Motivational Change in Addiction: Results from Animal Models

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Motivational Change in Addiction Results from
Animal Models

• Keith A. Trujillo
• Department of Psychology
• Office for Biomedical Research and Training

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What do you think? Should we get started on that
motivational research, or not?
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Animal Models and Clinical Research

• Animal Models
• Basic Science
• Clinical Research
• Therapy Development
• Health Services

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Motivation and Addiction

• Acute Drug Effects
• reward
• Chronic Drug Effects
• plasticity/neuroadaptations
• tolerance
• physical dependence
• sensitization
• Is there evidence for motivational change in
  animal models of addiction?

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Reward and Addiction

• Reward mediated by specific neural circuits
• addictive drugs directly stimulate reward
  circuits
• reward transmitters dopamine, endogenous
  opioids, serotonin, endocannabinoids

From NIDA
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Reward and Addiction

• Reward does not explain addiction
• pleasurable effects cannot account for compulsive
  drug seeking
• majority of users do not become addicts

reward contributes to drug use reward ? addiction
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Plasticity / Neuroadaptation

• Paradigm shift changes in response to chronic
  drug use important to addiction
• neuroadaptations contribute to addiction by
  modifying motivational effects of drugs
• modify positive and negative reinforcement
• tolerance
• physical dependence
• sensitization

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Tolerance

• Decrease in an effect following chronic use

tolerance to the analgesic effect of morphine in
rats Peterson and Trujillo

• addicts may take increasing amounts of drug due
  to decreases in desired effects or decreases in
  side-effects

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Tolerance and Addiction

• Tolerance does not explain addiction
• addiction can occur in absence of tolerance
• tolerance often seen in absence of addiction
• tolerance often follows, rather than precedes
  addiction

tolerance contributes to drug use tolerance ?
addiction
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Physical Dependence

• Change in functioning following chronic use
• further drug is needed to avoid withdrawal
  syndrome

naloxone-precipitated morphine withdrawal in
rats Trujillo and Akil

• negative reinforcement addicts take drugs to
  avoid withdrawal

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Physical Dependence and Addiction

• Physical dependence does not explain addiction
• addiction can occur in absence of physical
  dependence
• physical dependence often occurs in absence of
  addiction
• symptoms dont explain intense desire for drug
• relapse in addicts often occurs long after
  symptoms of withdrawal subside

physical dependence contributes to drug
use physical dependence ? addiction
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Sensitization

• Increase in an effect following chronic use

sensitization to the locomotor stimulant
effect of morphine in rats Ruzek and Trujillo

• reward sensitization (increased liking)
• incentive-sensitization (increased wanting)
• may be responsible for craving

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Sensitization and Addiction

• Does sensitization explain addiction?
• hypothesized that repeated drug use leads to
  increased desire for drug
• craving may develop via sensitization
• sensitization well-studied in animal models
• relevance to human addiction presently unclear

sensitization contributes to drug
use sensitization ? addiction?
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Glutamate Involved in Neuroadapations
Sensitization
Tolerance
Physical Dependence
Trujillo and Akil Mendez and Trujillo
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Glutamate Antagonists Slowly Reverse
Neuroadaptations
Peterson and Trujillo
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Escalation in Self-Administration with Long-Access

• Ahmed Koob, Science (1998)
• long-access increases cocaine self-administration
  (also heroin)

Long (6hr/day)
Short (1hr/day)
Effort
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Addiction-Like Changes in Self-Administration
with Long-Access

• Deroche-Gamonet et al, Science (2004)
• Vanderschuren Everitt, Science (2004)
• long-term cocaine self-administration produces
  motivational change (in some rats)

Resistance to Punishment
Persistence
Effort
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Questions

• What motivational mechanisms are changed?
• positive reinforcement negative reinforcement
  incentive salience, others?
• What are the neural substrates of the changes?
• Can the changes be reversed?

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Summary

• Reward important in drug abuse and addiction
• Plasticity/Neuroadaptation important in drug
  abuse and addiction
• Plasticity/Neuroadaptation is reversible
• Animal studies more closely modeling addiction
• motivational changes seen with long-term use

A better understanding of motivational changes in
addiction should lead to better treatment
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Acknowledgements

• Graduate Students (former undergrads)
• Kathleen Warmoth
• Michelle Lewellen
• David Peterson
• Karen Watorski
• Dawn Albertson
• Ian Mendez
• Erik Ruzek

• Undergraduates
• Kate Kubota
• Angelica Runno
• Juan Zamora
• University of Michigan
• Huda Akil
• Grant Support
• NIDA (DA11803)
• NIGMS (GM59833)
• CSU San Marcos

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positive reinforcement
negative reinforcement
reward
incentive salience
hedonic dysregulation
wanting
liking
pleasure
dysphoria
euphoria
hedonia
allostatic dysregulation
incentive sensitization
craving