www.mghcme.org

The Neuroscience of Addiction: A mini-review

Jim Morrill, MD, PhD MGH Charlestown HealthCare Center

Massachusetts General Hospital

www.mghcme.org

Disclosures

Neither I nor my spouse/partner has a relevant financial relationship with a commercial interest

to disclose.

www.mghcme.org

Why review addiction neurobiology?

1) To better understand the complex relationship between addiction and free choice in our patients

2) To understand (and innovate) effective treatments

3) To continue changing the culture– toward clinical and scientific optimism!

www.mghcme.org

Impaired Cognition and

Control

Drug Use

Choice

Drug-related Morbidity

Neurobiological Changes

Hijacked “Salience” Detection

Medical

Substance Use Disorder Psychosocial

Physiologic Tolerance and

Withdrawal Genetic

“Loading”

Environment

Risk and Protective

Factors

Framework for addiction

www.mghcme.org

Impaired Cognition and

Control

Drug Use

Choice

Drug-related Morbidity

Neurobiological Changes

Hijacked “Salience” Detection

Medical

Substance Use Disorder Psychosocial

Physiologic Tolerance and

Withdrawal Genetic

“Loading”

Environment

Risk and Protective

Factors

Framework for recovery

www.mghcme.org

Anatomy of the “salience” (wanting) pathway

http://medicalterms.info/anatomy/Basal-Nuclei/

Human brain, midline view

Head of caudate nucleus

Brain showing corpus striatum

Tail of caudate nucleus

Amygdaloid nucleus

Putamen

Thalamus

Globus pallidus

Biological Psychology, Sinauer Associates, 2010

www.mghcme.org

From Hyman and Malenka

(2001) Nat Rev: Neurosci 2:

695.

Prefrontal cortex

Nucleus accumbens Ventral

tegmental area

Human Brain

Rat Brain

Cortex

Nucleus accumbens Ventral

tegmental area

Anatomy of the “salience” (wanting) pathway

www.mghcme.org

• Striatal “medium spiny neurons”

receive wide input from the

cortex and limbic system

• These neurons give output to

the “motive” centers of the basal

ganglia (the “ancient” brain

which drives motor activation)

• They integrate information into a

neural decision to allow or inhibit

action

Cellular basis of memory for addiction. Eric J. Nestler, MD, PhD. Dialogues Clin Neurosci. 2013;15(4):431-443.

http://www.dialogues-cns.com/?post_type=publication&p=34119

The ventral striatum may be the seat of decisions about salience

Medium Spiny Neurons

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The brain reward circuitry in mood disorders. Scott J. Russo & Eric J. Nestler. Nature Reviews Neuroscience 14, 609–625 (2013)

doi:10.1038/nrn3381. http://www.nature.com/nrn/journal/v14/n9/abs/nrn3381.html

Rat Brain

The ventral striatum may be the seat of decisions about salience

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• The function of ventral striatal neurons is modulated by dopamine supplied by midbrain neurons

• Dopamine provides a salience signal to highlight survival-relevant natural stimuli

• In rats, the behavior-shaping properties of addictive drugs depends on dopamine signaling in this brain region.

The ventral striatum may be the seat of decisions about salience

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Natural stimuli evoke controlled dopamine signals

Dopamine secretion in

the nucleus accumbens

after a food stimulus

From Di Chiara et al. (1999) Eur J Pharmacol 375: 13. Shutterstock stock photo

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Addictive drugs evoke exaggerated dopamine signals

Response to amphetamine Response to cocaine

Fro

m D

i Ch

iara

an

d Im

per

ato

(1

98

8)

PN

AS

85

: 52

74

.

Dopamine vs. control dialysate

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Why do addictive drugs become more compelling than natural stimuli?

Processing

Context

Natural Stimulus

Dopamine Signaling

Shaping of Behavior

DRUG

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Repetitive Dopamine input to striatal neurons can evoke long lasting modifications of their synaptic connections through changes in gene expression.

From Chao and Nestler (2004) Annu Rev Med 55: 113.

Changes in neuronal structure and function

Changes in neuron communication Changes in neuron structure

From Robinson and Kolb (1999) Eur J Neurosci 11: 1598. From Nicola et al. (1996) J Neurosci 16: 1591.

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Persistence of addiction may depend on very long-lasting molecular signals

FOS-related antigens (FRAs),

such as “ΔFosB”: • Very long-lasting proteins induced

inside neurons by exposure to

dopamine

• Last for weeks to months, and

correlate with changes in neuron

structure and function

• When activated in the neurons of

transgenic mice, these proteins

can “transplant” cocaine-addicted

behavior into unexposed mice

(Kelz et al., 1999)

From Nestler (2001) Nature Rev: Neurosci 2: 119.

