Alcohol: Neurobiology of Addiction

By George F. Koob, Michael A. Arends, Mandy L McCracken and Michel Le Moal

A current survey and synthesis of the most important findings in our understanding of the neurobiological mechanisms of addiction is detailed in our Neurobiology of Addiction series, each volume addressing a specific area of addiction. Alcohol, Volume 3 in the series, explores the molecular, cellular, and neurocircuitry systems in the brain responsible for alcohol addiction using the heuristic three-stage cycle framework of binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation.

• Outlines the history and behavioral mechanism of action of alcohol relevant to the neurobiology of alcohol addiction
• Includes neurocircuitry, cellular, and molecular neurobiological mechanisms of alcohol addiction in each stage of the addiction cycle
• Explores evolving areas of research associated with all three stages of the alcohol addiction cycle, including neurobiological studies of neurodevelopmental effects of early exposure to alcohol, sleep disturbances caused by alcohol, pain interactions with alcohol, sex differences in the response to alcohol, and epigenetic/genetic interactions with alcohol

• Language: English
• Publisher: Academic Press
• Release date: Jul 7, 2021
• ISBN: 9780128167946

George F. Koob

George F. Koob, Ph.D., received his Bachelor of Science degree from Pennsylvania State University and his Ph.D. in Behavioral Physiology from The Johns Hopkins University. He was recently appointed (in 2014) as Director of the National Institute on Alcohol Abuse and Alcoholism (currently on a leave of absence as Professor at The Scripps Research Institute, Adjunct Professor in the Departments of Psychology and Psychiatry at the University of California San Diego, and Adjunct Professor in the Skaggs School of Pharmacy and Pharmaceutical Sciences at the University of California San Diego). As an authority on drug addiction and stress, he has contributed to our understanding of the neurocircuitry associated with the acute reinforcing effects of drugs of abuse and the neuroadaptations of the reward and stress circuits associated with the transition to dependence. Dr. Koob has published over 780 scientific papers. In collaboration with Dr. Michel Le Moal, he wrote the renowned book Neurobiology of Addiction (Elsevier, 2006). He was previously Director of the NIAAA Alcohol Research Center at The Scripps Research Institute, Consortium Coordinator for NIAAA's multi-center Integrative Neuroscience Initiative on Alcoholism, and Co-Director of the Pearson Center for Alcoholism and Addiction Research. He has trained 75 postdoctoral fellows and 11 predoctoral fellows. He is currently Editor-in-Chief of the journal Pharmacology Biochemistry and Behavior and Senior Editor for Journal of Addiction Medicine. Dr. Koob taught for 35 years in the Psychology Department at the University of California San Diego, including courses such as Drugs Addiction and Mental Disorders and Impulse Control Disorders, courses that regularly matriculated 400-500 students each. He also taught Contemporary Topics in Central Nervous System Pharmacology at the Skaggs School of Pharmacy and Pharmaceutical Sciences at UCSD for 9 years. Dr. Koob's research interests have been directed at the neurobiology of emotion, with a focus on the theoretical constructs of reward and stress. He has made contributions to our understanding of the anatomical connections of the emotional systems and the neurochemistry of emotional function. Dr. Koob has identified afferent and efferent connections of the basal forebrain (extended amygdala) in the region of the nucleus accumbens, bed nucleus of the stria terminalis, and central nucleus of the amygdala in motor activation, reinforcement mechanisms, behavioral responses to stress, drug self-administration, and the neuroadaptation associated with drug dependence. Dr. Koob also is one of the world's authorities on the neurobiology of drug addiction. He has contributed to our understanding of the neurocircuitry associated with the acute reinforcing effects of drugs of abuse and more recently on the neuroadaptations of these reward circuits associated with the transition to dependence. He has validated key animal models for dependence associated with drugs of abuse and has begun to explore a key role of anti-reward systems in the development of dependence. Dr. Koob's work with the neurobiology of stress includes the characterization of behavioral functions in the central nervous system for catecholamines, opioid peptides, and corticotropin-releasing factor. Corticotropin-releasing factor, in addition to its classical hormonal functions in the hypothalamic-pituitary-adrenal axis, is also located in extrahypothalamic brain structures and may have an important role in brain emotional function. Recent use of specific corticotropin-releasing factor antagonists suggests that endogenous brain corticotropin-releasing factor may be involved in specific behavioral responses to stress, the psychopathology of anxiety and affective disorders, and drug addiction.

