceptibility to alcoholic liver dis- obstructions in the liver (conditions Clinicians have observed that someease. Collagen is not a single protein; not uncommon among alcoholics with heavy drinkers do not develop liver the body produces at least 10 different liver disease) may exacerbate oxygen disease, even though these individu- types. Although this structural pro- deprivation. als may drink as much as others who tein is found in the healthy liver, the Adding to this process of potential do develop liver disease. This obser- amount increases dramatically in cir- liver injury is the finding that alcohol vation has prompted researchers to rhosis. Recent findings suggest that 56

44 Chapter V

individuals with alcoholic cirrhosis ceases. Sometimes the pain associated may produce a unique variant of one with this disease can be relieved only of the collagen genes, known as type I by removing the pancreas surgically. collagen. However, well before the onset of However, the significance of this pain, the disease is present and is pro- finding in understanding genetic vul- ducing chronic changes in the organ. nerability to alcoholic cirrhosis is The association between alcohol unclear. Perhaps this variant gene is a abuse and chronic pancreatitis has marker, identifying individuals who prompted researchers to question have heightened vulnerability to cirrhosis.In studying thisgene, how alcohol adversely affects the researchers may gain greater insight structure and function of the pan- into the mechanisms involved in the creas. Alcohol stimulates the produc- development of alcoholic cirrhosis tion of pancreatic digestive enzymes. and, in turn, may apply this knowl- This effect, combined with an obstruc- edge to improve approaches aimed at tion of enzyme flow through the pan- preventing and treating alcohol- creatic duct leading to the small intes- induced injury to the liver. tine, augments the levels of these digestive enzymes. It has been suggested that these digestive enzymes ALCOHOL'S DAMAGING may become activated in the pancreas EFFECTS ON THE PANCREAS rather than in the small intestine, where enzyme activation normally The pancreas, a large, elongated gland occurs, resulting in digestion of the positioned behind the stomach, serves pancreas by its own enzymes. Such as an accessory digestive organ that events may be responsible for the assists in the breakdown of ingested foods. It accomplishes its digestive development of pancreatitis in heavy function by secreting into the small drinkers. intestine specific enzymes that cat- Recent research has provided new alyze the breakdown of carbohy- insights into the mechanisms involved drates, proteins, and fats.In their in the development of this disease. chemically simpler forms, these nutri- Evidence from animal studies indi- ents can be absorbed easily by the cates that alcohol's action in increas- small intestine. ing the production of a highly reactive In addition to its digestive role, the form of oxygen, called oxygen free pancreas also functions to maintain radicals, may be one of the underlying blood sugar levels. Insulin and causes of pancreatitis. In experimental glucagon, two hormones synthesized studies, allopurinola drug that and released by the pancreas, act con- appears to block free radical forma- jointly to regulate blood sugar levels tionsignificantly reduced the severi- within a rather narrow range, despite ty of the disorder. Further, agents that wide fluctuations in sugar intake. More than three-quarters of destroy free radicals once they are patients with chronic pancreatitis--a formed also produced favorable painful inflammation of the pan- effects. Broadening these new find- creashave a history of heavy drink- ings through continued research may ing. Pancreatitis, which typically enable scientists to develop more appears after 5 to 10 years of excessive effective treatment approaches and drinking, produces severe abdominal prevention strategies for this painful pain that can recur even if drinking and debilitating disease.

45 Alcohol Research: Promise for the Decade

ing in bulk and size. Although this 1 adaptive response remedies the impaired functioning for a time, eventually the heart becomes unable to pump sufficient amounts of blood to meet the needsofthe body. Abstaining from drinking, however, can help patients with alcohol-induced heart disease to recover. Until recently, physicians did not suspect that weakness of the heart muscle occurs in alcoholic patients who do not manifest the clinical signs of alcoholic cardiomyopathy. New evidence suggests, however, that cardiac function may be impaired in a substantial number of alcoholics. Although alcohol's toxic effects on 2 the heart have been demonstrated, scientists continue to search for the mechanisms responsible for these damaging actions. Researchers have s i found that impaired functioning may result from the disruptive effect of alcohol on metabolic pathways in the ti heart. Alcohol is metabolized within the heart to a class of compounds known as fatty acid ethyl esters compounds that have the potential to impede functioning of the mitochon- dria (the energy producing structures in the cell). The effect of alcohol on this metabolic pathway may explain how alcohol abuse can lead to diminished cardiac muscle contractility and to cardiomyopathy. (1) Biopsy of a healthy heart. (2) Biopsy of heart muscle from an asymptomatic alcoholic patient shows fibrous tissue and enlarged muscle cells. Photographs courtesy of In addition, animal studies have Dr. Emmanuel Rubin. revealed that alcohol appears to impair the uptake and binding of calcium ions ALCOHOL'S EFFECTS ON THE diomyopathy. Characterized by a needed for muscle contraction. These CARDIOVASCULAR SYSTEM wasting of the heart muscle, alcoholic observations suggest that alcohol's cardiomyopathy is one of the most actions on calcium levels in cardiac serious consequences of drinking and muscle cells may contribute to the The Heart can be fatal. With this condition, con- reduced strength of cardiac contrac- Alcohol's toxic effect on the heart is tractility of the muscle cells decreases, tions associated with alcohol abuse. dose dependent: As total lifetime predominantly in the left ventricle of Although the effects of alcohol are alcohol consumption increases, mus- the heart (the chamber that pumps apparent with the observable damage cular strength decreases. Clinical tests oxygenated blood to the body). As on heart structure and function, scien- show that alcohol can cause the heart cardiac muscle fibers become dam- tists are just beginning to identify and muscle to deteriorate, leading to a aged or die, the heart attempts to characterize the underlying molecular condition known as alcoholic car- compensate for the injury by increas- mechanisms. As greater knowledge of 58

46 Chapter V

A heart in dilated cardiomyopathy, Normal Dilated compared to a normal heart. Heart Cardiomyopathy

ElMuscle Chambers Major Vessels

LA = Left Atrium LV = Left Ventricle RA = Right Atrium RV = Right Ventricle these mechanisms is gained through apparent at the level of three or four future research efforts, clinicians will drinks a day. Hypertension is a be able to better prevent and treat the known risk factor for hemorrhagic cardiac disorders associated with stroke and other disorders. alcohol abuse. As scientists continue to search for the mechanisms involved in alcohol- The Vascular System inducedhypertension,several In addition to possible direct effects on hypotheses are being explored. For the heart, alcohol also may affect the example, alcohol consumption is asso- vascular systemthe system of blood ciated with the loss of large quantities vessels extending throughout the of calcium and magnesium ions in the body. By affecting the release and urine. Reduced levels of magnesium actions of hormones and other regula- cause hypertension in both animals tory substances (such ascate- and humans. Further, diminished cholamines and cortisol, among oth- magnesium levels are associated with ers), alcohol may modify cardiac activ- increased amounts of calciuman ity, blood pressure, and blood flow. element that heightens the tone of Ultimately, such changes may damage blood vessels, leading to hyperten- the heart and vascular system. sion. Alcohol-induced magnesium Hypertensionthe persistent ele- depletion may promote spasms in vation of blood pressureis a serious brain blood vessels, impeding blood illness that can be caused or aggravat- flow to the brain. This mechanism ed by alcohol use. Chronic drinking may contribute to the development of leads to hypertension, although, hypertension in chronic drinkers. when small doses of alcohol are con- Clinical studies have demonstrated sumed, peripheral blood vessels that a higher incidence of hemorrhag- dilate and blood pressure falls. In ic stroke and other intracranial bleed- fact, in many studies, hypertension is ing exists among heavy drinkers than

