Causes of Alcohol Abuse and Alcoholism: BiologicalBiochemical Perspectives

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Causes of Alcohol Abuse and Alcoholism
Biological/Biochemical Perspectives
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Neurobehavioral Aspects of Alcohol Consumption

• Source Eighth Special Report to the U.S.
  Congress on Alcohol and Health
• Secretary of Health and Human Services
• September, 1993
• pp 113-128

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Alcohol-Seeking Behavior and the Development of
Chronic Drinking

• Physical Dependence
• tolerance
• withdrawal
• cause or consequence?
• Psychological Dependence
• compulsive craving
• drinking independent of physical dependence and
  withdrawal
• A fundamental question is Are the reported
  pleasure sensations that lead to alcohol-seeking
  due to its euphoric effect, or to the reduction
  of some underlying anxiety?

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Reinforcement

• Reinforcement is the process whereby the
  probability of a response is increased if it
  results in a particular effect
• positive reinforcement
• learned behavior to achieve a reward
• negative reinforcement
• learned behavior to avoid discomfort

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Brain Stimulation Reward (BSR)

• BSR is intracranial self-stimulation
• measure response rate of self stimulation
• measure threshold current needed to sustain
  self-stimulation

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Alcohols Effects on Brain Stimulation Reward
(BSR)

• Rat response rates increased during BAC rise no
  effect during BAC drop phase
• Thought to be analogous to human sensations of
  pleasure and euphoria during BAC rise.

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Biphasic Action of AlcoholStimulation(low BAC)
then Sedation (high BAC)

• Low doses stimulate Spontaneous Motor Activity
  (SMA) in rats during rising BAC
• High doses give sedation and sleep
• SMA stimulation occurs through elevating dopamine
  levels in ventral tegmental area of the brain
  (nucleus acumbens reward center)
• These changes are correlated with the enhancement
  of the brain stimulation reward threshold

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Neurochemical Mechanisms of Alcohol Reinforcement

• Dopamine
• alcohol and cocaine stimulate concentrations in
  nucleus acumbens and other reward centers
• Dopamine antagonists increase alcohol intake in
  rats, e.g.., more alcohol is required to achieve
  pleasurable response
• Dopamine agonists decrease alcohol intake in rats
  , e.g.., less alcohol is required to achieve
  pleasurable response

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Neurochemical Mechanisms of Alcohol Reinforcement

• Serotonin
• alcohol increases serotonin concentrations in
  certain regions of the brain
• brain of alcohol preferring rats contain lower
  concentrations of serotonin than wild type rats.
• Serotonin agonists reduce alcohol intake

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Neurochemical Mechanisms of Alcohol Reinforcement

• Endogenous Opiates
• alcohol stimulates release of enkephalins and
  endorphinsproducing euphoria and pain
  attenuation
• Opiate receptor antagonists reduce the
  reinforcing effects of alcohol

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Genetic Evidence of the Biological Basis for
Problem Drinking -- Animal Models
Are there demonstrable genetic differences
(biological differences) that might make some
individuals more prone to alcohol-seeking
behavior? Are some individuals less likely to
experience withdrawal? Tolerance? What is the
genetic evidence that such traits are inherited
and thus based in biological difference?
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Alcohol Seeking Behavior

• Alcohol Preferring (P) and Alcohol non-Preferring
  (NP) Rats
• bred through repeated generations to maximally
  exhibit this behavior
• P rats will do anything to get alcohol -- very
  strong positive reinforcement -- despite harm

• Fast/Slow SMA Mice
• Fast mice quickly respond to stimulatory effects
  of alcohol
• Slow mice do not respond initially to the
  stimulatory effect
• Slow mice develop tolerance to depressive effect
  after 31 days and then are Stimulated

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Molecular Biol. Properties of P/NP

• P/NP have comparative differences in LTW-4
  protein
• LTW-4 Protein increases in both P and NP with
  increased alcohol consumption

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Sensitivity to Sedative Properties of Alcohol

• Long-Sleep/Short-Sleep mice
• differ by righting reflex
• LS loose righting reflex with 1/2 the alcohol
  level of SS
• LS looses righting reflex with 1/30 the alcohol
  when admin. to Purkinge cells

• Biochemical Differences
• LS more sensitive to alcohol augmentation of GABA
  function
• GABA receptor in LS mice has enhanced alcohol
  activation

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Differences in Withdrawal/Dependence

• Withdrawal-Seizure Prone(WSP) and
  Withdrawal-Seizure Resistant(WSR) mice
• 10x more severe symptoms
• no difference in sensitivity to other affects of
  alcohol including tolerance

• Biochemical Differences
• Must be Genetic Component to Dependence
• Glutamate receptors increase with alcohol
  consumption
• WSP have more hippocampal NMDA (glutamate)
  receptors

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Tolerance

• LS/SS tolerance differences
• P/NP differ in tolerance

• Biochemical Differences
• Probably some combination of known
  differences--see earlier slides

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End
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What About Humans?
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Genetic Evidence from Animal Models for a
Biological Cause of Problem Drinking

• P rats Alcohol Preferring
• NP rats Alcohol Avoiding
• Fast Spontaneous Motor Activity mice
• Slow Spontaneous Motor Activity mice

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Suggestive Trends

• 80 of alcoholics in inpatient treatment have
  close relative with an alcohol problem
• Seven times greater risk among first-degree
  relatives of alcoholics than that of the general
  population

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Goals of Genetic Investigations

• Detect and Quantify effects of Genetic
  Determinants on Problem Drinking
• Characterize Patterns of Inheritance
• Identify Genes that Confer Vulnerability
• Identify Factors other than Genes that affect
  pathogenesis of alcoholism
• Locating Specific Genes on the Genome that Confer
  Susceptibility

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Potential Benefits of Genetic Research Programs

• Important implications for
• Prevention
• Early Detection
• Treatment

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Twin Studies Concordance rates for DSM-III
alcohol abuse/alcohol dependence among identical
and fraternal twins.
0.36 0.25
0.76 0.61
0.59 0.36
0.25 0.05
Pickens et al (1991) Heterogeneity in the
inheritance of alcoholism. A study of male
and female twins. Archives of General
Psychiatry, 48, p19-28
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Swedish Adoption Studies

• Incidence of Alcohol Problem among genetically
  unrelated individuals in same home environment
• 2.5 fold increased risk for children of Alcoholic
  Parent
• Type I -- most common, mild, adult onset,
  dependent on environment
• Type II -- less comon, severe, in men, early
  onset, agressive behavior
• Type III -- like Type II but lacks agressive
  behavior

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Biochemical Risk Markers

• Genes for serotonin transporter
• Gene variant for GABA receptor
• Gene for catechol-O-methyltransferase (enzyme for
  dopamine metabolism) Variant leading to increased
  susceptibility to pain and anxiety also high risk
  for alcohol problems
• Variants of the µ-opioid receptor determine
  whether naltrexone is effective or not in
  treatment of alcoholism

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Identifying Markers of Inherited Vulnerability

• Electrophysiology Markers
• Biochemical Markers
• platelet monoamine oxidase and adenylate cyclase
  activities
• rate of platelet serotonin uptake
• Differences in Reactions to Alcohol
• Low response to alcohol
• alcohol-induced increase in baseline heart rate
• alcohol-induced decreases in plasma prolactin and
  cortisol

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Identifying Markers of Inherited Resistance

• Oriental Asian Flushing

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Temperament and Behavior

• hyperactivity
• hyperactivity and aggression
• low attention span
• task persistence
• labile emotional expressivity
• slow ability to calm oneself following stress
• facile social behavior