Neuroscience of Addiction
Part 2
Study Workshop: Overcoming
Barriers to Engagement with
Difficult and Different Clients
Neuroscience of Addiction Day 2
1
Review
Neuroscience of Addiction Day 2
2
Addiction is Complex
•
•
•
•
Psychological
Social
Spiritual
Biological
Neuroscience of Addiction Day 2
3
Addiction
“Addiction at its core is a biological
process”
Biological Agent
Biological Substrate
Nestler and Aghajanian, 1997
Neuroscience of Addiction Day 2
4
Biological Agents
• Drugs, which bind to specific receptors
• Directly or indirectly increase dopamine
transmission
Neuroscience of Addiction Day 2
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Biological Target
• Brain cells in nucleus accumbens get
“rush” of dopamine
• Changes in cell after chronic exposure
– Decreased dopamine transmission
– Other structural and functional changes
Neuroscience of Addiction Day 2
6
Neuroscience of Addiction
•
•
•
•
Craving
Compulsion
Cognitive problems
Poor insight
Neuroscience of Addiction Day 2
7
Review of Workshop Goals
• Part 1 Neuroscience
– Review brain
– Reward circuit
– Changes from drug use
– Who gets addicted?
• Genetics
• Environment
Neuroscience of Addiction Day 2
8
Review of Workshop/ Goals
• Part 2 Applied Neuroscience
– Understanding craving
– Correlates of compulsion
– Cognitive aspects of drug use
– Emerging pharmacology for treatment of
addiction
Neuroscience of Addiction Day 2
9
Overall Goal
• Understanding the neuroscience of
addiction will allow you to treat your
clients’ behaviors in a new way
Neuroscience of Addiction Day 2
10
Other Housekeeping
• Breaks
• Lunch
• Evaluations
Neuroscience of Addiction Day 2
11
Review: Brain Circuits Involved in
Drug Addiction
PFC
CONTROL
ACG
OFC
SCC
MOTIVATION/
DRIVE
(saliency)
Hipp
NAc
c
REWARD
VP
Amyg
Neuroscience of Addiction Day 2
MEMORY/
LEARNING
12
Network of Circuits
•
•
•
•
Reward Pathway
Motivation/ Drive Pathway
Memory and Learning Pathway
Control
Neuroscience of Addiction Day 2
13
What do these Circuits have in
Common?
• All receive dopamine directly from
dopamine neurons
• Connected to each other through direct
or indirect neuronal projections
– glutamate transmission
– No current PET tracers
Neuroscience of Addiction Day 2
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Review: Key Structures in these
Circuits
•
•
•
•
Nucleus Accumbens
Amygdala
Forebrain/ Frontal Lobe
Ventral Tegmental Area
Neuroscience of Addiction Day 2
15
Part 2 Applied Neuroscience
– Understanding craving
– Correlates of compulsion
– Cognitive aspects of drug use
– Emerging pharmacology for treatment of
addiction
Neuroscience of Addiction Day 2
16
Craving
• “The most persistent and insidious clinical
component of addictive illness.”
• Dackis and O’Brien, 2005
Neuroscience of Addiction Day 2
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Addiction Cycle
Neuroscience of Addiction Day 2
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Understanding Craving
Neuroscience of Addiction Day 2
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Cue Induced Craving*
• Environmental cues can trigger cravings
• What examples have you seen or heard?
• Have you seen relapse following long
abstinence from cue induced craving?
Neuroscience of Addiction Day 2
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Responses to Cocaine Video
Neuroscience of Addiction Day 2
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Environmental Cues
Neuroscience of Addiction Day 2
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FIGURE 2
Activation
of Orbitofrontal Cortex
Neuroscience of Addiction Day 2
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Functional Imaging of Craving
• Drug related craving linked to
functional natural drives
– Sex
– Food
Neuroscience of Addiction Day 2
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Functional Neuroimaging and
Craving
• PET, fMRI
• Activation of amygdala and anterior
cingulate cortex
• Degree of cue activation correlated with
craving severity
• Degree of activation correlated with
likelihood of relapse
– Cocaine, alcohol, heroin, nicotine
Neuroscience of Addiction Day 2
25
Cues for Cocaine and
Normal Pleasures Activate
Brain Sites
• Cues for Cocaine
– Cocaine abusers may experience
a powerful urge to use when they
encounter environmental cues
associated with use
– Brain areas are activated when
watching cocaine- related videos
Childress, 1999
Neuroscience of Addiction Day 2
26
Persistent Effects of Drug
• As a result of intracellular changes, the
previously cocaine addicted brain has
persistently altered functioning (craving)
Neuroscience of Addiction Day 2
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Treatment Applications for Childress’
Cue-Induced Cocaine Craving Study
•
Implications for Treatment
– Understand the importance environmental
cues play in initiating the craving process
– Review program educational materials to
ensure that potential environmental cues for
drug use are eliminated
– Normalize cue and craving responses for
clients
– Teach clients how to “urge surf” and to
identify potential environmental cues
Neuroscience of Addiction Day 2
28
Functional Imaging of Craving
• Frontal activation also with:
– Cocaine addicted patients watching cue
video
– Normal subjects watching sexually explicit
video
– Normal subjects reporting hunger in
response to food cues
Neuroscience of Addiction Day 2
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“Expected Reward”: Craving
• Reward processed by dopamine
neurons going to nucleus accumbens
• Memory processed by amygdala and
hippocampus
• Expected reward for drugs far
outweighs other reinforcers/ rewards
• Resetting of reward thresholds?
