The Road to DSM V Substance Use Disorders Alcohol: Learning the Lessons from the Past' Applying the

1
The Road to DSM V Substance Use Disorders
(Alcohol) Learning the Lessons from the Past.
Applying the State of the Science

• Roger E. Meyer, MD
• Clinical Professor of Psychiatry, Georgetown
• Clinical Professor of Psychiatry, VCU
• Adjunct Professor of Psychiatry, Univ. of
  Pennsylvania
• CEO Best Practice, Inc.
• July 27, 2007

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Conflict of Interest

• As CEO of Best Practice, Inc. since 1997, Dr.
  Meyer has consulted for multiple drug companies
  in the US. None of the consulting, or other work
  of Best Practice, Inc. relates to the topic of
  this talk.

3
Conclusions I Would Like You to Draw From This
Talk

• Prior versions of DSM (I-IV) sections on
  substance dependence have reflected the state of
  North American psychiatry. (e.g. DSM I and II
  categorized alcoholism with neuroses and
  personality disorders)
• The atheoretical, descriptive, categorical
  approach of DSM III, IIIR IV has failed to
  incorporate or advance the multidisciplinary
  science of addiction, or to convey the complexity
  of clinical phenomenology
• DSM V should opt for a dimensional approach to
  severity of alcohol dependence and a separate
  dimension of severity of alcohol problems to
  better meet the research and clinical needs of
  the field. It needs to respect the
  multidisciplinary roots of science in addiction

4
Basic Nomenclature

• The evolution of constructs and terminology
  related to alcoholism

5
The Concept of Alcoholism as a Disease

• Roots in late 18th-mid 19th century Benjamin
  Rush (loss of control), Thomas Trotter (a
  disease resulting in physical and mental
  dysfunction), Magnus Huss (chronic relapsing
  disease)
• 19th century typologies culminating in
  Jellineks mid-20th century 5 species
  (self-medication, organ damage, impaired control,
  inability to abstain, binge drinking alpha,
  beta, gamma, etc) )
• From 1964-Present, the nomenclature has been
  influenced by developments related to other drugs
  of abuse (as well as trends in psychiatric
  diagnosis)

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The 1964 WHO Criteria of Drug Dependence

• Defined 1) physiological dependence (tolerance
  and physical dependence) consistent with the then
  state of research in pharmacology 2)
  psychological dependence consistent with the
  social sciences (psychosocial determinants of
  drug use as self-medication)
• But the Criteria failed to anticipate 3 major
  developments
• Methadone treatment
• The Cohort effect in the drug abuse epidemic of
  the 1960s-1970s
• The development of animal models of drug self
  administration led to a new formulation

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Drug Reinforcement as Model of Dependence

• Conceived of addiction as behavior shaped by its
  consequences and not as a disorder or disease
• Emphasized the rewarding properties of drugs (not
  the host or the environment), drug commonalities,
  stimulus control of behavior, brain mechanisms
  of reward. Largely ignored risk related host
  factors or culture
• Downplayed importance of tolerance, withdrawal
  and post withdrawal states except as related to
  reinforcing potency (i.e. downplayed classical
  pharmacology)
• Other limitations inadequate explanation of
  alcohol dependence (most people use alcohol in
  moderation), culture and individual differences
  convey risk or protective effects not explained
  by the model, pharmacogenetics of
  preference/avoidance drinking in rats was not
  considered
• Most people who experiment with illicit drugs do
  not go on to develop dependence,
• Craving and loss of control (salient to
  clinicians) was ignored in the model.

