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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.

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causes of alcohol abuse and alcoholism biological biochemical perspectives

Causes of Alcohol Abuse and Alcoholism: Biological/Biochemical Perspectives

neurobehavioral aspects of alcohol consumption

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
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
  • 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
Brain Stimulation Reward (BSR)
  • BSR is intracranial self-stimulation
    • measure response rate of self stimulation
    • measure threshold current needed to sustain self-stimulation
alcohol s effects on brain stimulation reward bsr
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
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
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 reinforcement9
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 reinforcement10
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
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 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

Alcohol Seeking Behavior
molecular biol properties of p np
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/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

Sensitivity to Sedative Properties of Alcohol
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

Differences in Withdrawal/Dependence
tolerance
LS/SS tolerance differences

P/NP differ in tolerance

Biochemical Differences

Probably some combination of known differences--see earlier slides

Tolerance
genetic evidence from animal models for a biological cause of problem drinking
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
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
goals of genetic investigations
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
Potential Benefits of Genetic Research Programs
  • Important implications for:
    • Prevention
    • Early Detection
    • Treatment
slide23
Twin Studies: Concordance rates for DSM-III alcohol abuse/alcohol dependence among identical and fraternal twins.

0.76 0.61

0.36 0.25

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

swedish adoption studies
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
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
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
temperament and behavior
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