• What can compete with drugs?
Neuroscience of Addiction Day 2
30
Memory and Craving
• Place, person or thing: other wise neutral
stimulus that can trigger craving
• Conditioned Learning
– Paired associations
– Nucleus accumbens/ amygdala
• Habit Learning
– Well learned sequences become automatic
– Caudate/ putamen (neighbors to Nucleus
accumbens, the “striatum”)
Neuroscience of Addiction Day 2
31
Applications*
• What do you need to look for in your
treatment materials (videos, handouts)?
• What do you need to listen for in your
group therapy sessions?
Neuroscience of Addiction Day 2
32
Sensitization*
• Small amounts of substance lead to high levels
of craving and relapse
– Have you seen this?
• Cross-sensitization Rats sensitized with 6 days
of amphetamine
• 7 days later become hyperactive after 1 minute of sugar
• Consume more sugar when allowed to drink it for an hour
» Avena and Hoebel, 2003
– Alcoholics relapsing after pain meds
• Other examples?
Neuroscience of Addiction Day 2
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Orbitofrontal Cortex
• Low activity during drug withdrawal
• Overactivity when craving
• Degree of activity proportional to intensity
of craving
Neuroscience of Addiction Day 2
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Orbitofrontal Cortex and Craving
Neuroscience of Addiction Day 2
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Long Term Frontal Brain Changes
in Cocaine Abusers
• Up to 3 months drug free
• Decreased frontal lobe metabolism in
cocaine abusers compared to controls
• “Clinically silent” brain dysfunction
– Craving?
– Decreased executive functioning?
» Volkow 1992
Neuroscience of Addiction Day 2
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Other Aspects of Craving
• Neuroadaptation
– Depletion of dopamine in the nucleus
accumbens
Neuroscience of Addiction Day 2
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Exercise*
• In groups of 3 or 4, write an essay test
question to test knowledge of content
on craving
Neuroscience of Addiction Day 2
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Part 2 Applied Neuroscience
– Understanding craving
– Correlates of compulsion
– Cognitive aspects of drug use
– Emerging pharmacology for treatment of
addiction
Neuroscience of Addiction Day 2
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Correlates of Compulsion*
• Weakened brain “braking” or inhibitory
mechanisms
• When else do humans pursue pleasure/
desire with a similar lack of rational
thought?
Neuroscience of Addiction Day 2
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Biology of “Drive”
• Natural drives: food, water, sex
• Romantic love may overlap with addiction
– Dopamine
– Dark side: depression, stalking, suicide
Neuroscience of Addiction Day 2
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Correlates of Compulsion:
Loss of control
• Hallmark of addiction
• Source of societal stigma
• Even when the pleasure is gone
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What’s the worst consequence
you have seen?*
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Compulsions and Hypofrontality
• Reduced baseline metabolism in frontal
lobe associated with addiction
• Same regions become hypermetabolic
during active craving
Neuroscience of Addiction Day 2
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Compulsions and Hypofrontality
• “Hypo” –less active as measured by
blood flow
• Frontal Lobes= executive functioning
– “Top down” decision making
– Risk/ reward assessment
– Impulse control
Neuroscience of Addiction Day 2
45
Compulsions and Hypofrontality
• Poor functioning of frontal lobes may
contribute to
– Poor impulse control
– Lack of resolve
– Poor decision making
– Impaired control even when someone
expresses desire to not do something
Neuroscience of Addiction Day 2
46
Effect of Cocaine on PFC Cells
• Changes in branching and the number
of spines
• Changers in synaptic connections
• Related to changes in decision-making
or judgment?
• Loss of self-directed behavior?
• Increase in automatic behavior?
Neuroscience of Addiction Day 2
47
Dopamine Receptors
• D2 receptor changes associated with
addiction in people and animals
• Chronic exposure to stimulants,
opioids or alcohol leads to decreased
dopamine activity
– Downregulation of D2 receptors
– Decreased sensitivity to everyday rewards
– Increase drug seeking due to reward
intensity?