Book preview

Alcohol

Neurobiology of Addiction

Editors

George F. Koob

National Institute on Alcohol Abuse and Alcoholism and National Institute on Drug Abuse, National Institutes of Health, Bethesda, MD, Unites States

Michael A. Arends

The Scripps Research Institute, La Jolla, CA, United States

Mandy McCracken

Waggoner Center for Alcohol and Addiction Research, The University of Texas, Austin, TX, United States

Michel Le moal

University of Bordeaux and Neurocentre Magendie, Inserm, Bordeaux, France

Table of Contents

Cover image

Title page

Alcohol

Copyright

Dedication

Preface

Acknowledgments

List of abbreviations

Volume Three. Alcohol

1. Definitions

2. History of alcohol use, misuse, and addiction

3. Behavioral effects of alcohol

4. Pharmacokinetics

5. Misuse and addiction potential

6. Behavioral mechanism of action

7. Neurobiological effects

8. Summary

Index

Alcohol

Volume 3 of Neurobiology of Addiction series:

Volume 1: Introduction to Addiction

Volume 2: Psychostimulants

Volume 3: Alcohol

Volume 4: Opioids

Volume 5: Nicotine and Marijuana

Copyright

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Notices

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ISBN: 978-0-12-816793-9

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Dedication

Alcohol, Volume 3 of the Neurobiology of Addiction series, is dedicated to Floyd E. Bloom, MD, for his foresight to engage in research on the neurobiology of alcohol addiction at the Arthur Vining Davis Center for Behavioral Neurobiology at The Salk Institute. Without his profound contributions to science, this line of investigation, and hence this book, would not have been possible.

Preface

The present series of volumes of the Neurobiology of Addiction are a direct extension of our original book from 2006, Neurobiology of Addiction (Koob and Le Moal, 2006, Elsevier). As we embarked on updating the original book years ago, we quickly realized that a prodigious amount of new work had been done on the neurobiology of addiction during the ensuing years. From 2006 until 2021, the number of PubMed citations for alcohol addiction alone, and derivations thereof (∼52,000 as of May 2021), had nearly doubled over the total number up until 2006 (∼30,000). This extraordinary progress in the field of the neurobiology of addiction required a different theoretical and practical approach to writing our second book.

From a theoretical perspective, we chose to use a heuristically identified domain model that originated in our seminal Science paper on addiction: "Drug abuse: hedonic homeostatic dysregulation" (Koob and Le Moal, 1997). Here, based on the social psychology of self-regulation theory, experimental psychology, and psychiatry, we originally defined addiction as a cycle that consists of three stages: binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation. Eventually, three corresponding domains and neurocircuits coalesced around these three stages: binge/intoxication (incentive salience/pathological habits domain and basal ganglia neurocircuits), withdrawal/negative affect (negative affect domain and extended amygdala neurocircuits), and preoccupation/anticipation (executive function domain and prefrontal cortex neurocircuits). A recent human clinical, behavioral, and self-report study confirmed these three neurofunctional domains, at least for alcohol use disorder (Kwako et al., 2019). Thus, the new revised volume of the Neurobiology of Addiction series is a current survey and synthesis of the most important findings in our understanding of the neurobiological mechanisms of addiction, now organized along the three stage/three domain construct while retaining synthesis at the circuit, cellular, and molecular levels of analysis.

ALCOHOL, Volume 3 in the series, explores the molecular, cellular, and neurocircuitry systems in the brain that are responsible for alcohol addiction using the heuristic three-stage cycle framework. It outlines the history and behavioral mechanism of action of alcohol relevant to the neurobiology of alcohol addiction, including neurocircuitry, cellular, and molecular neurobiological mechanisms. We explore evolving areas of research that are associated with all three stages, including neurobiological studies of neurodevelopmental effects of early exposure to alcohol, sleep disturbances that are caused by alcohol, pain interactions with alcohol, sex differences in response to alcohol, and epigenetic/genetic interactions with alcohol.

