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Neurobiology of Addiction

Dr. Leo Kadehjian

Palo Alto, California

Molecules

Neurons / Cells

Neural Systems

Physiology / Behavior

Geneticsand

Environment

Initiation AbuseDependenceAddiction

Reinforcement

Genetics

Environment

ToleranceSensitization

Withdrawal

Relapse

Craving

Terminology

Reward

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RewardReinforcement

ToleranceSensitizationDependence

Withdrawal

CravingStress

RelapseNestler and Aghajanian, 1997

! DA

! " Receptor regulation! " 2nd messengers! " Gene expression

! NA, ! Glu, " DA, " 5-HT! Stress factors

Synaptic adaptations ?! Stress factors

Stimulants

Caffeine

Nicotine

CocaineEphedrine

Khat

Amphetamines

MDMA

Opiates

Morphine

Codeine

(Heroin)

(Oxy–, Hydro–)

Methadone, LAAMFentanyls

Meperidine

Sedatives

EthanolBenzodiazepines

Barbiturates

Methaqualone

Hallucinogens

MescalinePsilocybin

(LSD)PCP

Marijuana

Mother Nature vs. Chemists

Neurotransmitters

Amino acids Monoamines Peptides

Glutamate

GABA

Noradrenaline

Dopamine

Serotonin

Acetylcholine

Enkephalins

Substance P

Insulin

Aspartate

Glycine

Histamine

Adrenaline

Many others

100,000 1,000 1::

Oxytocin

Vasopressin

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MDMA, “Ecstasy”MethamphetamineAmphetamine

NoradrenalineDopamine

NH2

OH

OH

NH2

OH

OH

HO

NH2 HN

HN

OO

Dopamine

Role in reward circuits (1954)

Nicotine, alcohol, marijuanacocaine, morphine, amphetamines

Parkinson’s disease (deficit)

Schizophrenia (excess)

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“In this framework, the addicted person’s PFC can no longereven categorize decision problems correctly, much less regaincontrol over the choices that their nervous systems deemvaluable.”

P. Read Montague et al., 2004

Dopamine and Behavioral Control

“In addition, dopamine effects in the PFC may impair theability of the addicted person to suppress prepotent drug-seeking behavior.”

“Because these drugs directly engage dopamine-mediatedreinforcement learning signals, they generate a feedback loopthat reinforces behavior leading to drug consumption,establishing a vicious cycle of action and learning that explainsthe compulsive nature of drug addiction.”

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HN

HO

l–Ephedrine

HN

HO

d–Pseudoephedrine

NH2

OCH3

OCH3

H3CO

MescalineDopamine

NH2

OH

OH

Noradrenaline

NH2

OH

OH

HO

d–Amphetamine

NH2

d–Methamphetamine

HN

MDMA, “Ecstasy”

HN

OO

NH2

HO

Phenylpropanolamine

HN

CF3

d–Fenfluramine

NH2

Phentermine

NH2

OCH3

l–Cathinone ,“Khat”

HN

OCH3

CH3

Methcathinone, “Cat”

HN

HO

OH

l–Phenylephrine

HN

Propylhexedrine

N

l–Selegiline, Deprenyl

HN

CH3O

O

Ritalin (Methylphenidate)

Serotonin

Generally inhibitory

Role in aggression, violence, suicide,depression, alcoholism, cocaine use

Site of action for LSD, hallucinogens

Neurons damaged by MDMA, fenfluramine

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R

R

R

NH

HO

NH2

NH

HO

N

NH

H2O3PO

N

NH

NN

O

HO

F3C

HN

Serotonin Bufotenine Psi locybin

ProzacLSD

5

HO

N

HO

O

H3CO

N

HO

O

H3CO

N

O

O

OH

H3CO

N

O

O

HO

N

HO

O

HO

N

O

O

OH

HO

N

O

O

H3CO

N

HO

O

Hydromorphone

Codeine Oxycodone

Morphine

Hydrocodone

Oxymorphone Dihydromorphine

Dihydrocodeine

(Dilaudid) (Numorphan)

(Vicodin, Lortab) (Percodan, OxyContin) (Synalgos)

HO

N

H3CO

O

HO

Buprenorphine

HO

O

HO

N

Morphine

HO

N

O

O

OH

Naltrexone

ReVia, Vivitrol

N

Methadone

O

Treatment

Vaccines ?

