David P. Friedman, Ph.D.David P. Friedman, Ph.D.Director Director

Addiction Studies Program for JournalistsAddiction Studies Program for Journalists

An Introduction to the An Introduction to the Neurobiology of AddictionNeurobiology of Addiction

What We Have to DoWhat We Have to Do

• Review terminology• Develop an understanding of the

key behaviors related to addiction • Explore the biological basis of

addiction

Different Ways of Knowing Different Ways of Knowing

Contribute to Social KnowledgeContribute to Social Knowledge

Cultural/Historical

Public Attitudes Public Attitudes & Social Policy& Social Policy

Scientific/DiscoveryPolitical

Scientific Knowledge Scientific Knowledge Requires Strict Rules of Requires Strict Rules of

EvidenceEvidence

““The goal of science is The goal of science is not to open the door to not to open the door to everlasting wisdom, but everlasting wisdom, but

to set a limit on to set a limit on everlasting ignorance” everlasting ignorance”

Adapted from

Galileo in Galileo by Bertolt Brecht

A Collection of A Collection of Anecdotes Is Not Anecdotes Is Not

EvidenceEvidence

What Should We Do With What Should We Do With Drug Addicts?Drug Addicts?

Perspective

Drug addiction is a moral

failing

OutcomesJail

Treatment

Drug addiction Drug addiction is a brain is a brain disorderdisorder

The Meanings of Words Shift As The Meanings of Words Shift As They Are Used by Different They Are Used by Different

GroupsGroups

• Drug Use• Drug Abuse • Drug Addiction• Drug Dependence• Craving

What Are Drugs of What Are Drugs of Abuse? Abuse?

• Stimulants• Depressants• Hallucinogens

• Opiates• Club drugs• Inhalants

• Steroids

• Tobacco?

Stimulants Stimulants

• Cocaine– crack

• Methamphetamine• Ritalin

(methylphenidate)• MDMA• Caffeine • Nicotine

• Energize• Increase feelings

of well-being• Euphoria

• Anxiety• Paranoia• Seizures

DepressantsDepressants

• Alcohol• Sedatives and

tranquilizers– Valium – Xanax– Barbiturates

• Opiates• GHB• Rohypnol• Marijuana

• Euphoria• Reduced anxiety• Lowered inhibitions• Drowsiness

• Loss of coordination• Confusion• Loss of memory• Coma

HallucinogensHallucinogens

• LSD• Mescaline• Peyote• MDMA• Marijuana

• Distortion of reality

• Sensory illusions• Enhanced

emotions

• Panic • Exacerbate

underlying psycho-pathology

OpiatesOpiates

• Heroin• Morphine• Oxycontin

• Euphoria• Feelings of well being• Reduced anxiety• Pain relief

• Nausea• Confusion• Slowed breathing

Club DrugsClub Drugs

• Ecstasy• GHB• Rohypnol• Ketamine/PCP

InhalantsInhalants

• Glue• Paint thinner• Nitrous oxide• poppers

Anabolic Steroids Anabolic Steroids

• Testosterone-like

Drug Use

A voluntary behavior May be socially condoned Does not necessarily have

adverse consequences

Why People Use Drugs:

Drugs produce pleasure euphoria/reward

Drugs relieve anxiety Drugs produce novelty

Drug Abuse

• A voluntary behavior

• Drug taking that deviates from approved social patterns

— approved patterns vary for different drugs, times, and places— To many, the use of any illegal drug is drug abuse

• Does not necessarily have adverse consequences

• But, all drug addicts pass through a period of drug abuse

Drug Addiction:A Brain Disorder

• Loss of control of drug-taking behavior−Overwhelming compulsion to take drugs

−Craving when drugs not available

•Addicts are: −Tolerant

− physically dependent

− psychologically dependent

• A chronic, relapsing disorder

− Relapse can occur long after drugs are

gone from the body

What Does Loss of Control What Does Loss of Control Mean? Mean?

• Can’t control when drugs are used• Can’t control how much drug is

used– One drink leads to drinking to

intoxication• Use drugs in the face of adverse

consequences– Medical– Social– legal

What About Free Will?What About Free Will?

• Free will is impaired in addicts– The ability to chose other behaviors over drug

use is especially diminished– But it’s not completely absent

• It’s necessary for recovery to occur• Because addicts are self-destructive,

perhaps drugs alter function of brain structures central for survival

The Brain and BehaviorThe Brain and Behavior

• The brain controls our behavior• The working of the brain is the

source of our thoughts and feelings

– i.e., our mind

• Brain Damage alters thoughts, feelings, and behavior

Many Common Diseases Are Many Common Diseases Are Chronic Relapsing Disorders Chronic Relapsing Disorders

• Hypertension• Adult Onset Diabetes• Atherosclerosis

– Begin with voluntary behaviors– Result in biological changes– Medications can be useful treatments– Require lifestyle changes

Key Questions About Key Questions About AddictionAddiction

• What parts of the brain are engaged when people use drugs?

