Transcript Overview of Neurobiology of Addiction

ETHYL ALCOHOL (ETOH)
Alcohol
An Arabic Word Meaning
“Something Subtle”
Alcohol
• Made from the fermentation of carbohydrates
• Fermented in every culture on earth at some point in time
• Animals (monkeys and birds) consume fermented fruit
Alcohol History
• Probably the world’s oldest anodyne
• Beers & wines since about 6400 BC
– Berries, apples and honey
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Early use for spiritual ceremonies
First brewery in Egypt 3700 BC
Only natural fermentation until 800-900 BC
Process of distillation in Arabia
Alcohol History
• 1500s - high alcohol
consumption problems (reign of
Henry VIII)
• 1608 - first laws against
drunkenness passed in England
• Gin discovered in 1650 by Dutch
physician
– From corn mash poured over
juniper berries
• 1700s - gin epidemic - led to
decline in British population
– tried to regulate use - led to riots
• Coffee & Tea & Methodist
movement led to decline in
alcohol use
Alcohol History
In the US
• Was condoned to point of drunkenness
• Used as anesthetic in Civil War
• 18th Amendment (1920)
– Illegal to produce alcoholic beverages
– Increased number of drinking establishments
– Increased strength of organized crime
• 21st repealed 18th in 1933 – Happy Days are Here
Again
Alcohol: Forms
• Naturally Fermented (max 14%)
– Beer
– Wine
– Mead
• Distilled (up to 95%)
– Whiskey (40%)
– Gin (40%)
– Vodka (40%)
– Tequila (40%)
– Everclear (95%)
• Proof
– British Army used “proof” as a measure of concentration
• Poor alcohol on gunpowder and tried to light it
Alcohol Prevalence in US
• 90% Ever drank
• 65% Current drinkers (gender and age
differences). 70% men and 60% women
• >40% Temporary problems
• 10-20% Abuse
• 5-15% Dependence (Lifetime)
• 5% point prevalence of dependence
YEARLY COSTS IN US
$300 Billion Overall
$71 Billion Direct Costs
22,000 Deaths + 2,000,000 Injuries
4,600,000 Damaged Vehicles
15% - 25% Healthcare Budget
90% of Liver Disease
72% of Pancreatitis
41% of Seizure Disorders
13% of Breast Cancers
Copyright Alcohol Medical Scholars Program
8
Closer to Home – Consequences in
College Students
• Death: 1,700 college students between the ages of 18 and 24 die each year from
alcohol-related unintentional injuries, including motor vehicle crashes .
• Injury: 599,000 students between the ages of 18 and 24 are unintentionally
injured under the influence of alcohol.
• Assault: More than 696,000 students between the ages of 18 and 24 are
assaulted by another student who has been drinking.
• Sexual Abuse: More than 97,000 students between the ages of 18 and 24 are
victims of alcohol-related sexual assault or date rape.
• Unsafe Sex: 400,000 students between the ages of 18 and 24 had unprotected
sex and more than 100,000 students between the ages of 18 and 24 report having
been too intoxicated to know if they consented to having sex.
Closer to Home – Consequences in
College Students
• Academic Problems: About 25 percent of college students report academic
consequences of their drinking including missing class, falling behind, doing
poorly on exams or papers, and receiving lower grades overall.
• Health Problems/Suicide Attempts: More than 150,000 students develop an
alcohol-related health problem and between 1.2 and 1.5 percent of students
indicate that they tried to commit suicide within the past year due to drinking or
drug use.
• Drunk Driving: 2.1 million students between the ages of 18 and 24 drove under
the influence of alcohol last year.
Vandalism: About 11 percent of college student drinkers report that they have
damaged property while under the influence of alcohol .
Route/Absorption
• Oral is by far the route of choice
• Rapidly absorbed, primarily from small intestine
– 20% stomach, 80% small intestine
• Peak blood alcohol concentration (BAC) depends on:
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Amount and alcohol concentration of beverage
Rate of drinking
Food consumption and composition
Gastric emptying and gastric metabolism
Hepatic (liver) first pass
Gender
Metabolism
• Metabolism
– 90-98% metabolized in liver
Alcohol
Alcohol
dehydrogenase
Acetaldehyde
Aldehyde
dehydrogenase
Acetate
• A constant 0.015% per hr metabolized
• Accumulation of acetaldehyde associated with headache,
gastritis, nausea, dizziness (hangover)
• Those of certain Asian descent lack a gene that codes for
ADH (50%)
Pharmacokinetics: Gender Differences
• Gender Differences
– in absorption
• Differences in gastric ADH activity
– in volume of distribution
• Differences in body composition and total body water (TBW)
– in metabolism
• Differences in liver volume, ADH activity?