Neuroscience of Addiction Day 2
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Decreased Sensitivity to Natural
Rewards
• Dopamine regulated reward centers fail to
activate in response to experimental
rewards (money)
– Opiate addicts
– Tobacco smokers
– Cocaine abusers
Neuroscience of Addiction Day 2
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Decreased Dopamine Function
• Correlates with dysfunction of prefrontal
regions
• Correlates with
– Poor judgment, impulse control
– Decreased response to natural rewards
Neuroscience of Addiction Day 2
50
Dopamine Transporter Loss After
Heavy Methamphetamine Use
(PET analysis)
Comparison Subject
METH Abuser
Neuroscience
Addiction 158(3),
Day 2 pp. 377-382, 2001.
Source: Volkow, N.D.
et al., Am J.ofPsychiatry,
51
FIGURE 5
Neuroscience of Addiction Day 2
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Phineus Gage: Posterboy for
Hypofrontality
• Vermont railroad construction
• Mild mannered and responsible
• Accident with tamping rod and dynamite
Neuroscience of Addiction Day 2
53
Phineus Gage*
Neuroscience of Addiction Day 2
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Phineus Gage
• After the accident: Personality Change
– Rude
– Sexually inappropriate
– Poor impulse control
Neuroscience of Addiction Day 2
55
Animal Models of Relapse
• In animals, the most potent stimulus for
relapse is a “free” (non contingent)
“priming” injection of the training drug
– Equivalents in detoxified addicts
Neuroscience of Addiction Day 2
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Drug-triggered relapse
• In animals, “cross-priming” from one class
to another has been widely demonstrated
– ie. priming with cocaine can lead to opiate
self administration and vice versa
– Stewart J: Reinstatement of heroin and cocaine self
administration in the rat by intracerebral application of
morphine in the ventral tegmental area Pharmacol
Biochem Behav 1984:20 917-923
Neuroscience of Addiction Day 2
57
Effect of Drug Use on Decision
Making
• Iowa Gambling Task
• Compare with patients with damaged
Ventromedial Prefrontal Cortex
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Correlates of Iowa Gambling task
• Oblivious to future positive or negative
consequences
• Guided by immediate prospects
– Bechara Nature Neuroscience 2005
Neuroscience of Addiction Day 2
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Iowa Gambling Task Experiments
Neuroscience of Addiction Day 2
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Cocaine Addiction and Iowa
Gambling Task
• 63% of addicts as impaired as brain
damaged patients (some variability)
• Impaired decision making
• Unable to learn from recent feedback
Neuroscience of Addiction Day 2
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Iowa gambling task
"Bad" decks
-£1500
+100
+200
+100
"Good" decks
+50
+25
-50
+25
+100
-1000
+500
+100
-50
+50
+25
+50
Normal subject
A
Bad
Decks
B
C
Good
Decks
D
0
10
20
30
40
50
60
Neuroscience of Addiction
Day 2
Trial number
70
80
90
100
62
Orbitofrontal lesion
A
Bad
Decks
B
C
Good
Decks
D
0
10
Neuroscience of Addiction Day 2
20
30
40
50
Trial number
60
70
80
90
100
63
Skin conductance response
Neuroscience of Addiction Day 2
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Impairments in Decision Making
• Alcohol, cannabis, cocaine, opioid,
methamphetamine
– Meth may be more harmful than others
– Some people will NOT have impaired
decision making
– More functional, less likely to “bottom out”
and enter treatment
Neuroscience of Addiction Day 2
65
Back to Stress
Neuroscience of Addiction Day 2
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The Stress Hormone Cycle
Hypothalamus
CRF
Stress Responses
Pituitary
Gland
ACTH
CRF:
Corticotropin
Releasing
Factor
Adrenal
Glands
CORTISOL
Kidneys
Neuroscience
of Addiction Day 2
67
Responses
Stress Reliably Reinstates Drug Seeking in
*
Rats
Cocaine-trained rats
Alcohol-trained rats
100
80
60
40
Inactive Lever
Active Lever
*
*
*
20
Responses
0
Saline Cocaine Footshock
Water Alcohol Footshock
Nicotine-trained rats
Heroin-trained rats *
100
80
60
40
*
*
*
20
0
Saline Nicotine Footshock
Saline Heroin Footshock
Neuroscience of 1996,
Addiction
From: Psychopharmacology,
1998,Day
19992 ; J. Neurosci. 1996
68
Another Look at Stress
Neuroscience of Addiction Day 2
69
Addiction Cycle
Neuroscience of Addiction Day 2
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Part 2 Applied Neuroscience
– Understanding craving
– Correlates of compulsion
– Cognitive aspects of drug use
– Emerging pharmacology for treatment of
addiction
Neuroscience of Addiction Day 2
71
Neurobiological Aspects of
Chronic Drug Use (Meth)
• Cognitive
• Psychiatric
• Motor
Neuroscience of Addiction Day 2
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Neurotoxicity Methamphetamine
• Brain changes resulting from prolonged
use of psychostimulants, such as
methamphetamine may be reflected in
compromised cognitive and motor
functioning
Neuroscience of Addiction Day 2
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Neurotoxicity Methamphetamine
Neuroscience of Addiction Day 2
74
•
•
•
•
•
Poor Motor & Memory Performance
33 year old male- 80 days post detox
Low Severity- Parkinson Disease
Transporter losses may not recover
