Post on 16-Jul-2020
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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.
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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!
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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
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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
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• 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.
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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
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• 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)
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From Goldstein and
Volkow (2011) Nat
Rev Neurosci 12:
652.
The “IRISA” syndrome (Impaired Response Inhibition and Salience Attribution)
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From: Koob and Volkow (2010) Neuropsychopharmacol Rev 35: 217.
A “grand unified theory” of addiction: roles of three brain circuits
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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
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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?