Motivational Change in Addiction: Results from Animal Models

1. Motivational Change in Addiction: Results from Animal Models Keith A. Trujillo Department of Psychology Office for Biomedical Research and Training

2. What do you think? Should we get started on that motivational research, or not?

3. Animal Models and Clinical Research Animal Models Basic Science Clinical Research Therapy Development Health Services

4. 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?

5. Reward and Addiction • Reward mediated by specific neural circuits • addictive drugs directly stimulate reward circuits • reward transmitters: dopamine, endogenous opioids, serotonin, endocannabinoids From NIDA

6. 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

7. 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

8. 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

9. 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

10. 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

11. 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

12. 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

13. 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?

14. Glutamate Involved in Neuroadapations Sensitization Tolerance Physical Dependence Trujillo and Akil Mendez and Trujillo

15. Glutamate Antagonists Slowly Reverse Neuroadaptations Peterson and Trujillo

16. 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

17. “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

18. 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?

19. 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

20. 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

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