Neuroscience of Addiction Day 2
Volkow, et al. 2001
75
MOTOR FUNCTION
• Slowed gait
•Impaired balance
• Impairment correlates with
damage to dopamine system
Neuroscience of Addiction Day 2
76
Psychiatric Effects of
Methamphetamine
Neuroscience of Addiction Day 2
77
Self-Reports of Criminal
Behavior
• Legal charges (assault and weapons)
– 47% “Violent Crime”
– Wright 2001
• Aggressive actions
– 43% of ER patients using exclusively
methamphetamine
– Compared: 20% of those with other drug
and alcohol-induced disorders
– Szuster 1990
Neuroscience of Addiction Day 2
78
Self Reports of “Anger
Problems” in Meth Users
– 62% of interviewees “problems with
aggression”
– Wright 2001
– 50% of patients in psych emergency room
: “Aggressive Ideation”
• Compare: 24% other drug and alcohol users
– Szuster 1990
– 43% entering outpatient program
– Zweben 2004
Neuroscience of Addiction Day 2
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Implication of Aggression in
Meth Users
• Experienced aggression may motivate
some for treatment
• Safety concerns
• Violence history
• Anger management integrated into
treatment programs
Neuroscience of Addiction Day 2
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Other Effects of Use Over Time
• Brain damage
• Long-lasting psychosis
• Thinking problems
Neuroscience of Addiction Day 2
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Animal Studies of Brain
Damage
• Repeated low doses or single high
dose methamphetamine in rats
– Nerve endings die off
– Nerve cells dies off
• Decreased brain chemicals (dopamine
and serotonin)
Neuroscience of Addiction Day 2
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Neuroscience of Addiction Day 2
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Effects of Damage to Dopamine
Receptors
• D2 receptor availability decreased
– Caudate and putamen
• Motor impaired
• Cognitive impaired
Neuroscience of Addiction Day 2
84
Amphetamine and Psychosis
• First reported three years after the first
clinical trial in 1935
• Paranoia, delusions of reference, vivid
hallucinations (esp. visual), formication
Neuroscience of Addiction Day 2
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Amphetamine and Psychosis
• Experimental induction of
amphetamine psychosis
– Non-users
• Abrupt onset of paranoia (Griffith, 1968)
– Amphetamine users
• Psychosis in all subjects after 1-90 hours of ad
lib use (Bell,1973)
• Psychosis in 3 of 4 subjects after 72 hours
(Angrist, 1970)
Neuroscience of Addiction Day 2
86
Methamphetamine and
Psychosis
• Variable course
– Some persistent psychosis
– Some recurrent psychosis
• With repeat use
– Smaller, single doses for some
– Low dose Haldol prevented psychosis in some
» Sato, 1986
• With significant stress
» Yui, 2001
Neuroscience of Addiction Day 2
87
Cognitive Deficits From
Methamphetamine Use
• Animal studies
• Human studies
• Sara Simon 2002, 2004
Neuroscience of Addiction Day 2
88
Cognitive Effects in Naïve
Adults
• Improved performance in reaction time,
coordination, vigilance
• Effects most consistent in fatigued
subjects
Neuroscience of Addiction Day 2
89
Abstinence and Cognitive
Changes in Users
• Baseline: meth users vs non-users
• Meth users vs. early abstinence
• Meth users vs. relapse
– Relapses between weeks 1 and 14 of
abstinence
– Relapses lasted between 1 and 14 days
» Simon 2004
Neuroscience of Addiction Day 2
90
Cognitive Tests*
• Manipulation of information and
perceptual speed
• Ability to ignore irrelevant information
• Executive Functioning
• What do you see clinically that
suggests cognitive problems?
Neuroscience of Addiction Day 2
91
Cognitive Tests Cont.**
•
•
•
•
Mental Flexibility
Logical abilities
Learning
Memory
Neuroscience of Addiction Day 2
92
Findings
• Meth users did worse than non-users
– Many of the deficits similar to those in
normal aging (episodic vs semantic
memory)
– Length of use did not seem to correspond
to performance
– Daily users significantly more impaired
• Daily users > 10 times a day did worst
» Simon 2000
Neuroscience of Addiction Day 2
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Neuroscience of Addiction Day 2
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Findings
• Active users of methamphetamine did
BETTER than newly abstinent subjects
– Recall of words and Trailmaking B
– Stroop Test
– Relapse group did worst
Neuroscience of Addiction Day 2
95
Stroop Test**
Neuroscience of Addiction Day 2
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Impact of Cognitive Changes
• Treatment providers can expect
cognitive problems to worsen, at least
during the first three months of
abstinence
• Treatment may require strategies to
compensate for cognitive problems
• Unclear if cognitive performance ever
returns to baseline
Neuroscience of Addiction Day 2
97
• Dopamine
transporters
decreased
• Correlates with
cognitive and
motor deficits
Neuroscience of Addiction Day 2
98
Effect of Dopamine transporter
decrease on performance
Neuroscience of Addiction Day 2
99
Impact of Cognitive
Changes
• Cognitive impairment related to
treatment drop out
• Neuropsychological testing may
help tailor treatment
Neuroscience of Addiction Day 2
100
Abstinence and the Brain
• Higher whole brain
metabolism even
after 11+ months
abstinence
– Inflammation?