59 47 Alcohol Research: Promise for the Decade among nondrinkers. Scientists have holic may experience blackouts, ing from alcohol abusethat may suggested that alcohol-associated seizures, and hallucinations as a con- account for the impaired intellectual hypertension and a bleeding tendency sequence of alcohol's injurious effects and memory functions in many alco- due to heavy alcohol use both may on the brain. Moreover, heavy drink- holics.In addition, autopsy studies contribute to the development of hem- ing can seriously impair a person's have shown that alcoholics have gen- orrhagic stroke. ability to remember and to perform eral brain atrophy as well as specific In a recent large-scale study, scien- intellectual tasks. The type and severi- cell loss in at least two structures of tists examined the relationship ty of the brain damage linked with the brain that control memory. between alcohol consumption and the alcohol abuse, however, can vary Heavy drinking also alters certain risk for coronary artery disease in depending upon a person's genetic biochemical mechanisms in the brain males.Investigators monitored vulnerability, age of onset of drinking, that may impede cognitive and mem- approximately 45,000 men over a 2- the type and amount of alcohol con- ory processes. The loss of receptors for year period, excluding from the study sumed, and diet. the neurotransmitter acetylcholine in individuals with pre-existing health Scientists have found that alcohol the brain's frontal cortex is among the conditions that could increase the risk can harm the brain in a number of many alcohol-related biochemical dis- of heart disease. Researchers found a ways. Damage can result directly turbances under investigation. This decreased incidence of coronary from alcohol's toxic effects on the loss could disrupt the transmission of artery disease in individuals who brain. Further, alcohol-related damage messages between neurons in the drank approximately two to three to other organs, such as the liver, pan- brain, thereby causing varying drinks per day. Yet, these consump- creas, and heart, can impair proper degrees of impaired memory and tion levels did not have a favorable brain functioning. Finally, poor learning. effect on hypertension: The occur- dietary habits that frequently accom- rence of hypertension was greater in pany chronic drinking can lead to Organic Brain Disorders heavier drinkers than in lighter nutritional imbalances that, in turn, Two types of organic brain syndromes drinkers. More studies are needed to can impair the nervous system. The may develop in alcoholics: alcoholic determine conclusively whether mod- cellular and molecular mechanisms dementia and Wernicke-Korsakoff's erate drinking is the factor that con- involved in alcohol-induced brain syndrome. Approximately 10 percent tributes to diminished incidence of injury are unknown. Because the brain of patients in alcoholism treatment coronary disease. not only governs basic responses but display symptoms of these disorders. Even if moderate drinking lessens also is the center of such human facul- Alcoholic dementia is character- the risk for coronary artery disease, ties as thinking, abstracting, emotions, ized by a global loss of intellectual such drinking can harm other organs and memory, any damagemild or abilities. Physiological and structural in the body. In addition, the interac- severecan have a far-reaching abnormalities are evidenced by elec- tion of alcohol with medications that a impact on a person's daily activities. trophysiological and brain imaging moderate drinker may be taking can Thus, gaining knowledge about alco- techniques. All of these impairments produce very serious outcomes. hol's actions on the brain continues to are considered direct effects of alco- Finally, moderate drinkers risk be an important goal for alcohol hol's neurotoxicity. Research findings enhanced liability to addiction and researchers. suggest that some individuals may be behavioral changes that may threaten more vulnerable genetically than oth- their safety or that of other persons. Cognitive Function ers to alcohol's injurious effects on the Approximately 45 to 70 percent of brain. alcoholics entering treatment display Wernicke's disease is an alcohol- NEUROLOGICAL DISORDERS some difficulty with problem solving, related brain degeneration that pro- ASSOCIATED WITH abstract thinking, psychomotor per- duces general confusion, abnormal ALCOHOL ABUSE formance, and difficult memory tasks. gaze and gait, loss of muscle coordi- Scientists continue to search for the nation, and incoherent speech. This It is well documented that excessive mechanisms that underlie these disorder is associated with a deficien- drinking can harm the brain; the dam- impairments. The recent development cy of the vitamin thiamine, which is age often becomes evident with dis- of imaging techniques has enabled needed for cellular energy production. tinct behavioral and cognitive changes researchers to identify certain struc- Abstinence and vitamin supplementa- in the drinker. For example, an alco- tural abnormalitiespossibly result- tion can reverse this disorder.

60 48 Chapter V

In the acute stage, Wernicke's disease often occurs with Korsakoff's encephalopathy and patients are diagnosed as having Wernicke- Korsakoff's syndromecharacterized by a permanent state of cognitive dysfunction and an inability to remember recent events or to learn new information. The amnesia may result from widespread lesions and structural aberrations throughout the brain. Although amnesia is the most clearly defined symptom, Wernicke- Korsakoff's patients also may have limited attention, perception, motiva- tion, and emotion.

Genetic Susceptibility It is well recognized that Wernicke- Korsakoff's syndrome develops in some individuals following a history of chronic and heavy drinking. At present, however, it is unknown how alcohol causes distinctive injury to the brain. Given the grave consequences of Wernicke-Korsakoff's syndrome, researchers and clinicians are quite eager to identify the mechanisms involved in its development. It has been suggested that some individuals may have a genetic susceptibility to developing Wernicke- Korsakoff's syndrome involving an enzyme that requires thiamine for its function. Research has shown that alcoholics with Wernicke-Korsakoff's syndrome may have a defective variant of the naturally occurring enzyme transketolase. The variant form of this enzyme (which is a genetic defect) has an abnormally weak affinity for thiamine. Thus, vulnerability to this syndrome may be linked to the genetic defect in the transketolase enzyme gene and may be exacerbated by a dietary insufficiency of thiamine.

49 /$t.;-"T

41. FETAL VIALCOHOL SYNDROME

Throughout the course of history, a nal alcohol use and risk to the number of clinicians have noted the developing fetus? potentially harmful effects of alcohol Can drinking during pregnancy on a developing fetus. Their observa- result in pathology less severe tions and concerns appear to have than that of FAS? passed unheeded. What is the potential for prevent- It was not until 1968 in France ing injury in pregnancy, reversing and 1973 in Americathat scientists injury in pregnancy, or both? first described in published reports What are the physiological mech- the common pattern of birth defects in anisms by which alcohol causes children born to mothers who drank fetal injury? heavily during pregnancy. Labeled How do additional risk factors "fetal alcohol syndrome" (FAS), this (number of previous pregnancies, congenital disorder is characterized by a distinct cluster of symptoms, other drug use by the mother) including permanent physical abnor- influence the effect of alcohol on malities and mental retardation. The the developing fetus? recognition of FAS set in motion Prenatal exposure to alcohol can pro- research efforts to answer such critical FAS is one of the leading known duce a wide spectrum of conse- questions as: causesofmentalretardation. quences in the fetus, ranging from the severe physical and mental impair- According to research estimates, 1 to 3 ments seen in FAS children, to the less How extensive is the problem of babies are born with FAS for every prominent clinical features seen in FAS? 1,000 live births. Among the popula- those identified with FAE, to the various behavioral and learning problems What is the relationship between tion of known alcoholic mothers, the observed in other children whose moth- quantity and frequency of mater- rate of FAS increases substantially to a ers drank during pregnancy.