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In spite of the limitations of the WHO criteria
and the reinforcement model, they were grounded
in the science of their period.DSM I and DSM
II (and ICD 8) which were contemporaneous with
these models categorized alcoholism with
personality disorders and neuroses consistent
with the state of psychiatry at that time.
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DSM III (circa 1980)

• Defined substance dependence as a more severe
  form of substance use disorder than substance
  abuse and required the presence of either
  tolerance or withdrawal.
• Substance abuse was defined by a pattern of
  pathological use, impairment in social or
  occupational functioning due to substance use,
  and minimal duration of at one month.
• Ignored what had been learned subsequent to WHO
  criteria of 1964, the literature on drug self
  administration, differences between drug classes,
  and the Alcohol Dependence Syndrome construct
  (Edwards and Gross) first elucidated in 1976.
• New models ( paradigms) should emerge as old
  models fail to explain relevant phenomena. (Kuhn)
  The Alcohol Dependence Syndrome was an attempt to
  meet that need. DSM III was not.

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Alcohol Dependence Syndrome

• Alcohol Specific
• Centrality of Behavior
• Biological processes learning
• Separate dimensions of severity of alcohol
  dependence alcohol problems
• In the 1980s Rating scales were developed to
  quantify severity of dependence. Biobehavioral
  studies, twin studies, and outcome research also
  supported this dimensional approach to dependence
  severity.
• Problem severity is influenced by culture /or
  co-morbid psychopathology-not only by severity of
  dependence.

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The Alcohol Dependence Syndrome

• Narrowing of Drinking Repertoire
• Salience of Drinking
• Relief Avoidance Drinking
• Subjective Awareness of Compulsion to Drink
• Increased Tolerance
• Withdrawal Symptoms
• Rapid Reinstatement of the Dependence Syndrome if
  Drinking Resumes

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DSM IIIR (circa 1987)

• Adapted the Alcohol Dependence Syndrome
  dimensional construct to the categorical mandate
  of DSM IIIR
• applied the category across all drugs of abuse
• Dropped the differentiation between problem and
  dependence severity of Edwards Gross
• Retained category called Psychoactive Substance
  Abuse denoting a maladaptive pattern of substance
  use not meeting the criteria for Dependence

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More on DSM IIIR Substance Dependence (Red items
not in DSM IV)

• Substance often taken in larger amounts or over a
  longer time than person intended
• Persistent desire or one or more unsuccessful
  efforts to cut down or control use
• Much time spent in activities to get the
  substance
• Frequent intoxication or withdrawal symptoms when
  expected to fulfill major role responsibilities
• Important activities given up or reduced because
  of substance use
• Continued use despite knowledge of persistent
  social, psychological or health problem
  exacerbated by the substance
• Marked tolerance
• Characteristic withdrawal symptoms
• Substance use to avoid withdrawal

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Comparing DSM IIIR, IV and ICD 10

• All categorical.
• Withdrawal relief drinking in DSM IIIR and ICD 10
• Tolerance and withdrawal symptoms in all
• ICD 10 explicitly mentions compulsion to drink,
  narrowing of drinking repertoire, impaired
  capacity to control drinking consistent with
  Edwards and Gross.
• Field trials found that DSM IV yielded the
  highest prevalence of alcohol dependence followed
  by DSM IIIR and ICD 10with reasonably good
  cross system agreement. There was no agreement
  between Harmful Use in ICD 10 and Substance
  Abuse in DSM IIIR and IV.

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In the Addictions Field, the Categorical
Requirement in DSM IV

• Has failed to address issues of severity of
  dependencee.g. The same diagnosis of alcohol
  dependence in clinical and community populations.
• The different outcomes of recurrent drinking in
  clinical community populations
• Implications for the development of drug
  treatments. (A moderate drinking outcome in some
  naltrexone trials, not others. Is severity an
  issue?)
• Has resulted in a clinical research literature
  that emphasizes rather than clarifies the
  co-morbidity construct re addictive and
  psychiatric disorders.
• Has failed to address cultural differences that
  shape different manifestations of the disorder as
  in France, Sweden, Taiwan, USA.
• Has inhibited the development of research
  linkages between animal models and clinical
  phenomena,
• Has created confusion over the category,
  Substance Abuse. Is it a definable disorder, a
  milestone in the progression to alcohol
  dependence, or a behavioral risk factor
  associated with higher rates of accidents and
  other consequences? It is now a category with
  poor reliability and no clear validity.

