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Motivational Change in Addiction: Results from Animal Models. Keith A. Trujillo Department of Psychology Office for Biomedical Research and Training. What do you think? Should we get started on that motivational research, or not?. Animal Models and Clinical Research. Animal Models

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motivational change in addiction results from animal models

Motivational Change in Addiction: Results from Animal Models

Keith A. Trujillo

Department of Psychology

Office for Biomedical Research and Training

animal models and clinical research
Animal Models and Clinical Research

Animal Models

Basic Science

Clinical Research

Therapy Development

Health Services

motivation and addiction
Motivation and Addiction
  • Acute Drug Effects
    • reward
  • ChronicDrug Effects
    • plasticity/neuroadaptations
      • tolerance
      • physical dependence
      • sensitization
    • Is there evidence for motivational change in animal models of addiction?
slide5

Reward and Addiction

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

From NIDA

slide6

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

slide7

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
slide8

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
slide9

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

slide10

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
slide11

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
    • symptomsdon’t explainintense desire for drug
    • relapse in addicts often occurs long after symptoms of withdrawal subside

physical dependence contributes to drug use

physical dependence ≠ addiction

slide12

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
slide13

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?

glutamate involved in neuroadapations
Glutamate Involved in Neuroadapations

Sensitization

Tolerance

Physical

Dependence

Trujillo and Akil

Mendez and Trujillo

escalation in self administration with long access
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

addiction like changes in self administration with long access
“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

questions
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?
summary
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

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

Acknowledgements
slide21

positive reinforcement

negative reinforcement

reward

incentive salience

hedonic dysregulation

wanting

liking

pleasure

euphoria

dysphoria

hedonia

allostatic dysregulation

incentive sensitization

craving