63 51 Alcohol Research: Promise for the Decade range of 23 to 29 FAS babies for every FAE, can be prevented with maternal hol was administered at the beginning 1,000 live births. abstinence during pregnancy. of pregnancy as opposed to the fifth Initially, researchers questioned Still, women who are alcohol week of gestation. Additional research whether alcohol was the underlying dependent sometimes drink while with animals has shown that the fetal cause of FAS, or whether another fac- pregnant despite a strong desire to nervous system may experience sig- tor believed to be present in an alco- abstain. Many other women also may nificant injury when alcohol is con- holic woman (poor nutrition, other drink and expose the developing sumed during the "brain growth drug use, or inadequate prenatal med- embryo to alcohol in the early phase spurt" intervala period that is ical care) was the antecedent. Animal of pregnancy, before they are even equivalent to the latter half of preg- studies that enabled scientists to con- aware that they are pregnant. The nancy in humans. trol for all factors other than alcohol consequences that can result from Scientistsstill do not know established that alcohol actually is a these actions underscore the impor- whether the risk of harm to the fetus teratogenan agent that produces tance of continuing research dedicated is associated with the total amount of defects in offspring before birth. to identifying and characterizing the alcohol consumed by the mother dur- Researchers now have identified a mechanisms by which alcohol causes ing pregnancy, regardless of the time wide spectrum of consequences result- injury to the fetus. Toward this goal, interval for drinking, or with the max- ing from prenatal alcohol exposure, scientists are exploring such critical imum level of alcohol in the blood at ranging from the severe physical and issues as the timing of exposure to given times. Although animal studies mental impairment in FAS children, to alcohol throughout pregnancy, select suggest that the maximum amount of the less prominent clinical features alcohol in the blood is by far the more seen in children diagnosed as having important of the two risk factors, the fetal alcohol effects (FAE), to the vari- Even moderate time period in which alcohol is con- ous behavioral and learning problems sumed also is an important risk deter- maternal drinking observed in other children whose minant for the human fetus. The importance of drinking time schedule mothers drank during pregnancy. may pose risks to on fetal outcome became apparent in Children with FAS exhibit growth animal studies in which the same deficiencies that persist throughout a developing fetus, perhaps amount of alcohol was given to ani- childhood. These children have a mals over an 8-, a 12-, or a 24-hour characteristic cluster of facial features resulting in subtle effects period. Researchers found that the that includes small and widely spaced more compressed the time schedule, eyes and underdeveloped upper lips in offspring. the more devastating the harm that and mid-facial regions. Serious neu- was caused to the fetus. In human rological and behavioral problems, maternal factors, effects of alcohol on terms, if two pregnant women each such as intellectual impairment and the placenta, and alcohol's direct consumed seven drinks per week mental retardation, also are present. actions on the developing fetus. The the first drinking all seven drinks dur- Occasionally, FAS children have less knowledge obtained fromthis ing two weekend evenings and the specific malformations, such as car- research can augment efforts to pre- second drinking one drink on each of diovascular anomalies, genitourinary vent future injury to the unborn child the 7 days in the weekthe first defects, and muscle abnormalities. and enhance the development of treat- woman would place her child at far Although FAS appears to occur ment approaches for alcohol-induced greater risk for injury than the second exclusively in babies born to mothers injuries that occur in children exposed woman. who are heavy drinkers or alcoholics, prenatally to alcohol. Research has revealed that alcohol- researchers have not defined a safe Although drinking during preg- related fetal injury may stem from level of drinking during pregnancy. nancy is never risk-free, it appears alcohol's actions on the placenta (the Even moderate maternal drinking that the type of injury that results organ that links the mother to the may pose risks to a developing fetus, from alcohol use does depend on the developing baby and provides suste- perhaps resulting in subtle effects in prenatal period when alcohol is con- nance and protection to the fetus offspring. The damaging effects of sumed. In studies with primates, throughout prenatal development). It prenatal exposure to alcohol, so researchers found that injury to the has been observed that alcohol, at rel- apparent in children with FAS and offspring was more severe when alco- atively modest concentrations, can

52 64 Chapter VI

Children with FAS have characteristic ,..11=111111m... facial features. Artist's rendition by James Sottile, Jr. Skin folds at the Small head circumference corner of the eye

Low nasal bridge Small eye opening

Short nose -) Small midface

Indistinct philtrum Thin upper lip (groove between nose and upper hp)

induce a brief collapse of the blood alcohol produces injury to the fetus by vessels that support the uterus and altering prostaglandin levels. More fetus. Such a collapse could lead to research is needed in this area to shortages in nutrients and oxygen obtain a definitive understanding of supplies essential to fetal develop- the general relationship between hor- ment, causing injury to the fetus. mones and fetal development. This Additional research in this area in the knowledge will help to improve preg- coming years potentially will pinpoint nancy outcome in general, as well as how alcohol affects the placenta and to prevent alcohol-related fetal injury. which steps may be taken to reduce Alcohol researchers are continuing the risk of subsequent injury to the to explore the fundamental question fetus. of how alcohol may directly injure the Various maternal factors also may developing fetus. Although more influence some alcohol-related fetal research is needed to fully understand injuries. For example, the risk for FAS such effects, scientists are beginning increases with the mother's age and to identify the processes involved in with the number of prior pregnancies. alcohol-induced fetalinjury. Studying the role of prostaglandins Currently, studies have shown that (important hormone-like substances fetal exposure to alcohol affects the in the body) in increasing the risk of hippocampus, a region of the brain alcohol-induced fetal injury is another that is critical to learning and memo- consequential area of FAS research. In ry. The hypothalamus, a brain area animal studies, scientists have shown important to the regulation of hor- that the severity of alcohol-induced mones and behavior, also appears to injury to the fetus lessens when drugs be vulnerable to the injurious effects thatpreventanincreasein of alcohol. Such injuries may result prostaglandin levels are given prior to from alcohol's disruption of the tim- alcohol. Because prostaglandins are ing of nerve cell development, which known to play a key role in fetal causes errors in the migration of the development, it is conceivable that cells from their place of origin to their 65 53 Alcohol Research: Promise for the Decade

appropriate location in the mature the African-American population may Until now, research has focused central nervous system. Research be responsible for the heightened on the potential harm that maternal conducted over the next few years occurrence of FAS. drinking poses to the fetus. However, may reveal how this disruption of Onepromisingexplanation recent work suggests that paternal nerve cells leads to changes in the involves the metabolic enzyme alco- drinking also may pose some risks to brain that can profoundly affect intel- hol dehydrogenase (ADH). The rate at the fetus and that these risks are like- lect and behavior. which alcohol is metabolized differs ly to be distinct from those associated Animal models have enabled scien- among various ethnic groups and can with maternal drinking. Although tists to identify and characterize many be influenced by the variant form of this information is preliminary, it of the harmful effects of alcohol on ADH expressed in an individual. At represents an important area for fetal development. Their use in stud- present, three variant forms of ADH future investigation. ies analyzing the effects of alcohol on have been found: beta 1, beta 2, and immune system functioning has pro- beta 3. The beta 3 ADH variant has vided intriguing findings. For exam- been found in approximately 27 per- ple, animal studies have revealed that cent of the African-American popula- immune system functioningis tion; beta 3 is rarely found in other impaired and hormonal response to ethnic groups. Preliminary evidence stress is reduced in offspring exposed to alcohol prenatally. These preliminary findings suggest that children Genetic factors exposed to alcohol before birth may have increased susceptibility to infec- are believed to tion and delayed healing. influence vulnerability Genetic Vulnerability to both FAS and FAE. to FAS and FAE Although women who drink heavily during pregnancy are at risk of giving suggests that the beta 3 form of ADH birth to babies with FAS, not all who may be found at an even greater fre- consume alcohol will deliver a child quency inchildren with FAS. with the syndrome. The incidence of Although this finding must be ana- FAS also differs among ethnic groups; lyzed further, it may provide a foun- both Native American and African- dation from which scientists can learn American populations have a higher more about susceptibility for alcohol- incidence of the syndrome than other related fetal injury. populations. Although the reasons for Over the next several years, scien- this variability are not understood tists will continue to explore and fully, genetic factors are believed to define the direct and indirect means influence vulnerability to both FAS by which alcohol can cause harm to and FAE. unborn children. Future studies are Studies of alcohol use and preg- needed to assess the long-term impact nancy outcome have demonstrated on children's behavior and learning. that African-American children As a future goal, researchers are try- exposed to alcohol prior to birth are ing to develop strategies and methods more vulnerable to FAS than the off- to help children overcome the defi- spring of non-African-American ciencies that result from alcohol- women, despite similar maternal induced prenatal injury. These are drinking patterns and identical status important challenges to alcohol among the mothers on a number of researchers in the coming decade, other key factors, including nutrition. because the results will be critical to This suggests that a factor present in our future generations.