From a practical perspective, organization of the original book in different volumes was necessitated by the prodigious increase in research and publications from 2006 to present. We had prided ourselves in finding virtually all published work in 2006 and citing as much of it as possible. Most of the early cited literature has been retained in the present series, but such an approach of citing every study from 2006 to present was not humanly possible for the present series. As a result, for many of the topics, we rely on key seminal papers and review articles. For each seminal advance, where possible, we included summary figures. We hope readers will see how the field has substantially evolved at the level of refined techniques and consolidated theoretical approaches and apologize in advance to researchers who may have a key seminal paper that we missed.

We are very excited and encouraged about the tremendous advances that have been made in unveiling the neurobiology of addiction, both clinically and preclinically. We look forward to further insights that tomorrow's research will provide.

George F. Koob,

Michael A. Arends,

Mandy McCracken,

Michel Le Moal

References

1. Koob G.F, Le Moal M. Drug abuse: hedonic homeostatic dysregulation.  Science . 1997;278:52–58.

2. Kwako L.E, Schwandt M.L, Ramchandani V.A, Diazgranados N, Koob G.F, Volkow N.D, Blanco C, Goldman D.Neurofunctional domains derived from deep behavioral phenotyping in alcohol use disorder.  Am J Psychiatry . 2019;176:744–753.

Acknowledgments

The authors owe debts of gratitude to Dr. R. Adron Harris and Dr. Adrienne McGinn for their comments on a late draft of the manuscript and Janet Hightower for redrawing all figures that appear in the Neurobiology of Addiction series.

List of abbreviations

5-HT3    5-hydroxytryptamine-3

ACTH    adrenocorticotropic hormone

ADHD    attention-deficit/hyperactivity disorder

ALDH2    acetaldehyde dehydrogenase-2

AMPA    α-amino-3-hydroxy-5-methyl-4-isoxale propionic acid

BDNF    brain-derived neurotrophic factor

BK    large-conductance calcium-activated potassium

BOLD    blood oxygenation level-dependent

CaMKII    Ca²+/calmodulin-dependent protein kinase II

cAMP    cyclic adenosine monophosphate

COGA    Collaborative Study on the Genetics of Alcoholism

CREB    cyclic adenosine monophosphate response element binding protein

CREM    cyclic adenosine monophosphate response element modulator

CRF    corticotropin-releasing factor

DREADD    designer receptors exclusively activated by designer drugs

DSM    Diagnostic and Statistical Manual of Mental Disorders

EPSC    excitatory postsynaptic current

ERK    extracellular signal-regulated kinase

FAS    fetal alcohol syndrome

FASD    fetal alcohol spectrum disorder

FKBP5    FK506 binding protein 5

fMRI    functional magnetic resonance imaging

GABA    γ-aminobutyric acid

GWAS    genome-wide association study

HEK    human embryonic kidney

HMGB1    high-mobility group box 1

HPA    hypothalamic–pituitary–adrenal

ICD-10    International Statistical Classification of Diseases and Related Health Problems, 10th revision

