Neurobiology of Addiction

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Neurobiology of Addiction
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Degrees of Substance Use

• Occasional, controlled, or social use
• Abuse or harmful use
• Addiction

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Drug Addiction

• A chronic relapsing syndrome that moves from an
  impulse control disorder involving positive
  reinforcement to a compulsive disorder involving
  negative reinforcement

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Why do people use?

• Feel Good (Sensation Seeking)
• Feel Better (Self Medication)

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What is driving addiction?

• Positive Reinforcement - rewards that strengthen
  a conditioned response after it has occurred,
  such as the feeling of euphoria after taking a
  hit
• Negative Reinforcement stimuli (e.g., stress)
  that are removed when the desired response (e.g.,
  drug use) has been obtained
• Escape conditioning - learning to escape an
  unpleasant or aversive stimulus (using drugs to
  reduce stress)
• Avoidance conditioning Learning to avoid an
  aversive stimulus (e.g., stress) before it occurs
  (e.g., using drugs before going to a stressful
  mtg)

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A Major Reason People Take a Drug is They Like
What it Does to Their Brains
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Positive Reinforcement

• Go! System

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PET/fMRI of Cocaine CravingChildress et al.,
1999 Am.J.Psychiat
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Cocaine Cue Reactivity

• Drug Cues can trigger a strong, affect-positive
  state of drug desire (GO!)
• Cues can be used to study brain substrates of
  GO! in the imaging setting
• Brain substrates Limbic Activation
• Anterior cingulate
• Amygdala
• Insula
• Ventral Striatum (NAc)
• Orbitofrontal Cortex

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Same processes present in

• Opiates heroin craving correlated with inferior
  frontal lobe, prefrontal cortex, insula
• Nicotine smoking videos correlated with OFC,
  insula, anterior cingulate, DLPFC
• Sex arousal correlated with anterior cingulate,
  mPFC, OFC, insular, amygdala, ventral striatum

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But GO! isnt the whole story
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STOP System

• Frontal Lobes
• Critical for good decision making, disinhibition
• Lower activity (blood flow and glucose
  metabolism) in cocaine users
• Less concentrated gray matter (fewer nerve cells)
  in cocaine users and alcoholics
• Unclear if cause or consequence, yet children
  w/ADHD and CD have poor frontal lobe functioning

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Neurotransmitters - the Big Two

• Serotonin mood, emotion, sleep and appetite
• Dopamine pleasure and elation

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Natural Rewards Elevate Dopamine Levels
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Prolonged Drug Use Changes The Brain In
Fundamental and Long-Lasting Ways
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Dopamine Transporters in Methamphetamine Abusers
2.4
2.2
2.0
1.8
Normal Control
(Bmax/Kd)
Dopamine Transporters
1.6
1.4
1.2
1.0
Methamphetamine Abuser
p lt 0.0002
Methamphetamine abusers have significant
reductions in dopamine transporters.
BNL - UCLA - SUNY NIDA - ONDCP - DOE
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Dopamine Transporters in Methamphetamine Abusers
Motor Task
Loss of dopamine transporters in the meth
abusers may result in slowing of motor reactions.
Dopamine Transporter
Time Gait
Bmax/Kd
(seconds)
Memory Task
Loss of dopamine transporters in the meth
abusers may result in memory impairment.
Delayed Recall
(words remembered)
BNL/UCLA/SUNY
NIDA, ONDCP, DOE
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Normal
Cocaine Abuser (10 Days)
Cocaine Abuser (100 Days)
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Implications Down Regulation

• Immediate effect of drug use is an increase in
  dopamine or NTs
• Continued use of drugs reduces the brains
  dopamine (or NT) production
• Because dopamine is part of the reward system,
  the brain is fooled that the drug has survival
  value for the organism
• The reward system responds with drug seeking
  behaviors

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National Institute on Drug Abuse, 2002 Monkey
Brain
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• Volkow
• http//switchboard.real.com/player/email.html?PV6
  .0.12titleCMHClinkhttp3A2F2Fmedia.med.yale
  .edu3A80802Framgen2Fpsych2Flectures2Fcmhc35F
  55F04.rm

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Negative Reinforcement

• Transition to Addiction

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Oponent-process Model

• a process unconditional response positive
  mood state
• b process unconditional, counteradaptive
  negative opposite response negative mood state

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Brain Dysregulation in Addiction (CNS activity,
mood, behavior)
Normal
Addicted
Koob LeMoal, Neurobiology of Addiction, 2006
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• Allostasis maintaining stability (or
  homeostasis) through change
• Allostatic Load the wear and tear that the body
  experiences due to repeated cycles of allostasis
  as well as the inefficient turning-on or shutting
  off of these responses