54 OPERATEBEVERAGES MACHtNERY IMPAIRS AND YOUR MAY ABILITY CAUSE TO HEALTH DRIVE PROBLEMS A CAR OR PREVENTION VIIAND TREATMENT

The overriding aim of all alcohol settingsa task that is especially chal- research is to produce knowledge that lenging because, in the real world, will enhance our ability to prevent behavior may be influenced by many alcoholism, alcohol abuse, and associ- factors other than the strategy being ated problems and to treat alcoholism. evaluated. In each of the areas of alcohol investi- To control for these confounding gation highlighted in the preceding factors, scientists during the past chapters, scientists generate such decade incorporated rigorous experi- knowledge by exploring new research mental designs such as controlled questions; by replicating, or repeating, clinicaltrials, experiments that promising experiments both to verify attempt to determine a treatment's results and to determine the extent of effects in a manner that is unbiased by theirutility; and by applying external factors. In addition, they advanced experimental designs and applied innovative designs such as technologies to reveal previously inac- time-series analysis, a technique that cessible information. allows the analysis of multiple factors Like their counterparts in other over time, and advanced technologies areas of alcohol studies, many preven- such as computer simulation to exam- tion and treatment researchers con- ine the many factors that can influence centrate on gathering basic knowledge the developmentand the reduc- for developing or enhancing preven- tionof alcohol abuse, alcoholism, tion and treatment strategies. Others, and related problems. Research currently is being conducted called applied researchers, test the Withthesemethodological to assess the efficacy of warning labels on alcoholic beverage containers as a effectiveness of these strategies as advances, scientists revealed new prevention measure. Photograph cour- they are implemented in "real-world" information about the range of social, tesy of Stacey Hudson.

S 57 Alcohol Research: Promise for the Decade

psychological, and economic charac- interaction of individual and environ- sons who are genetically at risk for teristics present among alcohol mental factors. During the past alcoholism and to provide appropri- dependent persons and about the decade, preventionresearchers ate preventive interventions. relationship of these characteristics to worked to identify the individual fac- In addition to genetic risk for alco- treatment outcome. At the same time, tors that can place a person at risk and holism, researchers are focusing on they began to consider multiple fac- the environmental factors that can individual factors that contribute to torsincluding medical, social, and affect that risk. Further, they explored risk for alcohol-related problems. economic factorstogether with the interactions among these individ- Studies of life-course development are drinking behavior as measures of ual and environmental factors, with underway to determine how individ- treatment outcome. These new direc- the aim of identifying opportunities to ual physiological and psychological tions brought scientists to the brink prevent the onset of alcohol-related factors interact with early life events of concerted efforts to resolve the problems and the onset of alcoholism. to produce risk for alcohol-related most pressing need in treatment problems at various developmental research: To define which treatments Identifying Risk stages, including adolescence. Social are most beneficial for which types of and Vulnerability learning theory, which delineates the patients. Expanding these efforts is a Scientists studying individual vulner- processes by which individuals central focus of alcohol research dur- ability initiated studies to measure acquire and maintain behavior, is ing the 1990s. demographic, biological, and psycho- being used to explore whether chang- Across the past decade, researchers logical variablesincluding gender, ing drinking-associated thoughts or also gathered new information that family history, neurophysiological activities can prevent problematic documents the range and complexity characteristics, temperament, person- drinking behavior. Among social of alcohol-related problems through- ality, behavior, and social interac- learning approaches that evidence out society. As the effects of drinking tionsin large samples. One such promise for alcohol-problem preven- on a host of physical and social prob- study, initiated in 1989, is the multi- tion are cognitive restructuring, an lems (including injuries, disease, vio- site collaborative search for the gene approach that modifies beliefs or lence, homelessness, unemployment, or genes responsible for alcoholism, expectancies about appropriate drink- marital discord, and others) became ing behavior, and coping skills train- increasingly apparent, the focus of ing, an approach that teaches new prevention extended beyond prevent- Social learning theory is habits for exercising self-control when ing alcoholism to preventing conse- drinking. During the next decade, quences of alcohol use, including sin- being used to explore researchers will focus on identifying gle episodes of alcohol abuse. These promising targets for such interven- developments were facilitated by whether changing tions and on understanding their mediating mechanisms. improved measurement of alcohol- drinking-associated related problems, improved research Another aspect of understanding behaviors that lead to alcohol prob- design, and sophisticated theoretical thoughts or activities and conceptual models of the systems lems involves understanding the con- of alcohol use that give rise to physi- can prevent problematic tribution of environmental factors. cal and social problems. During the past decade, researchers These methodological and concep- drinking behavior. focused on identifying environmental tual advances will be critical for meet- factors that affect only a few individu- ing the challenges of a decade that als (for example, selected families, expected during the 1990s to report promises to produce a wealth of new peer groups, and work settings) and results that will provide insights into factors in the broader societal culture information for further enhancing pre- the etiology and developmental vention and treatment effectiveness. that affect many individuals (for course of different types of alco- example, price and availability of holism. Results of the genetics collab- alcohol, advertising, and media por- PREVENTION RESEARCH oration and the entire genetics trayals of drinking). Objectives for research agenda during the next research during the next decade Alcoholism and alcohol-related prob- decade should enable health care include developing effective measures lems are believed to result from an workers eventually to identify per- for modifying environmental risk and