IL-1β    interleukin-1β

IPSP    inhibitory postsynaptic potential

IPSP/C    inhibitory postsynaptic potentials/current

L-NAME    N-ω-nitro-L-arginine methyl ester

LTD    long-term depression

LTP    long-term potentiation

mGluR    metabotropic glutamate receptor

mIPSC    mini inhibitory postsynaptic current

miRNA    microRNA

MSN    medium spiny neuron

mSP    Marchigian Sardinian alcohol-preferring

mTORC1    mammalian/mechanistic target of rapamycin complex 1

nAChR    nicotinic acetylcholine receptor

NADH    nicotinamide adenine dinucleotide reductase

NCANDA    National Consortium on Alcohol and Neurodevelopment in Adolescence

NF-κB    nuclear factor κB

NMDA    N-methyl-D-aspartate

NOP    nociceptin opioid

NPY    neuropeptide Y

PET    positron emission tomography

PI3K    phosphoinositide 3-kinase

PKA    protein kinase A

PKC    protein kinase C

QTL    quantitative trait locus

RAGE    receptor for advanced glycation endproducts

RNAi    RNA interference

SNP    single-nucleotide polymorphism

SPECT    single-photon emission computed tomography

TLR4    Toll-like receptor 4

TNF-α    tumor necrosis factor α

Trk    tropomyosin-related kinase

Volume Three: Alcohol

Abstract

A current survey and synthesis of the most important findings in our understanding of the neurobiological mechanisms of addiction is detailed in our Neurobiology of Addiction series, each volume addressing a specific area of addiction. ALCOHOL, Volume 3 in the series, explores the molecular, cellular, and neurocircuitry systems in the brain responsible for alcohol addiction using the heuristic three-stage cycle framework of binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation. This volume of the Neurobiology of Addiction series outlines the history and behavioral mechanism of action of alcohol relevant to the neurobiology of alcohol addiction. It includes neurocircuitry, cellular, and molecular neurobiological mechanisms of alcohol addiction in each stage of the addiction cycle and explores evolving areas of research associated with all three stages of the alcohol addiction cycle, including neurobiological studies of neurodevelopmental effects of early exposure to alcohol, sleep disturbances caused by alcohol, pain interactions with alcohol, sex differences in the response to alcohol, and epigenetic/genetic interactions with alcohol.

Keywords

Addiction; Alcohol; Alcohol use disorder; Alcoholism; Ethanol; Neurobiology; Neurocircuitry; Misuse

1. Definitions

2. History of alcohol use, misuse, and addiction

3. Behavioral effects of alcohol

4. Pharmacokinetics

5. Misuse and addiction potential

5.1 Alcohol use disorder

5.2 Alcohol withdrawal

5.3 Alcohol tolerance

5.4 Alcohol toxicity

5.4.1 Epidemiology

5.4.2 Sexual dysfunction

5.4.3 Liver, heart, and cancer toxicity

5.4.4 Neurological disorders

5.5 Fetal alcohol spectrum disorder

6. Behavioral mechanism of action

7. Neurobiological effects

7.1 Binge/intoxication stage: acute reinforcing and anxiolytic effects

7.1.1 Neurobiological effects of low-dose alcohol on the brain

7.1.2 Neurobiological mechanism: neurocircuitry of acute reinforcing effects

7.1.3 Neurobiological mechanism: neurocircuitry of incentive salience

7.1.4 Neurobiological mechanism: neurocircuitry of pathological habits

7.1.5 Neurocircuitry of binge/intoxication stage: brain imaging

7.1.6 Neurodevelopmental vulnerability: binge/intoxication stage

7.1.7 Neurobiology of sleep in the binge/intoxication stage

7.1.8 Neurobiological mechanism: cellular

7.1.9 Neurobiological mechanism: molecular

7.1.10 Sex differences: binge/intoxication stage

7.1.11 Summary: binge/intoxication stage

7.2 Withdrawal/negative affect stage: tolerance, withdrawal, and dependence

7.2.1 Neurobiological mechanism: neurocircuitry

7.2.2 Neurobiological mechanism: cellular

7.2.3 Neurobiological mechanism: molecular

7.2.4 Summary: withdrawal/negative affect stage

7.3 Preoccupation/anticipation stage: reinstatement of alcohol-seeking behavior

7.3.1 Neurobiological mechanism: neurocircuitry

7.3.2 Neurobiological mechanism: cellular

7.3.3 Neurobiological mechanism: molecular

7.3.4 Summary: preoccupation/anticipation stage

8. Summary

References

1. Definitions

Alcohol is the king of liquids. It excites the taste to the highest degree; its various preparations have opened up to mankind new sources of enjoyment. It supplies to certain medicines an energy which they could not have without it.

Brillat-Savarin (1826), see also De Rasor and Youra (1980).

The word alcohol, according to Merriam-Webster's dictionary, finds its roots in the Arabic al-kuhul (or kohl, cohol, or kohol), to mean a powder of antimony or galena that is used by women to darken the eyebrows. The word alcohol was derived through Medieval Latin from Arabic and was afterward applied, on account of the fineness of this powder, to highly rectified spirits, a signification unknown in Arabia. Alcohol represents a broad series of compounds, but the alcohol that is suitable for drinking is ethanol. For the purposes of this volume, all references to alcohol refer to ethanol (see Fig. 1).