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Discontent with DSM IV is not Limited to the
Addiction Field

• Nancy Andreassen Research in psychopathology is
  dying. because of DSM IV. It is difficult to
  figure out who has, or what is, schizophrenia.
• Frederick Goodwin Kraepelins concept of
  recurrence comes closer to the realities of
  family history of bipolar disorder than the DSM
  construct of bipolarity.
• While DSM III, IIIR and IV provides generally
  satisfactory diagnostic reliability, the price
  has been an explosion of 200-300 separate
  disorders multiple co-morbid diagnoses.
  Andreassen argues that DSM IV has had negative
  consequences in teaching, clinical research, drug
  development, and the search for the
  pathophysiological (including genetic) basis of
  major psychiatric disorders.
• The creators of DSM IV considered and rejected a
  dimensional approach, even though it would
  increase reliability and communicate more
  clinical information than categorical
  approaches. And yet, in the rest of medicine,
  progress has brought us beyond descriptive
  diagnoses to grading severity and prognosis,
  understanding pathophysiology through linkages to
  animal models, and identification of critical
  risk factors.

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The Dimensional Model of Alcohol Dependence
Severity

• Offers a better foundation for building bridges
  to animal models, neuroscience, geneticsand to
  population research (Compared with Categorical
  Model)
• Patient Oriented and Population Researchers need
  to agree on a reliable and valid dimensional
  model of dependence severity that offers some
  predictive utility. The research literature
  following the Edwards Gross formulation may
  offer some clues.
• Human Geneticists should apply the dimensional
  model to their studies of familial risk
• Patient Oriented Researchers Behavioral
  Neuroscientists should translate the dimensional
  model of severity of alcohol dependence into a
  relevant animal model of dependence severity

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The Two Dimensional Model of Severity of Alcohol
Dependence Alcohol Problems

• Was constructed to identify a specific
  dependence severity dimension across cultures.
• Instruments like the Addiction Severity Index are
  useful in quantifying problem severity.
• Interventions targeted at alcohol-related
  problems need to be assessed in relation to those
  problems.
• Interventions targeted at preventing relapse to
  drinking (e.g. medications) may have modest
  effects on the consequences of prior drinking
  (residual problems).
• The level of residual disability (problems) is
  related to medical consequences, cognitive
  impairment, the presence (or absence) of a major
  psychiatric disorder (schizophrenia, bipolar
  disorder, antisocial personality), and persisting
  abnormalities related to sleep, negative mood,
  and stress response
• Alcohol-related psychosocial problems (and the
  prevalence of alcohol dependence) are each
  influenced by culture, gender, personality.

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Research Planning for DSM V

• White papers prepared for APA and NIMH in 6 Topic
  Areas to inform categories criteria
• Basic nomenclature
• Neuroscience
• Culture and psychiatric diagnosis
• Issues of gender age
• Personality disorders relational disorders
• Mental disorders and disability
• Developmental science
• The alcohol field actually can address each of
  these domains. (Perhaps at least as well as any
  other area of psychiatry)
• For the remainder of this talk, I will attempt to
  make this last point in a general overview of
  broad research areas.
• I apologize in advance for a cursory review of
  complex and non-overlapping areas of research.

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Patient Oriented Researchers Behavioral
Neuroscientists should translate a dimensional
model of severity of alcohol dependence into a
relevant animal model of dependence severity
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Alcohol Preferring Rat Strains

• An Excellent Model of Alcohol Dependence
• High levels of voluntary alcohol consumption
  leading to BACs of 50-250 mg
• Ethanol for its pharmacological rather than its
  caloric content
• 30 ethanol by oral consumption
• Intragastric or intracerebral route
• Tolerance as well as physical dependence
• Acute Tolerance and decreased ethanol sensitivity

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The Alcohol Dependence Syndrome