58 9 Chapter VII testing the effectiveness of selective sures designed to reduce individual modifications. risks (for example, license sanctions for alcohol use) and measures Targeting Adverse designed to reduce environmental Consequences of Drinking risks (for example, restricted access to An area of prevention research alcohol) among this population. In already focusing on the interaction of addition, they continue to assess the individual and environmental factors effects of minimum-drinking-age leg- is the study of adverse consequences islation, as well as community and of drinking. Researchers studying grassroots organizational efforts to alcohol-related accidents, trauma, reduce drinking and driving. crime and violence, and a possible Another environmental strategy association between alcohol and AIDS for preventing alcohol-impaired are gathering essential baseline infor- driving is server intervention, devel- mation about individual and environ- oped by the hospitality industry to mental risk factors and their interac- reduce the likelihood that alcohol is tion. Other researchers are testing the served to underage or visibly intoxi- effectiveness of specific efforts to cated persons. Server intervention modify those risks. Some research incorporates legislation (dram-shop directions related to alcohol-impaired laws), education (server training), and driving and to alcohol and AIDS illus- changes in the context in which alco- trate the importance of this work. hol is served (for example, time-of- day, drinking occasion, food-service Drinking and driving.Current data practices) to modify environmental show that the percentage of drivers risk. In conducting studies of server- who were intoxicated in fatal crashes intervention, researchers will gather decreased by 18 percent from 1982 basic information about public drink- through 1988. This declining trend ing and drinking contexts and identify was especially evident among teenage the most effective service policies and drivers, who experienced a 36-percent programs to modify both individual decrease in the proportion of drivers and environmental risks. Because the who were intoxicated in fatal crashes. majority of driving-while-intoxicated However, analysis based on a per- offenders do most of their drinking in miles-driven measure demonstrates bars, it is important to determine the that alcohol nevertheless is involved contribution of drinking site to in a disproportionate number of fatal alcohol-related problem outcomes. crashes among teenage drivers relative to other age groups. Among plau- Alcohol and AIDS.Scientists have sible reasons for this disparity are shown that alcohol consumption teenagers' relative inexperience with affects the body's immune function. both drinking and driving, inadequate Researchers are exploring whether school-based educational programs, alcohol consumption in persons who and teenagers' ability to circumvent are HIV-infected may contribute to minimum purchaseagelaws. the progression to AIDS or to Consequently, researchers continue to increased severity of immune dys- gather information about individual function associated with AIDS. (for example, drinking frequency Psychosocial research has shown among young drivers) and environ- that alcohol use can influence sexual mental (for example, access to alcohol) behavior, and the findings of some risk factors among young drivers and studies suggest that alcohol use may to explore the effectiveness of mea- increase high-risk sexual behavior. An 79 59 Alcohol Research: Promise for the Decade exploratory study conducted in San and environmental risk factors and to areas of study for the early 1990s Francisco, California, reported that explore their interactions. For exam- include school-based and community homosexual men were less likely to ple, family studies of the past decade programs, the impact of alcohol- use condoms following drinking or produced procedures for measuring warning labels, and worksite programs. drug use, and a Massachusetts survey important family variables and gener- of adolescents and adults reported ated hypotheses relating certain vari- School-based and community pro- that heterosexual respondents who ables to alcohol abuse among the chil- grams.Researchers have shown that averaged five or more drinks daily dren of alcoholic parents. From this promising techniques for health pro- were less likely to use condoms than work evolved such technologies as motion include targeting individuals their peers who drank less. multiple cohort studies, multigenera- and groups at risk, imparting skills Although we do not know that tional designs, and refined longitudi- necessary for behavior change, exert- alcohol use contributes to increased nal studiesall of which will be used ing multiple strategies simultaneous- risk of HIV-infection or to the devel- in the next decade to examine the ly, and timing prevention messages to opment of AIDS, the threat posed by effects of individual and environmen- achieve maximum effects. the AIDS epidemic demands that sci- tal family factors in the development In addition, they have found that entists continue to explore any possi- and perpetuation of alcoholism and school-based prevention programs ble biological effects of alcohol use on alcohol-related problems. based on social learning theory show HIV infection and AIDS. In addition, In addition, researchers will use promise for reducing alcohol use the AIDS crisis demands that sophisticated prospective studies to among young people. Social learning researchers seek new information enhance understanding of the etiology programs can teach drink-refusal about the role of alcohol in risk-taking of alcohol problems and prevention skills, correct inaccurate expectations behavior and about alcohol use as a trials to test the effectiveness of specif- about alcohol's effects, and alert coping behavior in individuals with ic interventions. Because prevention young people to misleading messages high-risk or HIV-positive status. trials can target and intervene with a contained in advertising and media presumed risk factor in a healthy pop- Refining Research Technology ulation, this approach allows for portrayals of alcohol use. Most of these programs emphasize the role of Among the new tools to assist experimental manipulation that will research on drinking and driving and enhance the value of the research. peers in influencing drinking behav- other prevention strategies is comput- Prevention trials also can produce ior. During the 1990s, researchers will er simulationan approach that, information about etiology by testing develop and refine the social-learning unlike conventional statistical tech- causal theories. approach, test new school-based niques, can be used to analyze In addition, researchers will avail approaches, and determine the most dynamic social and economic environ- themselves of natural experiments (for effective match of age group and pre- ments in which many factors interact example, changes in zoning laws gov- vention approach. over time. Planners in San Diego, erning alcohol sales) to observe the In addition, prevention science has California, recently used computer effects of specific environmental inter- advanced to the point that is appro- simulation to document the extent of ventions. Natural experiments can priate to develop prototypes for com- alcohol-involved traffic problems, produce information that is both real- prehensive community programs to understand the complex system in istic and socially relevant and of prevent underage drinking, drinking which the problems occur, and project immediate practical utility. and driving, and alcohol use during the effects of various prevention pregnancy and to test those programs strategies on reducing alcohol- Evaluating Prevention in long-term community trials. involved traffic problems. Strategies Community trials in other areas of Together with such new technolo- Asnoted,appliedprevention health promotion and disease preven- gies as computer simulation, preven- researchers assess the effectiveness of tion have shown that the potential tion research during the next decade purposeful actions designed to change exists for beneficial, synergistic effects will rely on several proven experi- individual behaviors (educational when several approaches are com- mental designs that have developed programs, for example) and measures bined. Accordingly, alcohol over time. Many areas of alcohol designed to modify the drinking envi- researchers during the 1990s will eval- research have contributed research ronment (minimum-drinking-age leg- uate the feasibility of such trials for designs that help to isolate individual islation, for example). Some focal alcohol-problem prevention, pilot test

60 Chapter VII

program components, and develop related problems and enhancing and initiate prototype programs. worker productivity, especially among such employee subgroups as Alcohol-warning labels.Public Law women and ethnic minorities. Also 100-690, which required that warning needed is research to assess the labels be placed on all containers of impact of screening and testing on alcoholic beverages, created an oppor- business costs, worker morale, tunity to assess the impact of such turnover, and productivity. labels on public knowledge, attitudes, Few studies have examined how and behavior. The findings of research the workplace may contribute to the to evaluate the effectiveness of warning labels on nonalcohol products suggest that the effectiveness of the Some focal areas labels may depend on such factors as characteristics of the labels and char- of study for the early 1990s acteristics of the population to which the warnings are directed. include school-based and During the next decade, prevention researchers will assess the impact of community programs, warning labels on alcoholic beverages in different situations (including situ- the impact of ations in which several preventive actions are used simultaneously and alcohol-warning labels, situations in which competing messages favoring consumption are and worksite present) and in different populations. programs. Moreover, they can compare drinking behavior before and after labeling and can measure actual reductions, if they development of alcohol abuse, alco- occur, in alcohol-impaired driving holism, andrelatedproblems. and drinking during pregnancy Consequently, researchers during the next decade also will gather basic Worksite programs.During the past information about worksite factors, two decades, numerous strategies worker factors, and their interactions have been developed that aim, either that may increase or decrease the inci- directly or indirectly, to prevent the dence, duration, and severity of alco- occurrence of alcohol abuse or alcohol problems in the workplace. holism in employees (for example, health promotion programs, quality of work life programs) or to prevent the TREATMENT RESEARCH progression of such problems when they exist (for example, screening and The strategies discussed earlier in this testing programs, employee assistance chapter are aimed at preventing the programs). Although some research onset of alcoholism, alcohol abuse, or has been conducted on the effective- alcohol-related societal problems or at ness of employee assistance programs, preventing some combination of those additional, methodologically ad- problems. In contrast, most treatment vanced research will be required strategies are designed specifically to during the next decade to assess the ameliorate alcoholismthe most relative effectiveness of various types severe alcohol problemwhen it of programs for reducing alcohol- occurs. 72