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Epigenetics and molecular memory in addiction

From Nestler (2013) Dialogues in Clinical Neuroscience 15: 431.

DNA

Modifiers

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Epigenetic changes and synergistic effects of nicotine and cocaine

Summary slide used with

persmission from Dr. Susan

Weiss, NIDA.

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Addictive substances activate the human salience (wanting) pathway

Mapping the dynamic response to an IV cocaine infusion with fMRI

From Breiter et al. (1997) Neuron 19: 591.

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Fro

m B

reiter

et al. (

1997)

Neuro

n 1

9: 591.

Addictive substances activate the human salience (wanting) pathway

From Breiter et al. (1997) Neuron 19: 591.

www.mghcme.org

From Breiter et al. (1997) Neuron 19: 591.

KEY: AC and PC = ant, post cingulate; Cau = caudate; Put = putamen;

Thal = thalamus; Hip = hippocampus; Pahip = parahippocampus;

BF = basal forebrain; VT = ventral tegmentum; NAc = nucleus accumbens; Amy = amygdala.

Addictive substances activate the human salience (wanting) pathway

www.mghcme.org

Impaired Cognition and

Control

Drug Use

Choice

Drug-related Morbidity

Neurobiological Changes

Hijacked “Salience” Detection

Medical

Substance Use Disorder Psychosocial

Physiologic Tolerance and

Withdrawal Genetic

“Loading”

Environment

Risk and Protective

Factors

Framework for Addiction

www.mghcme.org From NIDA slide set (www.nida.gov)

INHIBITORY

CONTROL

HABIT

FORMATION

REWARD

SALIENCE

MOTIVATION

DRIVE

MEMORY/

LEARNING

From NIDA slide set www.nida.gov

Multiple neural systems are now implicated in addiction

www.mghcme.org

• PET scans done in control subjects and chronic cocaine users.

• A chronic decrease in the density of Dopamine (D2) receptors (a) correlates with a decrease in regional brain metabolism in the orbitofrontal cortex (b).

• Suggests structural change / “damage” to key cortical structures involved in motivation and inhibitor control.

From Volkow and Li (2004) Nat

Rev Neurosci 5: 963.

Imaging studies show frontal cortex changes in cocaine addicts

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Prefrontal cortex functions that may be damaged by addiction:

• Motivation and task persistence

• Behavioral control

• Emotional regulation

• Self-awareness and insight

• Flexible attention and memory

The “IRISA” syndrome (Impaired Response Inhibition and Salience Attribution)

www.mghcme.org

From Goldstein and

Volkow (2011) Nat

Rev Neurosci 12:

652.

The “IRISA” syndrome (Impaired Response Inhibition and Salience Attribution)

www.mghcme.org

From: Koob and Volkow (2010) Neuropsychopharmacol Rev 35: 217.

A “grand unified theory” of addiction: roles of three brain circuits

www.mghcme.org

Impaired Cognition and

Control

Drug Use

Choice

Drug-related Morbidity

Neurobiological Changes

Hijacked “Salience” Detection

Medical

Substance Use Disorder Psychosocial

Physiologic Tolerance and

Withdrawal Genetic

“Loading”

Environment

Risk and Protective

Factors

Framework for recovery

www.mghcme.org

Impaired Cognition and

Control

Drug Use

Choice Neurobiological Changes

Hijacked “Salience” Detection

Physiologic Tolerance and

Withdrawal

Detoxification

Individual and group therapy:

• MET, CBT and DBT

• Contingency management

• Neurotransmitter antagonists

• Anti-epileptic drugs

• Cocaine / Nicotine vaccines?

• Transcription factor or epigenetic manipulations?

Opioid Maintenance

Therapy

(Agonist, Partial

agonist, Antagonist)

Framework for recovery

www.mghcme.org

Drug Use

Choice

Drug-related Morbidity Medical

Substance Use Disorder

Psychosocial

Genetic “Loading”

Environment

Risk and Protective

Factors Strategies for Reduction

of Negative

Consequences

Primary Medical and

Psychiatric Care

Prevention Strategies

“Wraparound” care:

• Social support

• Therapeutic communities

• Self-help

Framework for recovery

www.mghcme.org

THANK YOU! F

rom

: V

olk

ow

and L

i (2

004)

Nat R

ev N

euro

sci 5: 963.

Fro

m: V

olk

ow

et al. (

2001)

J N

euro

sci 21: 9414.

Questions?