• Effect of menstrual cycle on alcohol pharmacokinetics
• Effect of sex hormones (OC) on alcohol PK
Pharmacodynamics: CNS Effects
• Alcohol is a CNS depressant
• Apparent stimulatory effects result from depression of
inhibitory control mechanisms in the brain
• Characteristic response: euphoria, impaired thought
processes, decreased mechanical efficiency, sedation
Concentration-Effect Relationship
BAC [%]
Effects
0.02-0.03
Mood elevation. Slight muscle relaxation.
0.05-0.06
Relaxation and warmth. Increased reaction time. Decreased fine
muscle coordination.
0.08-0.09
Impaired balance, speech, vision, hearing, muscle coordination.
Euphoria.
0.14-0.15
Gross impairment of physical and mental control.
0.20-0.30
Severely intoxicated. Very little control of mind or body.
0.40-0.50
Unconscious. Deep coma. Death from respiratory depression
Alcohol as a Reinforcer
• Reinforcer: a substance whose pharmacological effects
drive the user to continue to use it
• Positive reinforcing effects:
– Gain pleasure
– Altered consciousness
– Conform to behavior of peers
• Negative reinforcing effects:
– Relief of stress and negative emotions
– Relief of withdrawal symptoms
Alcohol as a Reinforcer: Neural Systems
Activation of mesocorticolimbic system
Alcohol as a Reinforcer: Evidence
• Animal models of alcohol preference
– Selectively bred animal lines show innate differences in limbic
structures and neurotransmitter function
• Animal models of self-administration
– Animals trained to chronically self-administer alcohol show
differences in neurotransmitter levels in the mesolimbic system
– Animals will bar-press repeatedly for intra-cranial injections of
alcohol into the VTA (ventral tegmental area)
Reinforcement: Neurochemical systems
Enkephalin or
Dynorphin
Inhibitory Neuron
Glutamate
Excitatory Input
k Opioid
Receptors
Enkephalin
Inhibitory
Neuron
Dopamine Receptors
Dopamine Neuron
m Opioid
Receptors
REWARD
GABA-A Receptors
GABA Inhibitory Feedback
GABA
Inhibitory
Neuron
GABA
Neuron
Presynaptic
Opioid
Receptors
(m, d?)
Ventral Tegmental Area
(VTA)
Nucleus Accumbens
(NAc)
Neuropharmacology: Summary
Experience
euphoria/pleasure
anxiolysis/ataxia
sedation/amnesia
nausea
neuroadaptation
stress
withdrawal
Transmitter/Receptor
Dopamine, Opioids
 GABA
 GABA +  NMDA
5HT3
NMDA, 5HT
CRF
GABA, NMDA ( Ca, Mg)
Negative Health Effects
• Exacerbates ulcers
• Can cause cancer (head, neck, oral, GI)
• Liver disease
– Fatty Liver
– Fibrosis
– Cirrhosis
• CVD
• Accidents & Violence
Health Benefits
• Protective against CVD – Increases HDL
• Stress inoculation????
• Bone mineral density
• Men 3 or less/day
• Women 2 or less/day
• Never more than 5
Tolerance: Definitions
• Acute Tolerance: during the time-course of a single
exposure to drug
• Chronic Tolerance: over repeated use of drug
• Cross Tolerance: Tolerance to one drug leads to tolerance
to other drugs in a class
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Benzos
Barbs
General Anesthesia
GHB
Tolerance: Significance
• Why is tolerance to alcohol important?
– One of the determinants of increased alcohol consumption
• maintains or aggravates alcohol dependence
• increases risk of organic complications of alcoholism
– Cross-tolerance to other depressant drugs
– Genetic determinants exist
– Low response predicts alcoholism
Withdrawal
• Tremors, sweating, anxiety, perspiration, headache,
nausea, vomiting
• As withdrawal continues, one can have grand mal
seizures
• DTs – Severe agitation, hallucinations, high fever,
delirium
• The most likely of all drug withdrawals to be fatal
Dependence
• DSM-IV Disorder
• It is the model for all other substance dependence
• Public Health Model
– Agent Factors
– Host Factors
– Environment
Agent Factors
• CNS Depressant
• Potentiates GABA, Dopamine, Endorphins. Inhibits
glutamate
• Produces stimulation, sedation, motor incoordination
• Withdrawal potential
• Toxic to body/brain tissues
• Direct Effects
– GI/Liver
– Heart
– Brain
Host Factors
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Genetic Susceptibility
Males > Females
Age – College years
Personality/Psychopathology
Environmental Factors
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Models
Access
Policy
Peers
Media
Social Norms
Ultimately
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Use – Most people who drink
Misuse – College and/or drinking to cope
Abuse – Continued misuse
Dependence – Small percent - BIG TROUBLE
Be Careful If
• Family history
• Depression Anxiety ADHD
• If you can hold your liquor