• Narrowing of Drinking Repertoire
• Salience of Drinking
• Relief Avoidance Drinking
• Subjective Awareness of Compulsion to Drink
• Increased Tolerance
• Withdrawal Symptoms
• Rapid Reinstatement of the Dependence Syndrome if
  Drinking Resumes

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Tolerance, Dependence, Rapid Reinstatement

• Patient-Oriented Clinical Research in Addictions
  (1950-1965) described tolerance, alcohol
  withdrawal syndrome (Victor Adams) rapid
  reinstatement of dependence when drinking resumed
  (Mendelson Mello)
• Severity of alcohol withdrawal can be quantified
  using well established scales (CIWA).
• Quantification of tolerance (Patch clamp
  technique or assess cross tolerance. Issue of
  timing of assessment)
• Rapidity of Reinstatement Dependence Severity
  also observed in clinical outcome studies (Babor,
  et al)

• Alcohol preferring rats other animal models
  (e.g. sucrose fading technique in rats)
  demonstrate tolerance acute withdrawal and the
  role of GABA A and glutamate receptors in these
  processes.
• Severity of alcohol withdrawal tolerance can be
  quantified.
• Genetic influence on withdrawal severity
• Rapidity of Reinstatement Roberts, et al
  Resumption of high levels of drinking 4-8 weeks
  post-withdrawal

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Subjective Awareness of Compulsion to Drink
(Craving)

• The literature suggests two types of Craving
• A chronic dysphoric mood state following alcohol
  withdrawal persisting for as long as one yeara
  state which is ameliorated by alcohol
• Episodic craving triggered by specific cues
  (alcohol associated events, mood changes,
  environmental stimuli, stress, and by alcohol
  itself)

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Subjective Awareness of Desire to Drink Episodic
or Situational Craving

• Episodic Craving in Humans
• Measured on visual analogue scale
• Unconditioned response to alcohol withdrawal
• Conditioned response to internal or external
  drinking associated stimuli (cues)
• Alcohol Priming
• Stress

• Animal Model
• Drinking triggered by alcohol priming, response
  to alcohol withdrawal, Corticotropic Releasing
  Factor
• Conditioned place preference

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Alcohol Priming Effect on Craving

• The priming effect of low doses of alcohol on
  craving in humans appears to correlate with
  severity of alcohol dependence. (Ludwig Stark
  Kaplan, Meyer, et al Laberg, et al)
• The priming effect of low doses of alcohol on
  alcohol self-administration behavior in rodents
  appears to correlate with prior history of
  alcohol withdrawal and tolerance (Weiss, et al)

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Allostasis An Animal Model of? Protracted
Abstinence

• The allostatic state consequent to the
  development of alcohol dependence represents a
  chronic deviation of reward set point,
  dysregulation of reward circuits, and activation
  of brain and hormonal stress responses. It offers
  a useful animal model of protracted abstinence,
  and a useful model to inform clinical
  investigation of alcohol dependence severity.
  (Koob)

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A Brief Review of Animal Models and of
Historically Important Clinical Research

• Suggests the feasibility of linking a dimensional
  model of alcohol dependence severity to
  well-developed animal models and to use the
  animal models to frame questions for clinical
  research
• The combination of animal model research and
  clinical investigation of dependence severity
  will have real implications for medications
  development in the alcohol field

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Research Planning for DSM V

• White papers prepared for APA and NIMH in 6 Topic
  Areas to inform categories criteria
• Basic nomenclature
• Neuroscience
• Culture and psychiatric diagnosis
• Issues of gender age
• Personality disorders relational disorders
• Mental disorders and disability
• Developmental science

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Cross Cultural Research on the Prevalence and
Manifestations of Alcoholism Demonstrate