Gliosis?
– Volkow, Am J
Psychiatry 2001
Neuroscience of Addiction Day 2
101
Recovery of Dopamine Transporters
• PET scan shows levels of dopamine transporters
• Lower levels of dopamine transporters were
associated with poorer performance on tests of
memory and motor skills
• Impairments in motor skills and memory
continued
Neuroscience of Addiction Day 2
102
•
Volkow, et al. 2001
Implications of Cognitive
Impairment*
Neuroscience of Addiction Day 2
103
Matrix Model
Obert, et al. 2002
• Impairment
– Word recognition
• Patient handouts
were created that
used primarily
pictures
• Family education
lectures were videotaped
Neuroscience of Addiction Day 2
104
Brain Imaging Studies Conclude:
• In drug addiction, the value of the drug
and drug related stimuli is enhanced at
the expense of other reinforcers
[natural rewards].
Neuroscience of Addiction Day 2
105
Brain Imaging Studies
Conclude
• This is a consequence of conditioned
learning and of the resetting of reward
thresholds as an adaptation to the high
levels of stimulation induced by drugs
of abuse.
» Volkow, Fowler, Wang 2003
Neuroscience of Addiction Day 2
106
And more conclusions form
imaging studies:
• During exposure to the drug (or related
cues) the memory of the expected
reward results in overactivation of the
reward and motivation circuits while
decreasing activity in the cognitive
control circuit.
• An inability to inhibit [no brakes] the
drive to seek and consume drugs.
Volkow, Fowler, Wang 2003
Neuroscience of Addiction Day 2
107
Brains…
Get Rewired
by Drug Use
Neuroscience of Addiction Day 2
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Summary
• Interactive circuits: craving, drive
memory, impulse control
• Choices among available alternatives
Neuroscience of Addiction Day 2
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Part 2 Applied Neuroscience
– Understanding craving
– Correlates of compulsion
– Cognitive aspects of drug use
– Emerging pharmacology for treatment of
addiction
Neuroscience of Addiction Day 2
110
Pharmacology of Addiction
• Pharmacologic Targets
– Euphoria
– Craving
– Responsivity to cues
– Impulse
– Denial
Neuroscience of Addiction Day 2
111
Pharmacology of Addiction
• Additional layer of understanding of the
neuroscience of addiction
Neuroscience of Addiction Day 2
112
Pharmacology of Addiction:
Blocking Euphoria*
• Each drug of abuse has a specific
receptor it needs to bind to for effect
• What happens if that receptor becomes
unavailable for binding?
Neuroscience of Addiction Day 2
113
Targets of Medication
• Methadone and Buprenorphine
Activate opioid receptors
• Naloxone
Block opioid receptors
• Nicotine gum/patch
Activate nicotinic receptors
Neuroscience of Addiction Day 2
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Pharmacologic treatment
• Methadone
– Slow release synthetic that eliminates w/d. Relieves
craving
– Some treatment centers have majority Rx opioid
patients
• Buprenorphine
– Mixed agonist/ antagonist
• Naltrexone
– Long acting
– Highly motivated patients
– Support abstinence by blocking drug effects
• Naloxone
– Treat overdoses
Neuroscience of Addiction Day 2
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Blocking Euphoria with
Naltrexone
An opiate receptor antagonist
Blocks opiates access to receptor
Heroin, methadone, Oxycontin: no where
to bind
Blocks drug effect
Neuroscience of Addiction Day 2
116
Naltrexone: Opioid
Antagonist
• Does not effect craving
• Drug cravings leads to stopping
Naltrexone and restarting drug
• Long lasting Naltrexone injections may
help with this
• Not in US
Neuroscience of Addiction Day 2
117
Naltrexone: Opioid
Antagonist
• Alcohol effects mediated by beta-endorphins
(endogenous opioid)
• Reduce “reward” from alcohol by blocking
receptor so endorphins cannot bind
• Significant reduction in daily drinking
• May be especially helpful for those with
genetic predisposition
– Opioid gene variant
higher binding and
higher risk of alcoholism and heroin addiction
Neuroscience of Addiction Day 2
118
Pharmacology of Addiction:
Craving
• Naltrexone decreased alcohol craving
• Decreased and slowed alcohol
consumption following “priming”
compared to placebo
Neuroscience of Addiction Day 2
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Neuroscience of Addiction Day 2
120
Craving as a Biological Event
