Drug Addiction

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Drug Addiction

• What is drug addiction?
• Reward Systems in the brain
• Mesolimbic DA system
• Other systems
• How does use turn into addiction?
• Adaptive changes
• Solomon Corbits opponent process theory
• Neurobiological substrates
• Why do individuals relapse?
• Lessons from imaging studies
• Craving and the brain
• Risk factors

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Drug Addiction
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Drug Use
Drug Abuse
Addiction
Compulsive use of the drug with a loss of control
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Learning Refresher

• Positive Reinforcement the behavior produces an
  appetitive event, increasing the likelihood of
  that behavior in the future
• Negative Reinforcement the behavior eliminates
  or prevents an aversive event, increasing the
  likelihood of that behavior in the future

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• James Olds and Peter Milner 1954
• Examined the effects of electrically stimulating
  different parts of the brain
• Discovered that activation of some pathways were
  reinforcing

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Rat pressing a lever for electrical stimulation
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Activation of the mesolimbic DA system

• Signals saliency of events
• Drives motivation
• Facilitates memory consolidation of salient evente

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Drugs of abuse activate the mesolimbic
dopaminergic system, either directly, or
indirectly
Stahl, 2002
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How can we study reinforcing properties of drugs
with animal models?

• 1- Self administration
• 2- reduction in threshold for intra-cranial
  self-stimulation
• 3- place preference

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Extended Amygdala
Opioid and serotonergic systems may be
independently reinforcing
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Reinforcing effects of drugs of abuse
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Increase of DA in humans with methylphenidate
Volkow et al, Mol Psychiatry, 9, 2004
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Nestler Malenka, 2004
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Dopamine release is modulated by expectation

• Cocaine-induced increases in DA are larger when
  animals are given the drug in an environment
  where they previously received the drug
• Cocaine-induced increases in DA are larger when
  animals self-administer than when administration
  is involuntary

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• Drugs of abuse have positive reinforcing
  properties
• How does that lead to abuse and addiction?

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How does drug use turn into abuse and addiction?

• Neuroadaptive changes
• Sensitization
• Counteradaptation
• may reduce the initial euphoric effects and cause
  withdrawal
• These 2 processes may occur at different times
  during development of drug dependence, may
  operate on different response to the drug, and
  may occur differently for each drug of abuse

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Sensitization

• Increase in response to the drug with repeated,
  intermittent exposure
• Postulated to contribute to the wanting or
  craving of the drug
• Glucocorticoids can promote sensitization

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Counteradaptation

• Opposing changes with repeated exposure
• Tolerance reduction in response to drug with
  repeated exposure
• Withdrawal opposing signs during cessation of
  drug intake

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Solomon Corbits opponent process theory
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Manifest Temporal Dynamics of Opponent-Process
SystemAfter First Few Stimulations
100
Peak of A
State A
Steady level of A
Baseline
Neutral
Decay of B
State B
Peak of B
ON
OFF
OFF
100
TIME
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Changes in Opponent Processes Over Time
First Few Administrations
After Many Administrations
A
A - B
Manifest Affective Response
A - B
0
B
A
A
Underlying Opponent Processes
B
B
ON
Stimulus Event
OFF
OFF
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• With repeated presentation of the drug, the B
  process becomes stronger and longer-lasting
• This reduces the initial emotional reaction and
  lengthens the after-reaction

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• The strengthening of the B process leads to
  tolerance and withdrawal
• Change from taking the drug because of the
  positive reinforcing properties to taking the
  drug because of negative reinforcing properties

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Neuronal mechanisms?