• Countries with high per capita rates of alcohol
  consumption have higher rates of alcohol
  dependence
• In countries or cultures with low per capita
  rates of alcohol consumption, alcoholism is
  highly associated with antisocial personality
  disorder. (Implications for psychosocial
  problems)
• In countries with high rates of illegal drug use,
  co-morbid alcohol and other substance dependence
  is not uncommon.
• Historical data indicates that heavy drinking
  norms can change during disruptive cultural
  changes (e.g. Poland after WW II)
• Prevalence of alcohol dependence among indigenous
  peoples in North America and Australia
• At the macro (state) and micro (tavern) level,
  there is a relationship between the price of ETOH
  and per capita consumption rates
• The prevalence of heavy drinking and of risky
  behavior while drinking can be affected by public
  health campaigns that discourage public
  drunkenness and drunk driving.
• Genetic factors related to acetaldehyde and
  alcohol metabolism contribute to lower drinking
  rates among some East Asians and among Ashkenazi
  Jews.

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Influence of Personality

• Heritable externalizing personality traits
  associated with high novelty seeking and low harm
  avoidance and reward dependence are associated
  with a highly heritable type of alcoholism.
  (Cloninger)
• Alcoholics with antisocial personality disorder
  appear to be most treatment resistant.
• A subtype of alcoholism associated with
  antisocial behavior has been described in the
  literature for more than 100 years.

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Developmental Pathways to Alcoholism

• The association between antisocial personality
  characteristics and risk of alcoholism has been
  confirmed by population geneticists, by social
  scientists clinical investigators in the past
  40 years using different approaches
• Apart from this subtype, heritability of
  alcohol-related responses has been demonstrated
  in animal models and in sons of alcoholics but
  the endophenotype(s) bringing increased risk of
  alcohol dependence in humans is unknown
• In rodents, ethanol sensitivity, proneness to
  ethanol withdrawal seizures, tolerance
  development and alcohol preference drinking are
  each genetically distinct characteristics. Each
  characteristic is influenced by the interaction
  of multiple genes, and each trait is independent
  of other traits (e.g. preference drinking and
  alcohol sensitivity).
• Alcohol related responses are distributed
  dimensionally and not as traits related to a
  single gene
• Alcoholic twins show same levels of alcohol
  dependence severity based on Edwards and Gross
  criteria (Gurling)
• Schuckit found reduced ethanol sensitivity as a
  risk factor in sons of alcoholics but it is
  unclear how this trait leads to alcohol
  dependence.
• A dimensional approach to assessment of
  dependence and problem severity is necessary to
  define steps along the path to more severe levels
  of pathology.

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The Take-Home Message

• A dimensional model of severity of alcohol
  dependence with a separate dimension of problem
  severity can be informed by research findings
  across relevant disciplines.
• With a robust dimensional model, testable
  hypotheses can be examined through clinical
  observation, basic clinical investigation,
  clinical trials and outcome studies, animal
  models, genetics, neuroscience, epidemiology,
  behavioral and social science.
• And ultimately leading to the development of new
  medications for treatment, and of validated
  non-pharmacological approaches to treatment and
  prevention.
• DSM V should build on multidisciplinary science
  and good clinical observation to create an
  alcohol specific diagnostic paradigm that will
  help to advance researchor at least not inhibit
  further development.

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FinPreguntas?
35
Gender

• Rates of alcohol dependence are lower in women
  which are likely related to
• Cultural norms
• Different alcohol elimination rates (compared
  with men). (Women tolerate less alcohol.)
• ?Differences in heritability
• Different pattern of co-morbid psychopathology
  (e.g. lower rate of antisocial personality
  disorder than in men higher rates of co-morbid
  depression and depression as a possible risk
  factor in women).

36
A Two Dimensional Model of Severity of Alcohol
Dependence Alcohol Problems

• Is consistent with the research literature on the
  culture, gender and personality influence on the
  manifestations of alcoholism.
• The relationship between level of problem
  severity (and problem types) and dependence
  severity varies between cultures and individuals
• Problem severity can be quantified using
  instruments like the Addiction Severity Index.
• Problem severity (and specific problems) and
  alcohol dependence (risk of relapse or initiation
  of abstinence) represent different targets for
  treatment.