• Withdrawal Craving = GABA, Glutamate
• Euphoric Recall = Dopamine,
Endorphins, Glutamate
• “Stress” = Serotonin, (dopamine)
Neuroscience of Addiction Day 2
121
Pharmacologic Treatment
• Methadone and Buprenorphine require
special license
• Methadone managed in a program
• MD needs training in how to effectively
use buprenorphine
Neuroscience of Addiction Day 2
122
Pharmacology of Addiction:
Euphoria and Craving
• Buprenorphine for opioid addiction
– Partial mu-opioid antagonist: blocks
binding
– Partial mu-opioid agonist: blocks craving
Neuroscience of Addiction Day 2
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Suboxone
• Buprenorphine plus
Naloxone
• Bup absorbed
sublingually
• Naloxone not
absorbed
– But if injected–
precipitates withdrawal
Neuroscience of Addiction Day 2
124
Buprenorphine
• Partial agonist
• Controls cravings
– Still some sense of euphoria
• Safer than heroin
– Not as addictive, little risk of overdose
• Longer-lasting than methadone, not as long as
LAAM
– 24-60 hours
• Lowest category drug for treatment of heroin
addiction (cat. III)
• Easier than methadone to manage
Neuroscience of Addiction Day 2
125
Buprenorphine
• Opioids attach to receptors and lead to
dopamine release
• Stimulation of reward system
Neuroscience of Addiction Day 2
126
Buprenorphine
• As opioids leave receptors, stimulation
ends
• Withdrawal and cravings
Neuroscience of Addiction Day 2
127
Buprenorphine
• Bup attaches to empty opioid receptors
• Mild stimulation of receptors (agonist)
– “Ceiling” to amount of agonist effect
• Prevent w/d and craving
Neuroscience of Addiction Day 2
128
Ceiling Effect
Neuroscience of Addiction Day 2
129
Buprenorphine
• Bup binds tightly
• Opioids cannot bind (antagonist)
Neuroscience of Addiction Day 2
130
Buprenorphine
• At maintenance doses, bup remins tightly
bound
• Mild stimluation
• Block other opioids
Neuroscience of Addiction Day 2
131
Buprenorphine
• History
– A treatment plan was approved by the FDA in 2003
• It included a buprenorphine pill during the initial tolerance phase
• The maintenance phase uses a different pill, containing
buprenorphine and naloxone
**Not all buprenorphine is approved for heroin addiction treatment!
Buprenorphine is not safe in an unsupervised setting!
Neuroscience of Addiction Day 2
132
Buprenorphine
• Problems and Questions
– There is little information on the effect of
buprenorphine on pregnant women
• A few cases have showed no problems
– The withdrawal effects are not completely
masked by buprenorphine
• They are much milder
Neuroscience of Addiction Day 2
133
Clinical Case Studies
Involving Buprenorphine
• Buprenorphine is equally effective as moderate
(60 mg per day) doses of methadone.
• It is unclear if buprenorphine can be as effective
as higher doses of methadone.
Neuroscience of Addiction Day 2
134
Clinical Case Studies
Involving Buprenorphine
• Buprenorphine is mildly reinforcing, encouraging
good patient compliance.
• After a year of buprenorphine plus counseling,
as many as 75 percent have been retained in
treatment compared to none in a placebo plus
counseling condition.
Neuroscience of Addiction Day 2
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136
Bupropion Blocks Binding Sites
Neuroscience of Addiction Day 2
137
Buprenorphine Taper
• Buprenorphine is a partial mu opiate
receptor agonist
• Withdrawal symptoms are milder and
course is shorter
• Can be Rx in the community
• Difficult to overdose and die
• Typically, 3 day dosing than stop
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138
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Buprenorphine Taper
• Still requires specialty training to Rx
• In tolerant individuals can cause
withdrawal if dose is to high or too low
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Alcohol Dependence
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Medications tried in Alcohol
Dependence
•
•
•
•
•
•
Naltrexone
SSRI’s and other antidepressants
Buspirone
Ondansterone
Acamprosate
Valproic acid, carbamazepine,
gabapentin
• Corticotrophin Releasing Factor
• Topiramate Neuroscience of Addiction Day 2
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Naltrexone for Alcohol
Dependence
• “In the Lab” Subjects reported
decreased stimulation from Etoh and
decreased craving. “Still needs further
study”
• Fairly large number of studies.