Alcohol is found in all substances that contain glucose. It is the product of the saccharine principle that takes place during alcohol fermentation (De Rasor and Youra, 1980). Fermentation is the conversion of glucose and water in the presence of yeast to produce alcohol and carbon dioxide, and this is a common biological reaction in nature. Five agents are required for alcohol fermentation: sugar (or starch to form glucose), water, heat, ferment (usually yeast Saccharomyces cerevisiae), and air. Yeast will convert glucose to alcohol up to about the 12% level until the alcohol level rises to a concentration that is toxic to the yeast and the yeast dies. Such a process occurs in nature in seed germination and the ripening of fruit. Any source of glucose is sufficient to produce alcohol through the process of fermentation and thus forms the basis of numerous alcohol beverages worldwide (Table 1). Yeast that is used for brewing can tolerate alcohol up to a concentration of approximately 5%. Beyond this concentration, brewer's yeast cannot continue fermentation and dies. However, wine yeast can usually tolerate up to ∼12% alcohol, but this concentration can reach as high as 21% alcohol, depending on the specific strain of yeast and environmental and fermentation conditions. To raise alcohol (ethanol) concentrations above fermentation levels, the yeast-converted fermentation mixture must be distilled. The fermentation mixture is heated, and the ethanol vaporizes at a lower temperature than water. When cooled in some form of condensation device (often a cool metal or glass apparatus), the ethanol can be captured as a liquid again.

Figure 1 Chemical structures and registry numbers for various alcohols from the Chemical Abstracts database.

Table 1

For more information, visit http://en.wikipedia.org/wiki/Alcoholic_beverage#Types_of_alcoholic_beverages; Accessed October 30, 2020.

2. History of alcohol use, misuse, and addiction

Alcohol is a ubiquitous substance in our society and widely used at moderate doses in the form of alcohol beverages for enjoyment of its psychoactive properties. Alcohol beverages are considered to have drug effects but also are a source of calories; as such, alcohol is unique among drug preparations. Alcohol ingestion per capita has been steady since 1850 in the United States, with the exception of the period of Prohibition from 1919 to 1933 when the sale of alcohol was prohibited (National Institute on Alcohol Abuse and Alcoholism, 1999).

Alcohol is a well-known social lubricant that is used to produce disinhibition in social situations, but excessive use produces the most harm to society of all drugs with addiction potential. The following address to the legislature by Mississippi State Senator Judge Noah S. Sweat in 1952 represents the dilemma faced by society in addressing the various aspects of the impact of alcohol on society:

You have asked me how I feel about whisky. All right, here is just how I stand on this question: If when you say whisky, you mean the devil's brew, the poison scourge; the bloody monster that defiles innocence, yea, literally takes the bread from the mouths of little children; if you mean the evil drink that topples the Christian man and woman from the pinnacles of righteous, gracious living into the bottomless pit of degradation and despair, shame and helplessness and hopelessness, then certainly I am against it with all of my power … But, if when you say whisky, you mean the oil of conversation, the philosophic wine, the stuff that is consumed when good fellows get together, that puts a song in their hearts and laughter on their lips and the warm glow of contentment in their eyes, if you mean holiday cheer; if you mean the stimulating drink that puts the spring in the old gentlemen's step on a frosty morning; if you mean the drink that enables a man to magnify his joy, and his happiness and to forget, if only for a little while, life's great tragedies and heartbreaks and sorrows, if you mean that drink, the sale of which pours into our treasuries untold millions of dollars, which are used to provide tender care for our little crippled children, our blind, our deaf, our dumb, our pitiful aged and infirmed, to build highways, hospitals, and schools, then certainly I am in favor of it. This is my stand. I will not retreat from it; I will not compromise.

Sweat (1952).

The 2019 United States National Survey on Drug Use and Health (Substance Abuse and Mental Health Services Administration, 2020) estimated that 50.8% of Americans aged 12 and older (139.7 million people) were current drinkers of alcohol, defined as having at least one drink in the past 30 days, and 24% of people aged 12 and older (66 million people) were binge alcohol drinkers, defined as having four or more drinks on the same occasion for women or five or more drinks for men on at least 1 day in the past 30 days (Table 2). In 2019, 5.8% of Americans aged 12 and older reported heavy drinking, defined as binge drinking on at least 5 days in the past 30 days prior to the survey. An estimated 8% of Americans aged 16 or older (20.5 million people) drove under the influence of alcohol at least once in the past year (Azofeifa et al., 2019). In 2019, an estimated 20.4 million people aged 12 or older (7.4%) were classified with any substance dependence or abuse in the past year based on the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV; American Psychiatric Association, 1994). Of these, 2.4 million were classified with dependence or abuse of both alcohol and illicit drugs, and 12.1 million were classified with dependence on or abuse of alcohol but not illicit drugs.