37
Research Planning for DSM V

• White papers prepared for APA and NIMH in 6 Topic
  Areas to inform categories criteria
• Basic nomenclature
• Neuroscience
• Culture and psychiatric diagnosis
• Issues of gender age
• Personality disorders relational disorders
• Mental disorders and disability
• Developmental science

38
The Developmental Pathway from Childhood Conduct
Disorder to ASP and Increased Alcoholism Risk

• The heritability of high novelty seeking, low
  harm avoidance and low reward dependence is
  estimated at 40-60 (meaning the remainder is
  related to environmental factors) (Cloninger)
• Heritability is a significant predictor of the
  stability of antisocial behavior from adolescence
  to adulthood
• Social scientists explain antisocial behavior on
  the basis of family dysfunction, parental
  antisocial behavior and poor family management,
  and/or the quality of sibling and peer
  relationships.
• Severe childhood stress and a rhesus monkey model
  of early childhood stress (maternal separation)
  can be associated with increased aggressiveness
  and hazardous behavior and excessive alcohol
  consumption in adults.
• Gene environment not either/or!
• The socially deviant peer group is the single
  most important factor predicting early onset
  alcohol and other substance use problems.

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The Developmental Pathway to Alcoholism for Other
Heritable Traits is Less Clear

• In rodents, ethanol sensitivity, proneness to
  ethanol withdrawal seizures, tolerance
  development and alcohol preference drinking are
  each genetically distinct characteristics. Each
  characteristic is influenced by the interaction
  of multiple genes, and each trait is independent
  of other traits (e.g. preference drinking and
  alcohol sensitivity).
• Alcohol related responses are distributed
  dimensionally and not as traits related to a
  single gene
• Alcoholic twins show same levels of alcohol
  dependence severity based on Edwards and Gross
  criteria (Gurling)
• Schuckit found reduced ethanol sensitivity as a
  risk factor in sons of alcoholics but it is
  unclear how this trait leads to alcohol
  dependence.

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The Developmental Pathway to Alcoholism for Other
Heritable Traits is Less Clear (2)

• Heritability of alcoholism results from the
  aggregate influence of multiple genes
• Alleles at many different gene loci increase the
  risk of disease only when inherited with alleles
  at other loci, and in the presence of specific
  environmental factors
• Many combinations of predisposing alleles,
  environmental factors and behavior all could lead
  to the same outcome re alcohol dependence
• Gene Expression in Brain
• Influenced by stage of development
• Factors in the environment
• Consequences of behavior and learning.

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For the Future

• Patient Oriented and Population Researchers need
  to agree on reliable and valid dimensional models
  of alcohol dependence and problem severity that
  offers some predictive utility.
• Human Geneticists should apply the dimensional
  model to their studies of familial risk
• Longitudinal databases in which genetic,
  developmental environmental data are collected
  over time are critical in defining the varieties
  of developmental paths and endophenotypes
  associated with alcoholism risk. NIAAA already
  has the beginnings of this effort in the
  Collaborative Study on the Genetics of Alcoholism
  and its longitudinal community surveys.

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The Take-Home Message

• Over the past 30 years, 137 distinct
  discipline-based models of addiction have been
  proposed (West 2001). None of these models
  accounts for data beyond its methodology none
  offers an adequate structure for
  interdisciplinary research hypothesis testing.
• DSM III, IIIR and IV are part of this problem.
• Progress in medicine over the past 150 years has
  moved us beyond descriptive diagnoses to grading
  severity prognosis, to understanding
  pathophysiology through linkages between human
  disease and animal models (and ultimately
  molecular biology), and to the identification of
  critical risk factors through rigorous
  epidemiological research.

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The Take Home Message

• If there is a hierarchy in science that is based
  on explanatory power, then findings in
  neuroscience, molecular biology and genetics in
  the next decades will have to accommodate (if not
  account for) findings on the clinical
  manifestations of alcoholism, as well as data on
  differential risk, course and recovery that come
  from the behavioral and social sciences,
  epidemiology, and from clinical observations and
  clinical studies.