Different methodologies with
heterogeneous populations
• Results have been mixed, but tend to
be positive
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Naltrexone for Alcohol
Dependence
Most studies in abstinent subjects show:
1. Prolonged time to first relapse
2. Increased % of days abstinence
3. In one study, Increased days to first
drink
4. In one study at follow-up, relapse
rates approached placebo after study
ended
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Naltrexone for Alcohol
Dependence
Two studies in non-abstinent subjects
with relapse as outcome:
1. CBT and naltrexone better than CBT
and placebo
2. Supportive therapy and naltrexone no
better than supportive therapy and
placebo
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Naltrexone for Alcohol
Dependence
• Eligible:
1. Etoh dependent, medically stable and
not on opiates
2. Willing to begin a supportive
relationship with health care provider
or support group and work toward
abstinence
3. Willing to take medication
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Naltrexone for Alcohol
Dependence
•
Not eligible:
1.
2.
3.
4.
•
Liver failure
Acute hepatitis
Pregnant or Nursing
Possibly the very obese
Watch Drug Interactions with
NonSteroidals
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SSRI’s for Alcohol
Dependence
• In the laboratory, alcohol consumption
decreased in animals given SSRI’s
• But human studies have been mixed
and disappointing
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SSRI’s for Alcohol
Dependence
•
In various studies and to various
degrees each of the following
disorders has been linked to
Serotonin Dysregulation:
1.
2.
3.
4.
5.
Alcohol Dependence
Major Depression
Anxiety Disorders
Impulse Control Disorders
Compulsive Disorders
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SSRI’s for Alcohol
Dependence
•
Studies involving SSRI treatment of Alcohol
Dependence and other disorders which
may involve serotonin dysregulation, when
taken as a whole showed
1. Poor tolerance
2. Poor outcome
3. In some cases, worse outcome than
placebo
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SSRI’s for Alcohol
Dependence
• Researchers are now hypothesizing
that subtypes of Alcohol dependent
subjects account for uneven test
results and that medications that effect
different parts of the serotonin system
may be effective for each different
subtype.
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Depression In Alcohol
Dependence
• In some studies, Depressed Alcoholics
showed improvement in abstinence
commensurate with their improvement in
depression
• In other studies, mild improvement in
abstinence over what would be expected
with improved depression
• Some only showed improvement in Etoh and
depression when naltrexone was added.
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Buspirone and Alcohol
Dependence
• Buspirone is a partial agonist of a
specific serotonin receptor, which has
effects on large portions of serotonin
system.
• Buspirone is used in humans to treat
anxiety. Takes several weeks to work.
Well tolerated. Approved for doses up to
30mg/day, but higher doses routinely
used.
• Rats showed less drinking when on
153
buspirone.Neuroscience of Addiction Day 2
Buspirone and Alcohol
Dependence
•
Studies in Anxious Alcoholics
comparing buspirone to placebo
showed:
1.
2.
3.
4.
5.
Better retention
Slower return to heavy drinking
Fewer drinking days
Decreased anxiety
Decreased anxiety did not fully account
for medication effect
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Ondansteron for Alcohol
Dependence
• Alcoholic subtypes 1 & 2 or A & B
• Type 2 or B show early onset, high
impulsivity and consistent serotonin
dysregulation
• Type 2 or B show increased side effects
from SSRI’s and Increase in drinking
with SSRI’s
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Ondansteron for Alcohol
Dependence
• Ondansteron is an antagonist of
(blocks) a specific serotonin receptor
subtype
• In humans it is used for severe nausea
and vomiting from radiation or
chemotherapy
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Ondansteron for Alcohol
Dependence
•
In several studies comparing
ondansteron to placebo:
1. Increased number of days abstinent
2. Decreased number of drinking days
•
This was true for early onset
alcoholics and not nearly as much for
late onset
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Disulfuram
• Block aldehyde dehydrogenase and leads
to build up of toxic metabolites when
exposed to alcohol
• Flushing, nausea, vomiting, Autonomic
dysregulation.
Occasionally Death
• Does not appear to block biologic effects of
Etoh. Thus, can “drink on top of it” if
subject can do two things
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Disulfuram
•
Two VA studies:
1. No better than placebo
2. Beneficial in older, more motivated and
more medically ill patient population
•
“Impaired Impulsivity with Intact
Intelligence”
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Disulfuram
• Disulfuram has been found to increase
dopamine by inhibiting it’s metabolism
• One study has shown that disulfuram &
naltrexone had better outcome on
drinking than each drug alone
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Acamprosate (Campral) for
Alcohol Dependence
• Acamprosate decreases the effects
of glutamate at a specific receptor
• Takes a week to achieve “steady
state”
• Takes weeks to show effect
• Usual dose is 2 grams per day
• Major side effect is diarrhea
• Increase in SI?
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Acamprosate for Alcohol
Dependence
•
•
•
16 European studies involving 4500
subjects
Better consistency of findings
compared to Naltrexone database
Similar findings to Naltrexone:
1. Increased total abstinence days
2. Increased time to first drink
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Acamprosate for Alcohol
Dependence
• Abstinence rates remained higher in treated
group compared to placebo for up to 12
month after treatment was stopped.