According to the World Health Organization (2018), approximately 60% of the population in Europe aged 15+ are current drinkers (drinking at least once per year), and 26.4% engage in heavy episodic drinking (defined as ≥60 g, roughly 4.25 standard US servings of alcohol, on a single occasion at least once per month). Approximately 8.8% met the criteria for an alcohol use disorder (AUD) as defined by the International Statistical Classification of Diseases and Related Health Problems (ICD-10). Alcohol use varies widely between European countries. For example, fewer people consume alcohol in Italy, Croatia, and Hungary, and heavy episodic drinking is more common in Ireland, Germany, the Czech Republic, and Baltic countries (World Health Organization, 2019).

Table 2

Based on Substance Abuse and Mental Health Services Administration (2003), National Institute on Alcohol Abuse and Alcoholism (2004).

Patterns of alcohol use vary with a given culture, and per capita alcohol consumption varies across countries, from basically zero in Somalia and Afghanistan to over 13 L in Belarus and Andorra in 2010 (Tables 3 and 4). France consumed the most wine in the world as of 2010 (6.6 L per capita), but this number has steadily declined since 1970 (12 L in 1970, 10 L in 1990, and 8.6 L in 2000; World Health Organization, 2014). In 2010, the Czech Republic drank the most beer in the world (6.8 L) and ranked fourth worldwide in overall consumption (Table 3). The small Caribbean island nation of Grenada consumed the most alcoholic spirits per capita (8.21 L) in 2010 and ranked fifth worldwide in overall alcohol consumption. The United States ranked 37th worldwide in total per capital alcohol consumption (8.6 L), half of which (50%) was in the form of beer, followed by alcoholic spirits (33%) and wine (17%; World Health Organization, 2014).

Table 3

a  Includes fortified wines, rice wine, or other fermented beverages made of sorghum, millet, or maize. —, less than 0.01. See World Health Organization, 2014.

Data from World Health Organization, Global Information System on Alcohol and Health (http://gamapserver.who.int/gho/interactive_charts/gisah/consumption_adult/atlas.html).

Excessive alcohol consumption can lead to numerous medical conditions, ranging from cirrhosis of the liver and heart disease to pancreatitis, Korsakoff's dementia, and fetal alcohol spectrum disorder. Alcohol contributes to 1 in 10 deaths in the United States among adults aged 20–64 (Centers for Disease Control and Prevention, 2014). This includes deaths from fatal automobile crashes, other accidents, liver disease, heart disease, neurological diseases, and cancer. Although alcohol-impaired driving fatalities declined by 65% since 1982, 10,511 individuals in the United States died in alcohol-related traffic crashes in 2018, accounting for nearly 1/3 (29%) of all deaths from motor vehicle crashes that year (National Highway Traffic Safety Administration, 2019). The Centers for Disease Control and Prevention estimates that 95,158 Americans (67,943 men and 27,215 women) die from alcohol-related causes annually, making it the third leading preventable cause of death in the United States. Moreover, excessive alcohol use led to 2.8 million years of potential life lost annually in the United States from 2011 to 2015, shortening the lives of those who died by an average of 29 years (Esser et al., 2020). Worldwide, the harmful use of alcohol causes approximately 3.0 million deaths every year (or 5.3% of all deaths) and accounts for 5.1% of the total global burden of disease (World Health Organization, 2018). Among people aged 20–39 years, 13.5% of all deaths are alcohol related (World Health Organization, 2018).

Table 4

3. Behavioral effects of alcohol

Alcohol has a range of behavioral effects and for centuries has been widely regarded as both a sedative and a stimulant. To quote Shakespeare from Macbeth Act II, Scene III:

Porter. Faith, sir, we were carousing till the second cock; and drink, sir, is a great provoker of three things.

Macduff. What three things does drink especially provoke?

Porter. Marry, sir, nose-painting, sleep, and urine. Lechery, sir, it provokes, and unprovokes; it provokes the desire, but it takes away the performance; therefore, much drink may be said to be an equivocator with lechery; it makes him, and it mars him; it sets him on, and it takes him off; it persuades him, and disheartens him; makes him stand to, and not stand to; in conclusion, equivocates him in a sleep, and, giving him the lie, leaves him.