• How does an addict’s brain differ from a normal brain?– What changes in the brain when a drug

abuser becomes a drug addict?

• Are these changes enduring?

Drug Actions Can Be Drug Actions Can Be StraightforwardStraightforward

Drug Drug Drug Drug Organ Organ Organ Organ Drug Drug EffectEffect Drug Drug EffectEffect

Acute EffectsLong- Term Effects

Acute EffectsAcute Effects

• Intoxication– Euphoria– Feelings of well being

• Sedation– reduce anxiety

• Hallucinogenic effects• Activation• Toxicity

Long-term EffectsLong-term Effects(Neuroadaptations)(Neuroadaptations)

• Tolerance• Physical Dependence

Homeostasis Helps to Homeostasis Helps to Explain How the Body Explain How the Body Responds to Drugs Responds to Drugs

• Physiological processes typically have a set point– Body temperature is 98.6o

• Disturbances that push the body away from the set point induce responses to return it to the set point

0

1

2

3

4

1st Use 2nd Week 4th Week 2 Months

Tolerance:Tolerance:More is LessMore is Less

Physical Dependence

Altered physiological state produced by

repeated drug administration Removal of drug leads to withdrawal Not necessarily pathological Can maintain addiction

No Physical No Physical DependenceDependence

Jamie Sale and David Pelletier

Physical DependencePhysical Dependence

Physical Dependence Is Physical Dependence Is Purely BiologicalPurely Biological

• Nose Spray• Steroids for inflammation• Anti-seizure medicines

• Blood pressure medicines

Develops during appropriate medical useof a variety of drugs

Drugs Differ In Their Ability to Produce Physical Dependence

Drug Physical Dependence

Alcohol +++Barbiturates +++Cocaine +LSD - Marijuana + Methamphetamine +Nicotine ++ Opiates +++PCP +Tranquilizers ++

Withdrawal

• Behavioral and physiological signs produced when a physically dependent person stops taking drugs

• Withdrawal signs vary across drug classes

Symptoms are often the opposite of a drug’s

effects

• Craving is a symptom produced by

a brain in withdrawal

Behavioral Contingencies Behavioral Contingencies Modify The Actions of Modify The Actions of

Addictive DrugsAddictive Drugs

DrugsDrugs BrainBrain

Behavioral Behavioral

ContingenciesContingencies

Acute Effects

Long- Term Effects(Neuro-

Adaptation)

Behaviorally-modified Effect

Drug Drug EffectEffect

Drug Drug EffectEffect

Effects of Cocaine on Effects of Cocaine on Dopamine Levels in the Dopamine Levels in the

BrainBrain

0

50

100

150

200

250

300

Cocaine

YokedCocaine

Yoked Saline

DOPAMINE

Cocaine Injection

Pain Patients Don’t Get Pain Patients Don’t Get AddictedAddicted

• They experience the acute effects• They undergo the neuroadaptations

• Their behavioral contingencies are different So what they learn is different

BUT

Psychological Dependence

When drug-taking becomes central to life

- replace other activities When a person considers drug-taking to be necessary for continued well being

Drugs Differ In Their Ability to Produce Psychological Dependence

Drug Psychological Dependence

Alcohol +++Barbiturates ++ Cocaine +++ LSD +/- Marijuana +Methamphetamine +++ Nicotine ++ Opiates +++

PCP +/- Tranquilizers +

Addiction Requires Interaction of Addiction Requires Interaction of the Drug With Specific Behaviorsthe Drug With Specific Behaviors

The combination of experience and directdrug effects is needed for addiction

DrugsDrugs Brain Brain

Behavioral Behavioral ContingenciesContingencies

Acute Effects

Neuroadaptations

PsychologicalDependence& Learning

Drug Drug EffectEffect

Drug Drug EffectEffect

Drug Addiction Is Drug Addiction Is LearnedLearned

• Explicit Memory – consciously recalled memories

• Implicit Memory– operant conditioning– classical conditioning

The Things We Need to The Things We Need to Survive Are RewardingSurvive Are Rewarding

We Learn to Repeat Behaviors We Learn to Repeat Behaviors That Produce RewardThat Produce Reward

Behaviors Can Be Reinforced Behaviors Can Be Reinforced by Activating Specific Brain by Activating Specific Brain

CircuitsCircuits

Drugs Also Activate the Brain Drugs Also Activate the Brain Reward System DirectlyReward System Directly

Animal Brains Are Good Animal Brains Are Good Models for Human Models for Human

BrainsBrains

The Brain and Behavior: Operant Conditioning

• Any behavior that is reinforced (rewarded) tends to be

repeated

•How does that happen?