• Some other TX effects were lost
• In one US study, better outcome if pts
wanted abstinence and if not multi drug
dependent
• Current study in US of naltrexone &
acamprosate (COMBINE)
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Topiramate for Alcoholism
• Anti-seizure medication
• Used in some mood disorders
• One study: promising
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“Treating The Disease”
•
“Ingestion as a problem solving
Technique”
1.
2.
3.
4.
Can reinforce technique
Can perpetuate use
Can prevent adaptation and growth
Can collude with “the great obsession”
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Addiction as a Biological
Event
• Withdrawal Craving = GABA, Glutamate
• Euphoric Recall = Dopamine,
Endorphins, Glutamate
• “Stress” = Serotonin, (dopamine)
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The Stress Hormone Cycle
Hypothalamus
Stress Responses
CRF
Pituitary
Gland
ACTH
CRF:
Corticotropin
Releasing
Factor
Adrenal
Glands
CORTISOL
Kidneys
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of Addiction Day 2
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CRF Agonist/ Antagonist
• Address the stress / relapse connection
• Must avoid disrupting natural axis
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Cocaine
• Many medications tested
• Recent promise from modafinil
– Medication targeting narcolepsy
– Wakefulness
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Modafinil
• Enhances transmission of glutamate
• Appears to decrease reward and
craving in cocaine users
• Three trials underway
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Methamphetamine Medications in
Development
Methamphetamine
Phase I
Bupropion
Disulfiram
Lobeline
Reserpine
Selegiline
Phase II
Baclofen
Gabapentin
Isradipine
Olanzapine
Ondansetron
Selegiline
Venlafaxine
Planned
Aripiprazole
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Beyond Pharmacology
•
•
•
•
Natural reinforcers
Devaluing drug reinforcers
Strengthen inhibitory control
Strengthen executive function
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Devaluing drug reinforcers
• Even if drug euphoria is blocked, what
about the cues that motivate drug
seeking?
• How to devalue the addicts biologically
learned perception of the drug?
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Addiction Cycle
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Experimental Drug Vaccines
• Antibodies to bind and deactivate
drugs
• Use animal immune system or
manufacture antibodies
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What would a perfect
medication be?*
• What would be general properties?
• What would the neurobiological targets
be?
• Can you draw a picture of the
mechanism of action?
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Future of Addiction Pharmacology
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Case 1
39 year-old white divorced female –
alcohol abuse disorder. History of both
inpatient/outpatient detoxification with
rehab multiple times. Longest period of
abstinence - 4 days. No improvement
with AA.
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Design a Treatment Plan
• Initial treatment
• What assessment tools would you use?
• What would be the initial placement?
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Treatment Plan
• What are the brain structures that lead to
relapse?
• What would the role of medication be?
• What is your chronic care plan?
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Case 2
• 24 year old man who began to abuse Rx
stimulants in college and progressed to
methamphetamine. Now smoking daily,
legal problems, homeless, hearing voices
and often paranoid.
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Design a Treatment Plan
• Initial treatment
• What assessment tools would you use?
• What would be the initial placement?
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Treatment Plan
• What are the cues in his environment to
watch out for?
• What would the role of medication be?
• Special challenges?
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Case 3
• 54 year old woman who lost her nursing
license after she began to abuse narcotic
pain medications. Was caught “doctor
shopping” and is starting to buy meds off
the street.
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Design a Treatment Plan
• Initial treatment
• What assessment tools would you use?
• What would be the initial placement?
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Treatment Plan
• What would she do if she needed dental
surgery?
• What would the role of medication be?
• Special challenges?
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Final Exercise*
• Write down two or three ways that
information from this workshop will impact
your clinical work.
• Describe a few specific examples
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Wrap up*
• Questions?
• Comments?
• How close to our goals did we come?
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The End!
• Thank you
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Selected Bibliography
• Dackis, C. and O’Brien, C. Neurobiology of addiction: treatment and
public policy ramifications. Nature Neuroscience 8:11 1431-36
• Everitt, B.J. and Robbins, T.W. Neural systems of reinforcement for
drug addiction:frokm actions to habits to compulsion, Nature
Neuroscience 8:11 1481-89*
• Nestler E. and Aghajan, G. (1997) Molecular and cellular basis of
addiction. Science 278; 58-63*
• Volkow, N. and Li, T. (2005) The neuroscience of addiction. Nature
Neuroscience 8:11 1429-30*
• Kreek M.J., Nielsen D.A., Butelman, E.R. and LaForge S. (2005) Genetic
Influences on impulsivity, risk taking, stress responsivity and
vulnerability to drug abuse and addiction Nature Neuroscience 8:11
1450-57*
• Nestler E. and Aghajan G. Molecular and cellular basis of addiction.
Science 278; 58-63*
• Volkow N., Fowler J., and Wang G. 2003 The addicted human brain:
insights from imaging studies. The Journal of Clinical Investigation
111, 1444-51*
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