Blood alcohol levels are measured in g%, in which 0.08 g alcohol/100 ml = 0.08 g% = 17 mM. This is the legal limit of intoxication throughout the United States. The amount one can drink to obtain a given blood alcohol level is illustrated in Table 5, but in general for a male who weighs 150 lbs, 4 ounces of spirits (100 proof or 50% alcohol), four glasses of wine, or four beers will result in a blood alcohol level of 0.10 g%. For a female who weighs 150 lbs, the same amounts would result in a blood alcohol level of 0.12 g%. The difference in blood alcohol levels in males and females has largely been attributed to differences in the distribution of body fat mass, with more fat per kilogram (thus less water) for females. An initial hypothesis that there are lower gastric levels of the alcohol-metabolizing enzyme alcohol dehydrogenase in females (Lieber, 2000) was not substantiated in later work (Matsumoto et al., 2001; Lai et al., 2000).

Table 5

Subtract 0.01% g% for each 40   min of drinking. 1 drink   =   1.25 ounce 80 Proof liquor, 12 ounce beer, or 5 ounce wine (http://www.alcohol.vt.edu/Students/alcoholEffects/estimatingBAC/).

Alcohol is a sedative hypnotic that produces dose-dependent behavioral effects in humans, such as sedation (decreases in activity) and hypnosis (sleep induction). At low doses (blood alcohol levels of 0.01–0.05 g%), alcohol produces personality changes, including increased sociability, increased talkativeness, and a more expansive personality (Fig. 2).

There is a mild euphoria with increased mood, good feelings, increased confidence, and increased assertiveness. There is also some release of inhibitions, tension reduction, and increased responsiveness in conflict situations. As blood alcohol levels increase from 0.08 to 0.10 g%, mood swings become more pronounced, with euphoria, emotional outbursts, and the release of inhibitions. Blood alcohol levels of 0.08 g% produce distinct impairments in judgment and motor function. At blood alcohol levels of 0.15–0.20 g%, there is marked ataxia, major motor impairment, staggering, slurred speech, muscular incoordination, and impairments in reaction time. Sensory responses are also impaired, including a loss of vestibular sense and a decrease in pain sensation. There is also a dulling of concentration and insight, impairments in discrimination and memory, significant impairments in judgment, and even greater emotional instability and the release of inhibitions. At this level (0.15 g%), blackouts can occur, in which a person, postintoxication, will have no memory of events that transpired while intoxicated. At a blood alcohol level of 0.30 g%, people have been described as stuporous but conscious. Here, one has reached the anesthetic level, with marked decreases in responsivity to environmental stimuli, severe impairments in motor function, and rapid and dramatic changes in mood. Vomiting can occur at this level. The lethal dose in 50% of individuals (LD50) is considered to be approximately 0.50 g% in nondependent individuals.

Figure 2 Progression of subjective and physiological changes corresponding to increasing blood alcohol levels.

In animals, alcohol has similar behavioral effects. Early paradigms that assessed the reinforcing effects of alcohol typically used an oral preference paradigm, in which animals were allowed to drink alcohol or water. A major breakthrough in this area was the development of a training procedure that involved access to a sweetened solution and the subsequent fading in of alcohol to avoid the aversiveness of the alcohol taste (for review, see Samson, 1987; see Animal Models of Addiction in Volume 1 of the present series, Neurobiology of Addiction). Following a sweet solution fadeout, rats will readily self-administer doses of alcohol in limited-access situations that result in blood alcohol levels that range from 0.04 to 0.08 g% (Weiss et al., 1990; Rassnick et al., 1993c; Fig. 3).

Figure 3 (Left) A saccharin fadeout protocol for alcohol dependence induction. Alcohol concentrations progressively increase, while saccharin concentrations are gradually decreased to zero. (Right) Blood alcohol levels as a function of alcohol intake during a baseline session in the two-lever, free-choice operant task in rats. The variation of these measures in this distribution reflects the nature of responding that is typically observed in a group of nonselected, heterogeneous Wistar rats. 

Taken with permission from Rassnick S, Pulvirenti L, Koob GF. SDZ 205,152, a novel dopamine receptor agonist, reduces oral ethanol self-administration in rats. Alcohol 1993;10:127–132.

