Transcript Causes of Alcohol Abuse and Alcoholism: Biological

Causes of Alcohol Abuse and
Alcoholism:
Biological/Biochemical
Perspectives
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
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?
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
Brain Stimulation Reward (BSR)
• BSR is intracranial self-stimulation
– measure response rate of self stimulation
– measure threshold current needed to sustain selfstimulation
Alcohol’s 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.
Biphasic Action of Alcohol:
Stimulation(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
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
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
Neurochemical Mechanisms of
Alcohol Reinforcement
• Endogenous Opiates
– alcohol stimulates release of enkephalins and
endorphins…producing euphoria and pain
attenuation
– Opiate receptor antagonists reduce the
reinforcing effects of alcohol
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?
Alcohol Seeking Behavior
• Alcohol Preferring (P)
and Alcohol nonPreferring (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
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
Sensitivity to Sedative Properties of
Alcohol
• Long-Sleep/ShortSleep 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
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
Tolerance
• LS/SS tolerance
differences
• P/NP differ in
tolerance
• Biochemical
Differences
– Probably some
combination of known
differences--see earlier
slides
End
What About Humans?
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
Suggestive Trends
• 80% of alcoholics in
inpatient treatment
have close relative
with an alcohol
problem
• Seven times greater
risk among firstdegree relatives of
alcoholics than that of
the general population
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
Potential Benefits of Genetic
Research Programs
• Important implications for:
– Prevention
– Early Detection
– Treatment
Twin Studies: Concordance rates for DSM-III
alcohol abuse/alcohol dependence among identical
and fraternal twins.
Diagnosis
Male Subjects
Female Subjects
Identical
Fraternal
Identical
Fraternal
Alcohol
abuse and/or
alcohol
dependence
0.76
0.61
0.36
0.25
0.76
0.61
0.36
0.25
Alcohol
depencence
0.59
0.59
0.36
0.36
0.25
0.25
0.05
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
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
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
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
Identifying Markers of Inherited
Resistance
• Oriental Asian Flushing
Temperament and Behavior
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hyperactivity
hyperactivity and aggression
low attention span
task persistence
labile emotional expressivity
slow ability to calm oneself following stress
facile social behavior