44
Given the current and projected knowledge base
on gender, personality, culture and genetic
influences on the course, severity, and
manifestations of alcoholism-and the past
limitations of categorical approaches to
nomenclature,How might a dimensional approach
be crafted that would inform and be informed by
new research findings in psychology (personality
and/or behavior), social science, epidemiology
and demography, and genetics? 1. Dependence
Severity2. Problem (Disability) Severity3. ASP
Severity4. Family Loading
45
Tonic (Rather Than Episodic) Craving (Protracted
Abstinence)

• Clinical studies of alcoholics in early months of
  recovery Mood HPA axis sleep EEG insomnia
  electrophysiology cognition relapse risk
• ?Stress responses in recovery ?motivation
  ?mood regulation ?incentivized behavior

• ?Evidence of protracted abstinence in animal
  models
• Allostasis (Koob) Event Related Potentials
  (ERP) in Monkeys??effects on sleep EEG
  Nestlers findings of changes in gene expression
  in the reward system ? Effects on motivation
  and incentivized behavior

46
Needed Nomenclature that Stimulates Clinical
Basic Research

• A validated dimensional model of alcohol
  dependence severity is a promising link to animal
  models
• The development of pharmacotherapies for the
  treatment of alcoholism depends upon the
  successful modeling of clinical phenomena such as
  protracted abstinence and situational craving in
  animal models.
• A revitalized program of translational research
  linked to studied in animal models offers the
  most likely route to teasing apart
  pathophysiology of progression from heavy alcohol
  use to alcohol dependence

47
Patient-Oriented Clinical Research in Addictions-
1950-1965 Tolerance, Withdrawal Syndrome Rx,
Pavlovian Conditioning of Cue Responses,
Protracted Abstinence
Neurobiology of Tolerance, Acute Withdrawal,
Craving, Protracted Abstinence in Animals
48
Linkages Between Clinical Animal Models

• Chronic Ethanol Treatment Alters Subunit
  Composition of GABAA and NMDA Receptors (Changes
  in Gene Expression).
• Changes in the GABA receptor may account for
  Ethanol Tolerance and Changes in the NMDA
  Receptor may account for Acute Withdrawal
  (Hoffman and Tabakoff )
• PET Scan Study of Cross Tolerance (Volkow, et al)
• Studies of Tolerance Acute Tolerance (OConnor
  Li)
• What are the molecular, cellular and systems
• processes that account for the transition to
  loss of control? (Koob and Le Moal)
  Neuroadaptive changes in DA activity and in GABA
  receptor function. But also Serotonin, Opioid
  Peptides, Acetyl Choline (nicotinic receptor),
  CRF.
• The Addiction Process Involves Multiple
  Neurocircuits and Transmitters Koob, et al

49
Protracted Abstinence ?Reln to Criteria of
Severity of Dependence?
2) Animal Models of Clinical PhenomenaAllostasis
ERP in Monkeys CRF 4) Nestlers Findings at
Molecular Level ?Effects on motivation,mood
regulation, incentivized behavior
1) Clinical Studies of Protracted Abstinence
Mood Endocrine Sleep ERP Relapse Risk
Tonic Craving 3) ?Stress Responses in
Recovery 5)?Motivation,mood regulation, incentiviz
ed behavior
50
Protracted Abstinence Animal Behavior and
Clinical Outcomes
Babor Outcome Study Dependence Severity
Predicts Dependence Severity Edwards Rapid
Reinstatement Funderburk and Allen
Roberts, et al Resumption Of Drinking 4-8 weeks
post- Withdrawal ?Evidence of Allostasis
51
Subjective Awareness of a Compulsion to Drink
Craving

• Not a Criterion of DSM IIIR or IV but a Proposed
  Target of Pharmacotherapy
• Tonic Vs. Episodic Craving
• Episodic Craving
• Measured on visual analogue scale
• Unconditioned Response to Alcohol Withdrawal
• Conditioned Response to Internal or External
  Stimuli
• Alcohol Priming