61 Alcohol Research: Promise for the Decade

Like optimal prevention strate- the population in need of treatment. tered screening procedures to identify gies, optimal treatment strategies are During past decades, researchers persons who have begun to develop facilitated by a strong research base. found that general medical expendi- or are at risk of developing alco- Central components of this research tures by alcoholics and their families holism. The most commonly used base include investigations that mea- are reduced substantially following screening tools are self-reports and sure patient factors, treatment factors, alcoholism treatment. In addition, the structured interviews, both of which and their relationship to treatment benefits derived from treating alco- may be supplemented by laboratory success and investigations that assess holics were shown to offset costs to tests designed to detect physiological the efficiency with which treatment the general health care system. In light changes often associated with exces- services reach persons in need of of these findings, efforts during the sive alcohol consumption. those services. next decade will focus on expanding Although most screening tools were Over the past two decades, information about the capacities, qual- developed to identify active cases of researchers showed that alcoholism ity, availability, utilization, and costs alcoholism, others are being developed treatment contributes to prolonged of alcoholism treatment services in to identify individuals who are at abstinence in some patients. However, relation to the need and the demand increased risk for the disease. During they also showed that most patients for those services. the next decade, researchers will con- experience at least one relapse to Also during the next decade, tinue to develop and evaluate low-cost, drinking following treatment. It researchers are expected to uncover rapid screening procedures that can be remains to be determined why some new knowledge of genetic factors in used routinely in primary health care, patients begin a period of permanent educational, and other settings. or prolonged abstinence immediately Resources also are being targeted following alcoholism treatment Research on typologies to further the development of diag- whereas others become abstinent at a nostic procedures that will provide later time or not at all. Also to be can provide moreand more valuableinforma- determined is whether treatment pro- tion for clinicians. These include diag- important information duces benefits in other areas of social nostic mechanisms that enable classifi- or psychological functioning for for understanding both cation according to severity of alcohol patients who do not immediately dependence. Mechanisms such as the achieve abstinence. the causation and AddictionSeverityIndex,the To better understand the benefits Diagnostic Interview Schedule, the of alcoholism treatment and to expression of various Alcohol Use Inventory, and the improve the percentage of patients Inventory of Drinking Situations gen- who experience those benefits, types of erate reliable, standardized scores that researchers are working to define the are useful in treatment planning and active ingredients of various treat- alcoholism. treatment research. Research during ment strategies and to determine the next decade should improve diag- which patient factors influence treat- alcoholism; brain actions and mecha- nostic specificity, thus enabling clini- ment outcome. Related efforts include nisms involved in reinforcement, tol- cians to design treatment plans that refining diagnostic classifications of erance, dependence, craving, and take account of each alcoholic's physi- alcoholism; developing improved relapse; and alcohol-associated med- cal, psychological, and social charac- tools for screening, diagnosis, and ical consequences. Translating this teristics, as well as drinking pattern. assessment; and improving treatment new knowledge into improved psy- outcome evaluation. As a result of chological and pharmacological inter- Biochemical Markers these activities, researchers can make ventions and ensuring that those of Alcohol Consumption important advances toward defining interventions reach persons in need At present, most physicians base a reasonable goals for specific interven- are among the most important chal- diagnosis of alcoholism on a patient's tions and determining the best treat- lenges of the 1990s. description of past alcohol consump- ments for specific patient types. tion patterns and current self-reported Further, researchers are working to Screening and Diagnosis problems with alcohol. Although provide information that will help to Researchers have developed a number helpful, this information, at times, is ensure that treatment services reach of easily and inexpensively adminis- incomplete or inadequate. 73

62 Chapter VII

Identifying specific, sensitive, and settings, and levels of intensity. In practicable biochemical markers of addition, research findings show that alcohol consumption is a major selectively matching patient character- research goal for the 1990s. The ideal istics to treatment characteristics can marker would objectively identify improve treatment outcome. heavy alcohol consumption and alco- A large, multisite clinical trial now hol dependence, thus assisting physi- underway is expected during the next cians in accurately identifying decade to identify a range of promising patients who are alcohol abusers or interactions between patient character- alcoholics, optimally before the onset istics and treatment characteristics. of serious drinking-related medical or This collaborative study employs large, social consequences. In addition, the representative sample groups, thus ideal marker would identify low lev- allowing for sophisticated statistical els of consumption, thus also enabling analyses and ensuring that results will treatment personnel (and, when be generalizable to a variety of alco- applicable, investigators conducting holism treatment programs. The clinical research) to monitor absti- patient-treatment matching study will nence during and following alco- measure treatment effectiveness from a holism treatment. cost perspective as well as a clinical Although such a marker is not yet at perspective, thus producing informa- hand, researchers have identified sever- tion to improve both treatment effec- al promising candidates. These candi- tiveness and treatment efficiency. dates range from several liver enzymes, Simultaneous with this study, to modified blood proteins, to the phys- researchers will continue to differen- ical appearance of red blood cells. tiate typologies, or subgroups, of alcoholics according to clusters of Patient-Treatment Matching shared traits. Research on typologies Over the past decade, researchers can provide important information have discovered that patient charac- for understanding both the causation teristics can be predictive of treatment and expression of various types of outcome and that patients with cer- alcoholism. Such typologies also tain characteristics appear to respond should have important implications better to certain treatment formats, for patient-treatment matching.

PERFORMANCE RESEARCH UNITS NIAAA Patient-Treatment Matching

Seattle

Providence

1 Farmington/ West Haven

Alb Project Match is a large clinical study Charleston being conducted at nine clinical research sites throughout the country. The goal of this project is to identify a range of promising interactions between patient characteristics and treatment approaches. Courtesy of Dr. Margaret Mattson.

7 4

63 Alcohol Research: Promise for the Decade

Treatment Outcome Evaluation within a single treatment settinga ered). Information about how varia- Alcoholism treatment outcome situation that creates difficulty in tions in treatment process affect out- measuring the independent effects of research in recent years has incorpo- come will provide important informa- rated many refinements in study any single treatment component. tion for enhancing treatment services. design, methodology, and analysis. Accordingly, assessment of treatment processthat is, the specifica- Health Services Research Among these improvements are ran- tion of events or factors that may Health services research develops dom sample selection, the use of con- facilitate or impede the success of knowledge of the capacities, quality, trols, methods for corroborating self- therapeutic activitieswill become an availability, utilization, and costs of reports of drinking behavior, multiple important research issue during the alcoholism treatment services. During and objective measures of treatment coming decade. Researchers will the 1990s, researchers will perform effects, adequate followup, and explore factors that influence a highly systematic evaluations of alco- sophisticated statistical analyses. patient's decision to seek treatment, holism treatment as it is now struc- Despite these accomplishments, remain in treatment, comply with tured and will collect cross-sectional however, scientifically rigorous out- program requirements, and accept data on treatment populations, includ- come research remains challenging referrals. Additional factors may ing prior treatment history, extent of due to the complexity of alcoholism include treatment program duration, impairment, sociodemographic fac- treatment itself. For example, patients counselor characteristics, and treat- tors, and other characteristics. Such usually are exposed to multiple inter- ment integrity (the consistency with comprehensive studies have the ventions and multiple caregivers which specific therapies are deliv- potential to provide information

20111...-

111113

111111.-

Research is focused on improving alcoholism treatment by enhancing current strategies and by developing and testing new approaches. 75

64 Chapter VII

about access to treatment, referral pat- ther exploration of relapse-prevention terns, payment sources, services strategies is warranted. received, treatment participation, and The next decade will produce a assessment techniques that can assist host of new pharmacological and non- effective program planning at the pharmacological interventions based Federal, State, and local levels. on findings in the burgeoning areas of Through health services research, genetics, neuroscience, and other investigators also have the potential to areas of investigation. The promise of measure hospital use and costs for the coming decade is that each discov- patients who are alcoholic and to ery brings with it the hope of resolv- explore the distribution of health con- ing alcohol problems in individual ditions associated with alcoholism. lives and throughout our society.

Innovative Treatments Even as research progresses toward understanding the brain processes involved in alcohol craving and reinforcement and toward developing appropriate pharmacological interventions, researchers have devised several nonpharmacological strategies designed to diminish, forestall, or attenuate the threat of relapse. Existing relapse-prevention strategies fall into two general categories:(1) cognitive-behavioral strategies, which are designed to alter a sequence of cognitive and behavioral events that may lead to relapse, and (2) cue- exposure strategies, which are designed to diminish alcoholics' responses to cues (for example, the sight or smell of alcohol or negative mood states) that may precipitate the desire to drink. Much research remains to be done to determine whether relapse- prevention strategies significantly affect the severity, frequency, or duration of posttreatment relapses and which strategies are most effective for specific populations at which points in the treatment process. For example, some cognitive-behavioral strategies that have been used only with alcohol abusers may be ineffective with alcoholic patients or may be effective for use only after patients complete a traditional alcoholism treatment program. To resolve these questions, fur-

- k 76 77 FocusON DEVELOPING NEW MEDICATIONS FOR ALCOHOLISM

Scientists have made great strides Modify drinking behavior to con- toward understanding how alcohol acts trol craving and prevent relapse on numerous networks in the brain to Induce sobriety in intoxicated exert its effects. This knowledge has patients launched a burgeoning era of research Improve mental abilities in patients efforts to develop medications that act with alcohol-induced cognitive on brain networks to impede the pro- deficits gression of alcoholism and lessen the Manage acute alcohol withdrawal risk for relapse to the disease. Treat the protracted withdrawal Because of the complex nature of syndrome Decrease alcohol consumption by alcoholism, it is unlikely that a single treating coexisting psychiatric pharmacological agent will be devel- disorders. oped to treat this disease. Rather, researchers are concentrating on developing agents to manage the spe- CONTROLLING CRAVING cific events that occur in the clinical AND PREVENTING RELAPSE course of alcoholism and complicate the recovery process. These new med- The recognition that certain pharma- ications can improve long-term treat- cological agents may reduce the desire ment outcome when coupled with for alcohol is one of the most exciting traditional verbal and behavioral developments in pharmacotherapy Research is ongoing to develop differ- therapies. Research efforts are and has launched a new area of ent classes of medications to treat the various aspects of alcoholism. focused on developing pharmacologi- research for developing medications. Photograph by Scott Sinklier, Pioneer Hi- cal agents to: Pharmacological agents may reduce Bred International, Inc.

