Terry E. Robinson Department of Psychology & Neuroscience Program The University of Michigan, Ann Arbor, MI

1. Terry E. Robinson Department of Psychology & Neuroscience Program The University of Michigan, Ann Arbor, MI Rate of drug delivery, sensitization and addiction

2. 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 …

3. Factors that influence the propensity to addiction Why does rate of drug entry into brain promote addiction? • Increased euphorigenic effects • Increased reinforcing efficacy

4. Rate of infusion has no effect on amphetamine or cocaine self-administration Fixed ratio H. Crombag

5. Rate of infusion has no effect on amphetamine or cocaine self-administration Fixed ratio Variable interval H. Crombag

6. “… 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

7. Progressive ratio … H. Crombag

8. Reinstatement … H. Crombag

9. 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 won’t 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)

11. Psychomotor Sensitization Challenge(time course) Challenge(dose-effect) Development Psychomotor Activation (data from Anagnostaras & Robinson, 1996)

12. “the molecules are counting it, registering and storing it up” Evidence? • Psychomotor sensitization • Sensitization of drug reward • Incentive sensitization

13. What conditions promote or retard the expression and/or the induction of sensitization?

14. Modulation by the circumstances surrounding drug administration Modulation of induction1.By rate of drug delivery Cocaine HCl “Crack”

15. 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)

16. Rapidly infused i.v. cocaine (2.0 mg/kg) more readily induces psychomotor sensitization (Samaha, Li & Robinson, J. Neurosci., 2002)

17. 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

18. Rapidly infused i.v. cocaine is moreeffective in inducing immediate early genes in a number of brain regions c-fos mRNA 5 s 25 s 100 s Saline Intravenous cocaine

19. Rapidly infused i.v. cocaine is moreeffective in engaging the striatum 5 s 25 s 100 s Saline (Samaha et al.,2004)

20. …and especially the mesocorticolimbic system Nucleus Accumbens (Samaha et al.,2004)

21. …and especially the mesocorticolimbic system Nucleus Accumbens Medial Frontal Cortex (Samaha et al.,2004)

22. Effect on dopamine half-life with Nicolas Mallet & Francois Gonon University of Bordeaux (Samaha et al.,2004)

23. Nicotine?

24. A single treatment with rapidly infused i.v. nicotine (0.5 mg/kg) more readily induces psychomotor sensitization (Samaha et al.,2004)

25. Rapidly infused i.v. nicotine is moreeffective in engaging the striatum (Samaha et al.,2004)

26. Rapidly infused i.v. nicotine is moreeffective in engaging the accumbens (Samaha et al.,2004)

27. Rapidly infused i.v. nicotine is moreeffective in engaging the medial frontal cortex … (Samaha et al.,2004)

28. 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.

29. 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

30. 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.

31. 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