Methadone, LAAM

GHB ?

Antagonists

Disulfiram

Naloxone

Agonists

Enzymes ?

Antibodies ?

Buprenorphine

Naltrexone

Anti-craving

Acamprosate

!-vinyl-GABA ?

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Diabetes

Hypertension

Asthma

Drug Abuse

Heritability

Treatment

Compliance

Relapse

Rates

Drug Dependence, A Chronic Medical Illness

A. McLellan et al., 2000

.8 Type II

.3–.55 Type I

.25–.5

.36–.7

.34 heroin (m)

.55 alcohol (m)

.52 marijuana (f)

.61 nicotine (m,f)

<60% Type I

<40%

<40%

40–60%

30–50% Type I

50–70%

50–70%

40–60%

ICR 25% C57 50% C57 75% C57 C570

20

40

60

80

100Genetics / Cocaine Addiction

E. Ruiz-Durántez et al., 2006Genetic composition

% “ addicted”

Global Speed Memory Verbal Learning Recall Abstract Motor0

10

20

30

40

50

60

70

Extensive metabolizersIntermediate/Poor metabolizers

M. Cherner et al., 2010

CYP2D6 and Methamphetamine Impairments% Impaired

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Contro

lEtO

H

Red wine

Meth

Meth +

EtOH

Meth +

Red wine

0

200

400

600

800

1000

1200

1400 Dopamine (ng/100 mg tissue)

S. Ali and S. Bondy, 2010

Red Wine Protects Against Methamphetamine Toxicity

Asn40 Asp400%

10%20%30%40%50%60%70%80%90%

100%

PlaceboNaltrexone

µ-Opioid Receptor Genotype and Naltrexone Response

R. Anton et al., 2008

% With good clinical outcome

Adverse childhood environment

MAO-A short vs. long allelles

5HTTLPR * adverse childhood environment

No vs. history of substance abuse

No vs. history of personality disorder

A. Reif et al., 2007

Odds ratio for violence

4.1 (2.6–6.5)

2.3 (1.1–4.7)

0.2 (0.1–0.4)

0.5 (0.2–1.0)

0.9 (0.4–1.9)

Serotonin, Genes, Adverse Childhood Environment, and Violence

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J

J

H

H

F

F

0

10

20

30

40

50

60

70

0

10

20

30

40

50

60

70

LLSL

SS

SS+SL

Serotonin Transporter Gene, Childhood Environment, and Violence

Adverse childhoodenvironment

No adverse childhoodenvironment

A. Reif et al., 2007

% violence

Epigenetics

Genes, DNA RNA Proteins

Histone methylationHistone acetylation

Inactive geneActive gene

Epigenetics: Histone methylation, acetylation DNA methylation microRNAs transposons, retrotransposons: “jumping genes”

ReceptorsCell functionBehaviors

Stress, bullying

Maternal nurturing

Transient toweeks/months

Methylation, inactive, molecular “scar”,depression< glucocorticoid receptor, increased stress response

Impulsivity Compulsivity

Positive reinforcementdrives behavior

Unplanned reactionswithout regard tonegative consequences

Negative reinforcementdrives behavior

Continued use despiteadverse consequences

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Impulsivity

Frontal cortexdysfunction

Chronic drug use

Addiction

Prefrontal Cortex Circuits in Addiction

Dorsolateral prefrontal cortex

Orbitofrontal cortex

Anterior cingulate cortex

Impaired inhibition control, impaired decisionmaking

Goal identification, selection, reward processing, guidingbehaviors

Decisionmaking, impulsivity, behavioral disinhibition,drug seeking despite adverse consequences, compulsiverepetitive behaviors

Assessment of consequences, error and conflict detection

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J. Feil et al., 2010

Does neuroscience undermine the role of personalresponsibility for development of and recovery from addiction?

n = 231 NAADAC counselors from 44 states

Development: Biofactors even more influential

Recovery: Personal responsibility even more influential (!?)

Examined e!ect of exposure to neuroscience on counselor views

For those with more exposure to neuroscience:

T. Steenbergh et al., 2012

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