67 7 Alcohol Research: Promise for the Decade the desire for alcohol in a variety of sumption is represented by the proto- the actions of GABA when it binds to ways. By decreasing craving, by type agent buspirone. Drugs from the GABA receptorhas increased blocking the reinforcing effects of this class usually are used to treat anx- abstinence in alcoholics during a 3- alcohol, or by producing aversive iety; thus, these agents may prove to month experimental period. reactions when combined with alco- be effective in alcohol treatment, par- Other medications show significant hol, these agents can help to prevent ticularly among alcoholics who promise in their ability to suppress relapse to drinking. recently have become abstinent and alcohol consumption. Naltrexone is an A number of neurotransmitter are experiencing high levels of anxi- opiate antagonista substance that systems influence an individual's ety. Although buspirone is not consid- inhibits or blocks the action of agents response to alcohol and underlie ered a serotonin uptake inhibitor, that activate the opiate receptorthat alcohol-seeking behavior. Research researchers believe that its ability to has reduced alcohol consumption in findings suggest that diminished lev- increase brain serotonin activity may humans and animals in precursory els of serotonin, a brain neurotrans- account, in part, for its potential thera- studies. Nonetheless, further study is mitter that affects mood and consum- peutic effects. needed to determine naltrexone's matory behavior, may influence the Dopamine, another neurotransmit- mechanism of action. appetite for alcohol. Accordingly, sci- ter influenced by alcohol consump- entists have begun to evaluate a tion, may play a role in the expression Aversive Agents promising new group of drugs, Other medications reduce drinking known as serotonin uptake inhibitors, not by acting directly on the central that act to enhance brain serotonin Naltrexone is an nervous system but by causing activity. These agents may reduce unpleasant effects when combined consumption by abating the desire or opiate antagonista with alcohol. Disulfiram (Antabuse), a craving for alcohol experienced by medication used in alcoholism treat- substance that inhibits many alcoholic individuals. The use of ment for more than 40 years, acts by these agents during the early stages of or blocks the action of blocking the activity of one of the pri- recovery, when craving for alcohol mary enzymes responsible for alcohol can be extreme, may help the recover- agents that activate the metabolism. The unpleasant reaction ing individual progress through this results from a rise in the noxious alco- stage and continue treatment. opiate receptorthat hol metabolite acetaldehyde when Several of these drugs successfully alcohol is consumed. However, have decreased alcohol consumption has reduced alcohol because patients who have difficulty in experimental animals. In studies complying with medication regimens with voluntary human participants, consumption in humans may not benefit from disulfiram ther- one of these drugs, citalopram, caused apy, researchers are seeking other alcoholic individuals to consume less and animals in aversive agents that may be more alcohol and remain abstinent for a precursory studies. practical for a number of patients. greater number of days. The serotonin uptake inhibitors currently available have an impor- of the alcohol-induced euphoria that INDUCING SOBRIETY IN tant limitation: People can become appears to reinforce continued drink- INTOXICATED PATIENTS tolerant to their effects within a brief ing. Pharmacological agents that time period. Nevertheless, the posi- mimic dopamine, such as bromocrip- Alcohol produces its effects by influ- tive results obtained from recent tine, may lessen craving and drinking encing a myriad of brain systems, studies indicate that, in the coming in dependent persons by blocking this making it difficult to find a single decade, researchers may be able to reinforcing effect. agent that reverses its intoxicating design analogs of these pharmaco- The neurotransmitter gamma- effects. Currently, researchers are logical agents with long-term poten- aminobutyric (GABA) also influences focusing on a range of medications tial for mitigating the craving or drinking behavior. Although the that counteract specific aspects of appetite for alcohol. results are preliminary, the GABA intoxication (amethystic agents). A different class of drugs with receptor agonist calcium bis acetyl Although the available agents do not potential for reducing alcohol con- homotaurinean agent that mirrors lessen the toxic effects of alcohol on

68 the body or modify drinking behavior, they can be useful in certain life- threatening conditions. An experimental benzodiazepine compound called Ro15-4513, which appears to block several of the intoxicating effects of alcohol, has produced promising results in animal studies. However, because this agent produces anxiety and promotes seizures, it cannot be used with humans. Nonetheless, the findings on Ro15- 4513 suggest that some of the pharmacologic properties of alcohol can be inhibited with the development of safe pharmaceutical agents. These findings lay the foundation for 4 enhanced research efforts in the coming decade to develop new medications that induce sobriety.

TREATING ALCOHOL- observed some memory improvement INDUCED COGNITIVE New areas of research on the molecu- IMPAIRMENTS in patients with Wernicke- Korsakoff's lar biology of the brain may generate syndrome. This drug acts by increas- dramatically new approaches to the At present, verbal, psychological, and ing the levels of the neurotransmitter pharmacologic treatment of alcoholism. Photograph courtesy of Genex. cognitive therapies remain the most serotonin in brain nerve cells. Agents effective forms of alcoholism therapy. that act on the serotonin system offer However, cognitive deficits, which are exciting potential as medications to a consequence of years of alcohol augment and restore cognitive func- abuse, may interfere with a patient's tion in alcoholic patients. capacity to learn (that is, to form new Clonidine, a pharmacological agent memories)a necessary ability in alco- that affects norepinephrine, also holism therapy. This pathological con- appears to provide some benefit to sequence of alcoholism may influence alcoholic patients with impaired cog- an alcoholic patient's capacity to suc- nitive function. The findings on flu- ceed in treatment. voxamine and clonidine suggest that Pharmacologicalagentsthat pharmacological agents within their enhance the recovery of brain func- respective classes can be developed as tion may offer a patient the potential effective medications for patients with to better benefit from traditional treat- less severe, reversible cognitive ment approaches. The severity of cog- impairments. nitive impairment can vary among These preliminary results have alcoholic patients; the most extreme encouraged researchers in their search damage is observed in alcoholics with for medications to improve alcohol- Wernicke- Korsakoff's syndrome, who induced mental deficits. Because these have amnesia for recent events and an deficits limit the daily functioning of inability to form new memories. impaired individuals and interfere Recently, clinical researchers using a with their ability to benefit from alco- drug calledfluvoxamine have holism treatment, the development of 80 69 Alcohol Research: Promise for the Decade

