Terry E. Robinson

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Terry E. Robinson Department of Psychology
Neuroscience Program The University of Michigan,
Ann Arbor, MI
Rate of drug delivery, sensitization and addiction
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Factors that influence the propensity to addiction

• it is widely accepted that drugs, formulations,
  or routes of administration that result in the
  rapid entry of a drug into the brain are
  potentially the most addictive

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Factors that influence the propensity to addiction

• Why does rate of drug entry into brain promote
  addiction?

• Increased euphorigenic effects
• Increased reinforcing efficacy

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Rate of infusion has no effect on amphetamine or
cocaine self-administration
Fixed ratio
H. Crombag
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Rate of infusion has no effect on amphetamine or
cocaine self-administration
Fixed ratio
Variable interval
H. Crombag
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duration of infusion 25-75 sec seems to
have little direct importance in controlling
either the frequency or the distributions of
responding for cocaine reinforcement.Pickens,
Dougherty Thompson, 1969
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Progressive ratio
H. Crombag
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Reinstatement
H. Crombag
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Factors that influence the propensity to addiction
Rate of infusion has no effect on amphetamine or
cocaine self-administration or reinstatement
H. Crombag
10
The transition to addiction-a thesis

• We are spinning our own fates, good or evil
  ... The drunken Rip Van Winkle ... excuses
  himself for every fresh dereliction by saying, I
  wont count this time! Well! he might may not
  count it, and a kind Heaven may not count it but
  it is being counted none the less. Down among
  his nerve cells and fibers the molecules are
  counting it, registering and storing it up to be
  used against him when the next temptation comes.
  (William James,1890)
• (with thanks to Jaak Panksepp)

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Psychomotor Sensitization
Challenge(time course)
Challenge(dose-effect)
Development
Psychomotor Activation
(data from Anagnostaras Robinson, 1996)
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the molecules are counting it, registering and
storing it up

• Evidence?
• Psychomotor sensitization
• Sensitization of drug reward
• Incentive sensitization

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What conditions promote or retard the expression
and/or the induction of sensitization?
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Modulation by the circumstances surrounding drug
administration

• Modulation of induction1. By rate of drug
  delivery

Cocaine HCl
Crack
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A-N. Samaha
Pharmacokinetic data provided by Dr. J.B.
Justice, Jr., (from Pan et al., 1991)
Effect of rate of i.v. cocaine delivery on the
acute psychomotor response to cocaine
(Samaha, Li Robinson, J. Neurosci., 2002)
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Rapidly infused i.v. cocaine (2.0 mg/kg) more
readily induces psychomotor sensitization
(Samaha, Li Robinson, J. Neurosci., 2002)
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A single injection of rapidly infused i.v.
cocaine (2.0 mg/kg) more readily induces
psychomotor sensitization
Pharmacokinetic data provided by Dr. J.B.
Justice, Jr., (from Pan et al., 1991)
A-N. Samaha
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Rapidly infused i.v. cocaine is moreeffective in
inducing immediate early genes in a number of
brain regions
c-fos mRNA
Saline
5 s
25 s
100 s
Intravenous cocaine
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Rapidly infused i.v. cocaine is moreeffective in
engaging the striatum
Saline
5 s
25 s
100 s
(Samaha et al.,2004)
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and especially the mesocorticolimbic system
Nucleus Accumbens
(Samaha et al.,2004)
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and especially the mesocorticolimbic system
Nucleus Accumbens
Medial Frontal Cortex
(Samaha et al.,2004)
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Effect on dopamine half-life
with Nicolas Mallet Francois Gonon University
of Bordeaux
(Samaha et al.,2004)
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Nicotine?
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A single treatment with rapidly infused i.v.
nicotine (0.5 mg/kg) more readily induces
psychomotor sensitization
(Samaha et al.,2004)
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Rapidly infused i.v. nicotine is moreeffective
in engaging the striatum
(Samaha et al.,2004)
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Rapidly infused i.v. nicotine is moreeffective
in engaging the accumbens
(Samaha et al.,2004)
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Rapidly infused i.v. nicotine is moreeffective
in engaging the medial frontal cortex
(Samaha et al.,2004)
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Summary

• Rapidly delivered cocaine and nicotine more
  readily induce behavioral sensitization, and
  presumably associated changes in the brain.
• reason why drugs, formulations and routes of
  administration that yield rapid entry of a drug
  into the brain may be more addictive is because
  this facilitates their ability to produce forms
  of neurobehavioral plasticity that have been
  associated with the compulsive pursuit of drugs -
  i.e., those associated with sensitization.

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Summary

• Rapidly delivered cocaine and nicotine more
  readily induce behavioral sensitization, and
  presumably associated changes in the brain.
• Rapidly delivered cocaine and nicotine more
  readily induce immediate gene expression in
  mesostriatal and mesolimbocortical regions

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Summary

• Rapidly delivered cocaine and nicotine more
  readily induce behavioral sensitization, and
  presumably associated changes in the brain.
• Rapidly delivered cocaine and nicotine more
  readily induce immediate gene expression in
  mesostriatal and mesolimbocortical regions
• The reason why drugs, formulations and routes of
  administration that yield rapid entry of a drug
  into the brain may be more addictive is because
  this facilitates their ability to produce forms
  of neurobehavioral plasticity that have been
  associated with the compulsive pursuit of drugs -
  i.e., those associated with sensitization.

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Major Contributors Anne-Noel Samaha Hans
Crombag In collaboration with Susan
Ferguson From the University of Bordeaux Nicolas
Mallet Francois Gonon
A-N. Samaha
H. Crombag
S. Ferguson