• Within-system adaptations
• Alterations in drug site
• Alterations in reward system
• Reduction in DA
• Reduced DA sensitivity
• Reduced 5-HT
• Between-system adaptations
• CRF
• Stress systems

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Reward systems are less active during drug
withdrawal
Koob et al., Neuroci Biobehav Rev, 27, 2004
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Reduction of DA 5-HT during acute withdrawal
Parsons et al., 1995
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Koob Le Moal, 2001
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Stress systems are more active during withdrawal
Pich et al., 1995
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Prolonged use of cocaine leads to increased ICSS
threshold
Koob et al., Neuroci Biobehav Rev, 27, 2004
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Change in reward system action
Koob et al., Neuroci Biobehav Rev, 27, 2004
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Koob Le Moal, 2001
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Adapted from Koob GF, ALCOHOLISM CLINICAL AND
EXPERIMENTAL RESEARCH, 2003, 27 232-243
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Why does a person relapse?

• Allostasis change in set point to maintain
  homeostasis (and meet the demands of a chronic
  situation)
• Allostatic Load the price the body pays for
  maintaining the new set point

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Opponent-Process and Allostasis
Koon LeMoal, 2001
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What is more

• Learning occurs

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• Cues associated with the drug can become
  conditioned reinforcers (either positive or
  negative reinforcers)
• Drug-induced increases in dopamine will
  facilitate conditioned learning

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Conditioned responses

• CS-US stimuli associated with drug taking become
  CS that elicit appetitive responses
• Anticipatory high
• CS-US stimuli associated with drug taking become
  CS that elicit compensatory responses
• Opposite reaction

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Shepard Siegel

• CONTEXT HEROIN ? pain
• CS US UR
• Development of tolerance
• CONTEXT Compensatory CR
• (opposite the UR)

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• Both types of learning lead to drug-taking
  behavior
• So, both nonassociative (opponent process) and
  associative processes can contribute to drug
  taking behavior

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So why do individuals take drugs after protracted
abstinence?

• Counteradaptive responses are long-lasting
• Learning cues are available
• Stress

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Long-term neurobiological changes in humans
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Goldstein Volkow, 2002
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Heroin, as well
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What evidence do we have that there are
long-lasting changes in the addicted brain?
Volkow, J Nuclear Med, 45, 2004
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• Prefrontal cortex is in a position to integrate
  information from various limbic area and modulate
  those responses to drug administration
• Orbitofrontal cortex
• Anterior cingulate cortex

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Potential involvement in drug addictionAnimal
studies

• Orbitofrontal cortex processes information about
  the rewarding properties of stimuli
• Lesions to the orbitofrontal cortex prevent
  cocaine-conditioned place preference and
  self-administration
• Damage to orbitofrontal cortex leads to
  perseveration and resistance to extinction of
  learned responses

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Volkow et al. 1992
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Studies of cocaine drug abusers

• Decrease in metabolism in orbitofrontal and
  anterior cingulate cortex 3-4 months after
  initial detoxification period (Volkow et al.,
  1992)

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• Disruptions in orbitofrontal cortex could affect
  the motivational process of assignment of
  saliency value to a stimulus as a function of its
  context
• Disruptions in the anterior cingulate cortex
  could affect the process of inhibitory control

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Related to dopamine?Volkow et al, 1993

• Cocaine abusers (within one month of last cocaine
  use) had lower DA D2 receptors in the striatum
• Decreases in striatal D2 receptors correlated
  with reduced metabolism in orbitofrontal and
  cingulate cortices in detoxified patients

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Striatal D2 receptors correlate with prefrontal
cortical metabolism
Volkow et al., Neuropharm, 47, 2004
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Volkow et al., 1993
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Volkow et al., Mol. Psychiatry, 9, 2004
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Studies in alcoholics

• Most studies find reduced metabolism in anterior
  cingulate gyrus and orbitofrontal cortex in
  alcoholics, even months after detox (e.g. Volkow
  et al. 1997)
• Alcohol can be neurotoxic to orbitofrontal cortex

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• Reductions in D2 receptors in alcoholics and
  delayed recovery of D2 receptor sensitivity after
  detox is related to relapse
• Blunted metabolic responses to GABA and 5HT in
  orbitofrontal cortex and striatum in alcoholics
  both during early detox and protracted withdrawal