Localization of FunctionLocalization of FunctionDifferent parts of the brain are devoted to

different functions

Judgment

Reward

A Pathway for RewardA Pathway for RewardPrefrontal cortex

Nucleusaccumbens

Ventral tegmental area

A Pathway for RewardA Pathway for Reward

Dopamine: a major neurotransmitterDopamine: a major neurotransmitter

Communications Between Communications Between Neurons Carries Out The Work of Neurons Carries Out The Work of

The BrainThe Brain

Synaptic transmission: Communication between

neuronsChemicalElectrical Electrical

©1998 GGN & Savantes© 1998 GGN & Savantes

Synapse

All Drugs of Abuse Work All Drugs of Abuse Work by Altering Synaptic by Altering Synaptic

TransmissionTransmission

Dopamine Neurotransmission

00100100200200300300400400500500600600700700800800900900

1000100011001100

00 11 22 33 44 5 hr5 hrTime After AmphetamineTime After Amphetamine

% o

f B

as

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Re

lea

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% o

f B

as

al

Re

lea

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AMPHETAMINEAMPHETAMINE

0

50

100

150

200200

0 60 120 180Time (min)

% o

f B

asal

Re

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Di Chiara et al.

Food

Long-term Cocaine Use Long-term Cocaine Use Alters the Dopamine System in Alters the Dopamine System in

the Nucleus Accumbensthe Nucleus Accumbens

Nucleus Accumbens

D2 Dopamine Receptors Dopamine Transporter

Control Cocaine

Cocaine Causes Enduring Cocaine Causes Enduring Changes in the Density of Changes in the Density of

Dopamine ReceptorsDopamine Receptors

[18F] FCP-labeled Dopamine D2 Receptors

Cocaine Naive

227 Days Abstinence

3 DaysAbstinence

Activation of the Brain Reward Pathway

Teaches us to repeat the behavior that activated it - i.e., it’s reinforcing

Release of the neurotransmitter dopaminedopamine is an essential step

Classical ConditioningClassical Conditioning

• Association between two stimuli

• Learned by repetition

• Long lasting

• Very difficult to extinguish because of

extensive over- learning

Genetics of Addiction Genetics of Addiction

• There are genetic risk factors for addiction

• Addiction changes the way that genes express themselves

Addiction Is a Complex Disease Addiction Is a Complex Disease With Genetic & Environmental With Genetic & Environmental

ComponentsComponents• Environmental factors:

– Socioeconomic status, family, peer culture, education, occupation, individual experiences, drug exp

• Genetic factors– Genetic predispositions

that underlie physiological response to drug

How Do We Know How Do We Know Genetics Are Important in Genetics Are Important in

Addiction? Addiction? First Line of evidence:

It runs in Families

Separating Nature from Separating Nature from NurtureNurture

• If genetics plays an important role, then:

– Twin studies: Identical twins will be more similar in their drug use behaviors than fraternal twins

– Adoption studies: Genetically related individuals raised in different environments will show similarities in drug use behaviors

©1972 The Estate of Diane Arbus

Genetic Factors Account For Genetic Factors Account For 50–80% Of The Risk For Addiction50–80% Of The Risk For Addiction

• Variability among drugs

• Gender variability

• “Heritability”– Risk for addiction

involves many factors

NIDA Notes, Vol. 15 No. 2 (2000)

Genetic Basis for Genetic Basis for AddictionAddiction

World Health Organization, 2004

To date: 15 loci on eight human

chromosomes thought to harbor

susceptibility genes for substances of

abuse

No proven correlations

“Candidate genes”

What Aspects of Addiction What Aspects of Addiction Might Be Genetically Might Be Genetically

ModifiedModified• Response to drug• Rick of persistent use• Becoming dependent• Usage per day• Ability to quit

Aldehyde Dehydrogenase Aldehyde Dehydrogenase (ALDH2)(ALDH2)

• Enzyme involved in alcohol metabolism

• Variants of ALDH2 affect sensitivity to alcohol– Variant1: Very active, found in most ethnic populations– Variant2: Inactive or low activity

• “Alcohol flushing response” & increased hangover symptoms• Protective: reduced occurrence of alcoholism• Common in some Asian populations

Addiction is a Disease ThatStarts in Childhood & Adolescence

NIAAA National Epidemiologic Survey on Alcohol NIAAA National Epidemiologic Survey on Alcohol

and Related Conditions, 2003and Related Conditions, 2003

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5 10 15 18 25 30 35 40 45 50 55 60 65 70

Age at 1st diagnosis of cannabis use disorder

Brain areas where volumes are smaller in adolescents than young adults.

Transition to AddictionTransition to Addiction

• Accompanied by conscious and unconscious learned changes about the meaning of drugs to the life of the user

• Accompanied by changes in the regulation of the dopamine system

• Accompanied by other brain changes

A Path to AddictionA Path to Addiction

Drug Abuse

Tolerance

Escalate Dose

Physical Dependence

Use Drugs to Solve Problems

Psychological Dependence

Brain Changes

Addiction

Operant ConditioningClassical Conditioning

Withdrawal (Craving)