Neurobiological Substrates of Stimulant Action and Reward

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Neurobiological Substrates of Stimulant Action
and Reward
Elliot A. Stein, Ph.D. Neuroimaging Research
Branch NIDA-IRP
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Outline

• The problem of drug abuse
• Acute CNS effects of nicotine
• Behavioral and neuropharm-
• acological actions of acute cocaine and
  methylphenidate
• Inhibitory control mechanisms
• Cocaine and IC

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The Problem of Substance Abuse

• Essence of addiction is the compulsive
  self-administration of drug. Multiple hypotheses,
  each with different degrees of emphasis on MCL DA
  system
• drugs are positively reinforcing- they feel good
• drugs fix a negative state, either pre-existing
  or due to withdrawal from use
• drugs of abuse hijack normal reward circuits
• drug-induced DA release leads to over-learning of
  reward/drug association
• Key point drug abuse is a recurring, relapsing
  brain disease with underlying pharmacological and
  behavioral mechanisms

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Transition
Mechanisms???
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A cigarette is the perfect type of a perfect
pleasure. It is exquisite and leaves one
unsatisfied. What more could one
want Oscar Wilde
Nicotine is the drug in tobacco that causes
addiction. The pharmacological and behavioral
processes that determine tobacco addiction are
similar to those that determine addiction to
drugs such as heroin and cocaine. Surgeon
General, 1988
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Nicotine as an Addictive Agent

• Capable of producing tolerance, physical
  dependence and withdrawal symptoms (increased
  irritability, anxiety and depression) upon
  cessation of use
• Animals and humans SA nicotine, which shares
  behavioral properties with other drugs of abuse,
  most notably the psychomotor stimulants
• Humans report IV nicotine as pleasant, often
  preferring it to cigarettes
• Human cocaine abusers identify IV nicotine as
  similar, and in many cases, identical to IV
  cocaine

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Objectives

• To determine the CNS sites and mechanisms of
  action of acute nicotine in human cigarette
  smokers using functional magnetic resonance
  imaging (fMRI)

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Nicotine (1.5 mg)
Stein, E.A. et al Am. J. Psych, 1998
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fMRI Analysis-binary decision model
Parameters defined from known pharmacokinetics
and empirically via visual inspection Bloom et
al. Human Brain Map 8 235-244, 1999
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OFG

insula
cing
Lat orb gyr
IFG
Stein, E.A. et al. Am. J. Psych 155 1009-1015,
1998
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Nicotine regional activation

• CORTEX
• Orbital (posterior, lateral)
• Cingulate
• Frontal (inferior, medial, superior)
• Temporal (inferior, medial, superior)
• Insula
• Visual (medial, inferior, lateral occipital
  cuneus, precuneus, lingual)

• SUBCORTICAL
• Thalamus VA, MD, LD, PL, VL, anterior n.
• Basal Ganglia putamen, caudate, NAcc, globus
  pallidus
• Limbic amygdala, hypothalamus
• Colliculus superior, inferior

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(No Transcript)
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Cocaine

• More reinforcing than amphetamines or
  opiates-monkeys SA cocainegt8000x/single injection
• Given choice-prefer cocaine to food, water or
  sexual contact
• Prefer cocaineshock to low (or no) cocaine
  without shock
• Given unlimited access-monkeys and rats SA to
  death

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Cocaine CNS effects
Breiter HC et al, Neuron, 19591-611 (1997)
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Experimental Procedure

• Day 1 (GCRC) each subject received IV cocaine
  (40mg/70kg) for safety toleration. Subjects were
  also trained on VAS behavioral assessment scales
  for HIGH, Pleasant, Nervous, CRAVING and Sour
  (1/min).
• Day 2, 3, and 4 subjects underwent 4 consecutive
  fMRI scans each day (GE-EPI, TR6s, TE40ms, 1.5T
  GE Signa) and were injected with saline and one
  of the 3 doses cocaine (10, 20, 40 mg/70 kg the
  order dose of injections were blind to the
  subjects)

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Finger-tapping
Before Cocaine

0
10
20
40
After Cocaine
Stein et al Unpublished data
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Methylphenidate

• Volkow et al PET (1994-present)
• IV cocaine - baboons and cocaine users
• IV MP healthy volunteers and cocaine users
• Pharmacokinetics, Cardiovascular, Behavior,
  Distribution
• Other neuroimaging - IV cocaine in humans
• PET London et al (1990)- global CMRglu decreases
• fMRI Breiter et al (1997)- mostly MCL regional
  activation

11C-Cocaine
11C-MP
Time (mins)
Time (mins)
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Experimental Design

• Experienced cocaine users
• IV drug injections in 3 scanning sessions on
  separate days
• 20mg/70kg cocaine (n13) 10 mg MP (n11) 20mg
  MP (n13)
• 2 x 38 min runs per scan 1 saline 1 drug
• Dose and drug/saline order single blinded

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BOLD Time Series
Time (min)
Dirckx,et al 2004
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Summary

• 20mg cocaine, 20mg MP and 10mg MP
• Signal Increases in LEFT
• ventromedial orbitofrontal cortex
• prefrontal cortex
• anterior cingulate
• caudate head/body
• dorsomedial thalamus
• Insula
• Signal Decreases in LEFT
• nucleus accumbens
• subcallosal gyrus
• Saline
• No significant changes (small LEFT NAc increase
  in 20MP saline condition)