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• Very different pattern of activation in the
  orbitofrontal and anterior cingulate cortices
  during craving

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Neurobiology of craving

• Activation of the amygdala and anterior
  cingulate, orbitofrontal cortex during craving
• Important for evaluation of reward
• In presence of cues associated with drug, there
  is activation of these brain regions and it
  correlates with reports of craving

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Orbitofrontal cortex and cocaine craving in humans

• Hyperactivity of orbitofrontal cortex is
  associated with self-reports of cocaine craving
• Increased orbitofrontal activity with cocaine
  theme interview vs. neutral interview (Wang et
  al. 1999)
• Increased metabolism of orbitofrontal cortex,
  amygdala, prefrontal cortex and cerebellum when
  viewed scenes that elicited craving (Grant et
  al., 1996)

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Wang et al. 1999
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Changes in opiate-dependent individualsActivation
of orbitofrontal cortex during drug-related
script compared to neutral script in abstinent
opiate-dependent subjectsActivation was
correlated with magnitude of craving
Daglish et al 2001
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• Methylphenidate exposure increased activity in
  right anterior cingulate cortex in all
  cocaine-abusers and the right orbitofrontal
  cortex and striatum ONLY in those who reported
  significant levels of craving

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Changes associated with alcohol
Heinz et al., Am J Psychiatry, 161, 2004
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Activation of cue-induced prefrontal cortex
correlates with striatal D2 receptors
Heinz et al., Am J Psychiatry, 161, 2004
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Cues and craving are also related to amygdala
activation
Childress et al., Am J Psychiatry, 156, 1999
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• Together, these data suggest that activation of
  prefrontal-striatal systems may play a role in
  craving and compulsive drug use

Volkow et al., Neuropharm, 47, 2004
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Volkow et al., 2003
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• Disruptions in the activity of the orbitofrontal
  cortex and anterior cingulate may underlie the
  compulsive drug intake and loss of control in the
  context of drug-related stimuli

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Similar to other compulsive disorders

• We will see that dysfunction of orbitofrontal
  cortex-striatum is related to OCD, Tourettes
  (disorders which share compulsive behaviors)

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Mesocorticolimbic DA Pathway
Cortico-thalamic-striatal loop
Adapted from Koob GF, ALCOHOLISM CLINICAL AND
EXPERIMENTAL RESEARCH, 2003, 27 232-243
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Risk factors

• Genes
• Biological factors
• Experience
• Early stress

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D2 Dopamine Receptors
Volkow , J Nuclear Med, 45, 2004
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Are individuals with fewer D2 receptors more
likely to become addicted?
Volkow , J Nuclear Med, 45, 2004
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How could you test this?

• Increase D2 receptors
• Cant in humans, have to return to animal models
• Genetically engineer mice with more D2 receptors
• Increased expression of D2 receptors led to
  reduced alcohol intake, which was reversed when
  D2 receptor levels were normalized

Thanos et al. J Neurochem, 78, 2002
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What influences D2 receptor levels?

• Genes
• Experience

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Volkow , J Nuclear Med, 45, 2004
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Social experience can influence neurobiology and
that can influence drug-taking behavior
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Other concerns Neurotoxicity
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Recovery of DA transporters and behavioral
function in abstinent Meth addicts
Volkow , J Nuclear Med, 45, 2004
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What about adolescents?

• Drug abuse might alter development of brain
  regions, like the frontal lobes, that are
  involved in executive functions and motivation

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Co-morbidity with mental illness

• Risk for substance abuse and addiction is
  significantly higher in individuals with mental
  illness compared to the general population

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Challenge

• Integration of genes, protein expression,
  neuronal circuits, behavior and social
  consequences into a comprehensive understanding
  of addiction

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Addendum
Volkow Li, Nature Reviews Neuroscience, 5, 2004