new medications to improve cognitive have been the medications of choice have been tested in clinical settings. function is a primary issue of alcohol for treating alcohol withdrawal. These These drugs (which suppress the research in the coming decade. benzodiazepines are anticonvulsive release of norepinephrine) have been agents that inhibit brain cell activity, found to control tremors, elevated thus preventing the onset of seizures. blood pressure, and heart rhythm MANAGING ACUTE These medications also counter such irregularity. However, they are less ALCOHOL WITHDRAWAL symptoms as elevated blood pressure, effective in alleviating restlessness irregular heart rhythm, and tremors. and insomnia and their usefulness in Managing alcohol withdrawal is the As we learn more about the physi- preventing seizures and delirium first step in alcoholism treatment. ological mechanisms involved in alco- tremens has not been established. Proper treatment for withdrawal can hol withdrawal, it becomes possible to Many of these findings are prelimi- help a patient to become detoxified in test new medications that expressly nary. Future research will determine a safe and comfortable manner and, control these processes. For example, the full potential of all of these phar- further, can foster the patient's moti- research findings have revealed that macological agentsincluding vation to enter rehabilitation therapy. the production of the neurotransmit- analogs of these drugs and newly The body adapts to heavy and ter norepinephrinea chemical mes- designed agentsas medications for habitual drinking by counteracting the senger associated with functioning of treating severe forms of withdrawal. depressanteffectsofalcohol: the sympathetic nervous system Research conducted in the past 10 Excitability of the brain increases in an years has provided a greater under- effort to "normalize" brain function. standing of the physiological process- When an individual abruptly stops Studies exploring es involved in alcohol withdrawal, drinking, however, the depressant knowledge that can be applied in the effects of alcohol also cease and the the underlying mechanisms search for new medications to man- adaptive increase in brain excitability age withdrawal. The discovery of involved in protracted becomes maladaptive. This maladap- agents that act on different sites and tive hyperexcitability of the brain is the withdrawal and its relation produce different yet complementary basis for acute alcohol withdrawal syn- effects can help to treat the complex drome, with symptoms ranging from to relapse will be an symptoms of alcohol withdrawal and restlessness, anxiety, tremors, irregular hasten a patient's entry into rehabili- heart rhythm, and elevated blood pres- important focus of tation therapy. sure to more severe consequences such as seizures. Delirium tremens, a life- research efforts in threatening stage of withdrawal that TREATING THE PROTRACTED involves profound confusion, halluci- the coming decade. WITHDRAWAL SYNDROME nations, and severe nervous system overactivity, also may develop. increases during withdrawal. This As noted, alcoholic individuals can Although the severity of withdraw- knowledge has energized the search experience insomnia, anxiety, irritabil- al symptoms varies from one person for pharmacological agents that can ity, fatigue, and depression during the to another, recent findings suggest counteract this process. Two such first days of abstinence. When milder that it may be important to treat agents, atenolol and propranolol, used forms of these symptoms persist for everyone who is suffering from alco- as adjuncts to benzodiazepines, have several weeks or months, however, hol withdrawal, regardless of symp- shown promise for alleviating tremors they indicate the development of a tom severity. Inadequate treatment and heart rhythm irregularity. condition known as protracted with- may lead to more serious withdrawal Further, atenolol appears to resolve drawal syndrome. Protracted with- episodes in the future. Moreover, the anxiety, agitation, and hallucina- drawal may contribute to relapse repeated untreated withdrawals from tions that may accompany withdraw- through two independent mecha- alcohol may cause damage to the part al; yet, it also appears to stimulate nisms. First, alcoholics may return to of the brain thought to be important processes in the body responsible for drinking in an effort to ease the dis- for memory and control of emotion. other withdrawal symptoms. comfort of its symptoms. Second, the For more than two decades, benzo- Two other drugs that act on norep- symptoms of protracted withdrawal diazepines such as diazepam (Valium) inephrine clonidine and lofexidine- may interfere with treatment progress 81

70 by preventing an individual from to treat psychiatric disorders also focusing on therapy. may be effective for treating alco- Although this syndrome is not well holism. Conversely, medications understood, researchers have found used to treat alcoholism may prove that its symptoms have a physiologi- to be useful in treating coexisting cal basis. The hyperexcitability of the psychiatric disorders. Continuing brain that is observed during acute investigations of the relationship withdrawal can continue long after an between alcoholism and coexisting individual stops drinking. psychiatric problems will be critical Although limited progress has been for the treatment of both alcoholism made toward developing medications and associated psychiatric disorders. for protracted alcohol withdrawal, experience with treatments for other drug addictions is encouraging. For example, some medications in the antidepressant class appear to lessen symptoms of protracted withdrawal among cocaine dependent persons. Studies exploring the underlying mechanisms involved in protracted withdrawal and its relation to relapse will be an important focus of research efforts in the coming decade. These studies will provide the basis for developing medications to treat protracted withdrawal symptoms.

TREATING COEXISTING PSYCHIATRIC DISORDERS

Alcoholics often display symptoms associated with such psychiatric disorders as depression, anxiety, manic- depression, and antisocial personality. Some of these symptoms may result from the acute and chronic effects of alcohol consumption. In some cases, however, the symptoms suggest a coexisting psychiatric problem. Some alcoholics use alcohol to alleviate psychiatric symptoms. In addition, alcoholism directly or indirectly may increase the risk for developing certain psychiatric problems. Regardless of the basis of the drinking or the psychiatric symptoms, researchers are trying to determine the effect that treatment of a coexisting psychiatric problem may have on drinking outcome. New medications 82

71 EPILOG

As we begin a new era in alcohol Their concerted efforts to gain addi- brain, are enabling scientists to probe research, we are inspired by the tional knowledge of the effects of the effects of alcohol on brain struc- impressive progress made in the field alcohol on the body, the nature of tures and functions. Tools in molecu- over the past 20 years. Today, the addiction, and the genetic and envi- lar biology are facilitating the search knowledge gained from prior studies ronmental factors that increase the for genetic factors that predispose is providing researchers with a sound risk for alcoholism and related med- individuals to alcoholism and alcohol- framework for understanding the ical pathologies will bring us closer to related pathologies. Sophisticated causes and consequences of alcohol conceiving effective methods for alco- computer models, which analyze the abuse and alcoholism. Despite our holism treatment. dynamic social and economic envi- many advances, however, these disor- Central to this pursuit are studies ronments with which alcohol abuse ders continue to be devastating and aimed at developing new medications occurs, are allowing researchers to costly health problems that affect mil- to treat alcoholism. In the coming project potential outcomes of various lions of individuals. decade, researchers will be searching prevention strategies. The seriousness of alcohol prob- for pharmacological agents that act on Building upon the strong founda- lems is heightened by the limited brain networks to impede the progres- tion laid by past findingsand galva- results obtained from current treat- sion of alcoholism and lessen the risk nized by new technologiesalcohol ment measures for alcoholism. for relapse. Although it is doubtful researchers will have exceptional Although current approaches pro- that one agent can be developed to opportunities to make new discoveries mote prolonged abstinence in some treat this disease, there is promise that about alcohol abuse and alcoholism in patients, the rate of relapse to drink- pharmacological treatments coupled the coming decade. Technology and ing is still too high. It is only through with traditional behavioral therapies increased knowledge will empower research that we can construct effec- can improve long-term treatment researchers to solve many of the unan- tive treatment strategies that will help outcome. swered questions in alcohol research those overwhelmed by the power of Powerful new technologies will and ultimately to effectively prevent alcohol addiction to achieve long- open many new avenues of investiga- and treat alcohol problems. term sobriety. Scientists within the tionduringthenextdecade. many biomedical and psychosocial Noninvasive neuroimaging tech- disciplines of the alcohol field are niques, which offer the unpreceden- working collectively toward this goal. ted opportunity to look into the living 83

72 U.S. DEPARTMENT OF EDUCATION Office of Educational Research and Improvement (0ERI) Educational Resources information Center (ERIC) ERIC

NOTICE

REPRODUCTION BASIS

This document is covered by a signed "Reproduction Release (Blanket)" form (on file within the ERIC system), encompassing all or classes of documents from its source organization and, therefore, does not require a "Specific Document" Release form.

This document is Federally-funded, or carries its own permission to reproduce, or is otherwise in the public domain and, therefore, may be reproduced by ERIC without a signed Reproduction Release form (either "Specific Document" or "Blanket").

(9/92)