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Dirckx,et al 2004
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Conclusions

• BOLD can used to follow time-and dose-dependent
  regional alterations in neuronal activity
  following acute drug administration
• Abused drugs appear to exert similar activation/
  deactivation effects (e.g. negative in NAcc and
  positive in ACC) on similar groups of structures
  (e.g. MCL regions)
• fMRI can be applied to follow real-time CNS
  pharmacokinetic and pharmacodynamic aspects of
  drug actions
• Given similar sites (so far), the different abuse
  liabilities of cocaine and MPh may be rooted in
  their differing pharmacokinetics (Volkow et al)

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Right Hemisphere Dominance of Inhibitory Control
an Event Related functional MRI Study Garavan,
Ross and Stein PNAS (USA) 96 8301-8306, 1999
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Significance of Inhibitory Control

• Suppression of irrelevant/interfering stimuli or
  impulses fundamental executive function
  essential for normal thinking
• IC deficits implicated in ADHD, Tourettes, OCD,
  other disinhibition syndromes-including drug
  abuse
• Characteristic of frontal lobe development

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Inhibitory Control Task
500 msec
L
Y
A
Y
M
T
A
X
P
G
Respond (Target 1)
Respond (Target 2)
1000 Letters (150 Targets - 25 Lures)
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Frontal-Parietal co-Activation
L R
IFG/OFG
Med Fr Cx
Post parietal
Garavan et al PNAS (USA) 96 8301-6, 1999
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Inhibitory Control
4
2
3
Mean AUC
1
Inf. Parietal Lob

• IFG-OFC
• MGF-dlpfc
• Insula
• Post Parietal lobe

r-0.67
Target RT
Garavan, Ross and Stein PNAS (USA) 96 8301-8306,
1999
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Inhibitory Control Conclusions

• Confirms a role for orbital frontal, parietal,
  and cerebellar regions in inhibitory control
• Implicates a preferential role for right
  hemisphere in response inhibition
• Baseline to compare with drug abuse Ss (on and
  off drug)

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IC and Cocaine Abuse

• Pharmacological effects of cocaine on MCL DA
  system insufficient to explain cognitive deficits
  often seen in chronic drug abusers (e.g. impaired
  attention, memory and IC reported)
• Failure to develop and/or loss of IC can
  profoundly impact ability to gate pre-potent, yet
  inappropriate and dangerous behaviors, e.g.
  cocaine use
• Cocaine users show decreased frontal, cingulate,
  insula and superior temporal gray matter
• Cocaine users show decreases in cingulate and OFC
  metabolism
• Functional consequences not well understood

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Inhibitory Control Task
Kaufman et al J Neurosci 23 2003
1180 Go and 80 NoGO stimuli over 4 runs, enabling
the study of both response inhibition and
error-related processes. Task difficulty varied
to equate behavioral performance
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Inhibitory Control
Users (n13)
Controls (n14)
Successful Inhibitions
Failed Inhibitions
Stops UltC ACC, Rt. insula
Errors UltC R. MFG/preSMA, ACC, L. insula, L.
IFG
Kaufman et al J Neurosci 23 2003
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Inhibitory Control
Users (n13)
Controls (n14)
Successful Inhibitions
Failed Inhibitions
Stops UltC ACC, Rt. insula
Errors UltC R. MFG/preSMA, ACC, L. insula, L.
IFG
Kaufman et al J Neurosci 23 2003
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Cocaine and Response Inhibition

• ACC, area critical for cognitive control esp. in
  urgent inhibitions, and activated by all abused
  drugs tested, less responsive in cocaine USERS
  for STOPS and ERRORS
• STOP related hypoactivity in R insula and rostral
  ACC, emotional processing areas, not in other IC
  areas, suggests hypoactivity not ubiquitous but
  specific
• ACC also hypoactive in Scz and hyperactive in
  OCD-consistent with problems in error monitoring
  system (failure to monitor and integrate in Scz
  overactive monitoring in OCD)

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1H-MRS in Cocaine Abuse
Basal ganglia
No change NAA/Cr
Thalamus
Basal ganglia
NAA/Cr

• Dec or viability of neurons
• Dec synaptic density
• Neuronal dysregulation/
• dysfunction
• Monoamine depletion

Thalamus
Cocaine (n21)
Control (n13)
Li et al Biol Psych 1999
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Clinical Implications

• Hypoactivity in USERS reduced IC, diminished
  action monitoring, reduced responsivity to self
  errors-may, at minimum, serve to prolong drug
  abuse
• Suggests USERS may be compromised in endogenous
  and volitional control of behavior thus behavior
  disproportionately determined by environmental
  contingencies, cues (drug craving cues) and
  automatized or habitual behaviors leading to
  reduced capacity to inhibit external influences
• May inform optimal therapeutic interventions and
  help identify casual users most at risk for
  becoming dependent

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The folks in the lab who REALLY did the work
Tom Ross Hugh Garavan BettyJo Salmeron Rob
Risinger John Pankiewicz Natalia Lawrence Alan
Bloom Stacy Engelbart Jackie Kaufman Veronica
Dixon Qiwen Mu Sharon Dirckx Shi-Jiang Li