52
Alcohol Self Administration Behavior is the
Common Thread Between Clinical Science and
Behavioral Neuroscience in Studies of
Situational Craving
The Most Reliable Trigger of Situational Craving
in Clinical Studies 1)Alcohol Cue 2) Expects
Consumption 3) Priming Effect Reln to Dependence
Severity!
The Importance of Self Administration of Alcohol
in 3 Animal Studies From Reward to Anticipation
53
Craving From Reward to Anticipation

• Tolerance to Liking Sensitivity to Wanting
  Robinson and Berridge
• Midbrain DA Neurons Response Shifts from Reward
  to Stimulus Onset Following the Learning of a
  Task Montague, et al, Weiss, et al
• Functional Imaging Studies of Alcohol
  Self-Administration by alcoholic subjects
• (consistent with NIAAA guidelines),
• coupled with homologous animal models monitoring
  mesolimbic dopamine activity in alcohol consuming
  animals, should help to clarify the biological
  substrates of situational craving and the priming
  effects of alcohol.

54
The Next Generation of Medications Will Have to
Come From a Better Under- Standing of the Biology
of Dependence and Better Metrics of Severity
If CRF is a factor in protracted abstinence ?CRF
Antagonists. If Sleep is a Predictor
Non-Dependence Producing Hypnotics? Alterations
in GABA and NMDA Receptors Dopaminergic partial
agonists situational craving ? Genetics and
Treatment Response
55
DSM IV Substance Dependence Criteria

• Substance dependence is a maladaptive pattern of
  substance use leading to clinically significant
  impairment or distress, as manifested by three
  (or more) of the following, occurring any time in
  the same 12-month period
• 1. Tolerance, as defined by either of the
  following
• (a) A need for markedly increased amounts of the
  substance to achieve intoxication or the desired
  effect or
• (b) Markedly diminished effect with continued
  use of the same amount of the substance.
• 2. Withdrawal, as manifested by either of the
  following
• (a) The characteristic withdrawal syndrome for
  the substance or
• (b) The same (or closely related) substance is
  taken to relieve or avoid withdrawal symptoms.
• 3. The substance is often taken in larger amounts
  or over a longer period than intended.
• 4. There is a persistent desire or unsuccessful
  efforts to cut down or control substance use.
• 5. A great deal of time is spent in activities
  necessary to obtain the substance, use the
  substance, or recover from its effects.
• 6. Important social, occupational, or
  recreational activities are given up or reduced
  because of substance use.
• 7. The substance use is continued despite
  knowledge of having a persistent physical or
  psychological problem that is likely to have been
  caused or exacerbated by the substance (for
  example, current cocaine use despite recognition
  of cocaine-induced depression or continued
  drinking despite recognition that an ulcer was
  made worse by alcohol consumption).
• Specifiers With or without physiological
  dependence. Remission Status

56
DSM IV Substance Abuse Criteria

• Substance abuse is defined as a maladaptive
  pattern of substance use leading to clinically
  significant impairment or distress as manifested
  by one (or more) of the following, occurring
  within a 12-month period
• 1. Recurrent substance use resulting in a failure
  to fulfill major role obligations at work,
  school, or home (such as repeated absences or
  poor work performance related to substance use
  substance-related absences, suspensions, or
  expulsions from school or neglect of children or
  household).
• 2. Recurrent substance use in situations in which
  it is physically hazardous (such as driving an
  automobile or operating a machine when impaired
  by substance use)
• 3. Recurrent substance-related legal problems
  (such as arrests for substance related disorderly
  conduct)
• 4. Continued substance use despite having
  persistent or recurrent social or interpersonal
  problems caused or exacerbated by the effects of
  the substance (for example, arguments with spouse
  about consequences of intoxication and physical
  fights).
• The symptoms have never met the criteria for
  substance dependence for this class of substance.