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Definitions

• Extended Amygdala Forebrain macrostructure
  composed of central medial amygdala, bed nucleus
  of the stria terminalis (BNST), and a transition
  zone in the medial part of the nucleus accumbens.
  A rich substrate for neurochemical and
  neurocircuitry interactions that produce the
  dark side of motivation.
• Corticotropin-Releasing Factor 41 amino acid
  polypeptide brain stress neurotransmitter that
  controls hormonal, sympathetic, and behavioral
  responses to stressors

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Neurochemical Changes in the Extended Amygdala
during the Development of DependenceImplications
for Emotional Processing
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Major neurocircuits underlying addiction

• Acute reinforcing effects of drugs
• Activation of extended amygdala system, ventral
  tegmental area, arcuate nucleus, ventral
  striatal-ventral pallidal thalamic cortical loops
• Acute withdrawal, negative affect, anxiety
• Decrease function in extended amygdala reward
  system
• Increase in brain stress neurocircuitry
• Preoccupation/anticipation/craving
• Increase activity in extended amygdala
  (prefrontal cortex basolateral amygdala)
• Transition to addiction
• Positive reinforcement ? extended amygdala
• Negative reinforcement - ? stress neurocircuits

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Neurochemical Changes Associated with the
Transition from Drug Use to Dependence
From Roberts AJ and Koob GF, Alcohol ethanol
antagonists/amethystic agents. in Adelman G and
Smith BH (Eds.), Encyclopedia of Neuroscience,
3rd edn, Elsevier, New York, 2003
http//203.200.24.1408080/Neuroscience.
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How can we measure negative reinforcement?
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Distress Tolerance

• Definition An individuals ability to persist in
  goal directed activity when experiencing
  affective distress
• Tools for measuring negative reinforcement
  behavior
• Paced Auditory Serial Addition Task (PASAT-C)
• Mirror Tracing Persistence Task (MTPT-C)

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For the sequence 2, 5,13, 6, 3, 12 Correct
answers are 7, 18, 19, 9, 15
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For the sequence 2, 5,13, 6, 3, 12 Correct
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For the sequence 2, 5,13, 6, 3, 12 Correct
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For the sequence 2, 5,13, 6, 3, 12 Correct
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For the sequence 2, 5,13, 6, 3, 12 Correct
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For the sequence 2, 5,13, 6, 3, 12 Correct
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Score

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Quit

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• Level 1 (Warm up 3 minutes)
• 5 second latency between number presentations
• Latency titrated based upon performance
• Level 2 (Measurement Level 5 minutes)
• Average latency of Level 1 for first 4 minutes
• Last minute extremely difficult (Latency ½ of
  first 4 minutes)
• Level 3 (Quit Option up to 5 minutes)
• Latency equivalent to last minute of Level 2
• Continues to be extremely difficult
• Participant can quit at any time
• Negative Affect Scale completed pre and post
• Distress Tolerance can be measured continuously
  or dichotomously as Quit or Persist

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Mirror Tracing Persistence Task

• Trace circle across star
• All movements reversed
• If center of circle goes out of line or
  stops for 500ms? buzz and restart
• Clearly impossible, but will last for 300
  seconds
• Participants have termination option
  termination latency is DV

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Low distress tolerance significantly related to

• Increased frequency of substance use
• (Quinn, Brandon, Copeland, 1996)
• Shorter durations of smoking, gambling, and
  illicit drug use abstinence attempts
• (Brown, Lejuez, Kahler, Strong, 2002
  Daughters, Lejuez, Strong, et al., 2005
  Daughters, Lejuez, Kahler et al., 2005)
• Increased rates of smoking treatment failure
• (Brandon et al., 2003)
• Increased rates of dropout from substance abuse
  treatment
• (Daughters, Lejuez, Bornovalova, et al., 2005)

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Distress Tolerance Paradigm

• Elicits real-time distress in the context of goal
  directed activity
• Repeatedly demonstrated a relationship with a
  number of real-world substance abuse outcomes
• Allows for the study of ones behavioral response
  to distress (i.e. quitting the task) during the
  experimental procedure

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Study Overview

• Purpose
• Collect pilot data on the neural indices of
  distress tolerance using fMRI (n 25)
• Examine the relationship between neural indices
  and important physiological, biological, and
  genetic correlates
• HPA Axis reactivity
• Genetic indicators
• Galvanic skin response
• Heart rate

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PASAT for fMRI


3, 4
4, 9

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Latency Test 3 Min
Relaxation 60s
Control Level 60s
Anticipation Period 15s
Distress Level 60s
Relaxation 60s
X 8
Distress Tolerance 5 min max
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Questions

• Sois addiction a Choice or disease?
• How does someone become an addict?
• How can we treat addiction?