The anxiolytic and tension-reducing properties of alcohol have been demonstrated in various behavioral situations in both animals and humans. An early observation involved a study of the effects of alcohol on neurotic behavior that was induced in cats in an approach-avoidance (conflict) situation (Masserman and Yum, 1946). Cats were trained to run down a runway to open a box for food when signaled by a bell-light conditioned stimulus, but a blast of air accompanied the food at irregular intervals. The animals developed bizarre, neurotic behaviors, such as the inhibition of feeding, startle, phobic responses, and aversive behavior in response to stimuli that were associated with the food/air blast conflict. Alcohol at doses of ∼1.0–1.5 g/kg significantly reduced this neurotic behavior (Masserman and Yum, 1946). The cats exhibited a restoration of simpler switch-and-signal responses and an attenuation of phobic-like behavior, motor disturbances, and other abnormal behaviors. Interestingly, alcohol disrupted, although to a lesser extent, the timing, spatial orientation, sequence, and efficiency of ‘normal’ goal-oriented responses (Masserman and Yum, 1946). This early study elaborated many of the features of alcohol's effect on conflict behavior, notably the ability of alcohol to block or reduce the suppression of behavior that is induced by punishment but also to decrease unpunished behavior, often at the same time or at the same doses.

Subsequently, the tension-reducing properties of alcohol were demonstrated in a variety of behavioral situations (Cappell and Herman, 1972; Sepinwall and Cook, 1978; Pohorecky, 1981; Liljequist and Engel, 1984). Alcohol produces anticonflict effects in the social interaction test (File, 1980; File and Hyde, 1978; Lister and Hilakivi, 1988) and elevated plus maze (Pellow and File, 1986; Lister, 1987), and alcohol reduces negative contrast that is associated with dramatic shifts in reinforcer value (Becker and Flaherty, 1982). Alcohol also produces an anticonflict effect in the lick suppression test (Vogel et al., 1971) and in a modification of the Geller–Seifter conflict procedure (Geller and Seifter, 1960) using incremental shock (Pollard and Howard, 1979; Liljequist and Engel, 1984; Aston-Jones et al., 1984; Koob et al., 1984, 1986, 1989; Thatcher-Britton and Koob, 1986; Fig. 4).

Effective doses in rats range between 0.5 and 1.0 g/kg intraperitoneally, which produce blood alcohol levels up to 0.077 g% 1 h postinjection (Morse et al., 2000). These same doses of alcohol dose-dependently decrease responding during the unpunished component, presumably reflecting the acute motor-impairing effects of alcohol (Aston-Jones et al., 1984; Koob et al., 1984). These anticonflict effects of alcohol also present rapid tolerance with repeated administration every 8 h, an effect that is not observed with benzodiazepines (Koob et al., 1987).

4. Pharmacokinetics

Alcohol (or ethyl alcohol or ethanol) has been described as the universal solvent. It is readily miscible in water and has low lipid solubility (P oil/water = 0.035, P membrane/buffer = 0.096; Leo et al., 1971; Lindenberg, 1951; McCreery and Hunt, 1978). As such, alcohol readily crosses cell membranes, although at equilibrium the membrane concentration of alcohol is only 3%–9% as high as in an aqueous medium (Kalant, 1996). Alcohol is absorbed in the stomach (20%) and small intestine (80%). In normal adults, 80%–90% of absorption occurs in 30–60 min. The absorption of alcohol is delayed if food is present in the stomach and the total amount of alcohol ingested is reduced, up to 4–6 h (Goldberg, 1943; Fig. 5).

Figure 4 Dose–response curves, expressed as a percentage of baseline (i.e., uninjected response rates) for ethanol alone during conflict and random-interval schedule components in rats (n = 18 for each component). Baseline data were obtained the day prior to drug test days. There was a significant effect of overall ethanol treatment on both conflict and random-interval response rates. Comparisons of individual means revealed that at least a 1 g/kg dose of ethanol was required to significantly increase punished responding during the conflict component (∗ P < 0.05, Newman–Keuls test), and a 0.75 g/kg dose was required to significantly decrease responding during the food-alone, random-interval component (∗ P < 0.05, Newman–Keuls test). 

Taken with permission from Aston-Jones S, Aston-Jones G, Koob GF. Cocaine antagonizes anxiolytic effects of ethanol. Psychopharmacology 1984;84:28–31.

By definition, the absorption of a drug is the movement of the drug into the blood stream. Blood alcohol levels have become the standard by which alcohol absorption can be measured and comparisons can be made of dosing between animals and humans and between experimental