1. Terry E. Robinson Department of Psychology & Neuroscience Program The University of Michigan, Ann Arbor, MI 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 l l 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? l Increased euphorigenic effects l Increased reinforcing efficacy

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

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

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 …

9. H. Crombag Rate of infusion has no effect on amphetamine or cocaine self-administration or reinstatement … Factors that influence the propensity to addiction

10. “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) The transition to addiction - a thesis

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

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

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

14. Modulation by the circumstances surrounding drug administration Modulation of induction 1. By rate of drug delivery Cocaine HCl “Crack”

15. 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) A-N. Samaha

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

17. Pharmacokinetic data provided by Dr. J.B. Justice, Jr., (from Pan et al., 1991) A single injection of rapidly infused i.v. cocaine (2.0 mg/kg) more readily induces psychomotor sensitization A-N. Samaha

18. Saline5 s25 s100 s Rapidly infused i.v. cocaine is more effective in inducing immediate early genes in a number of brain regions Intravenous cocaine c-fos mRNA

19. Saline5 s25 s100 s Rapidly infused i.v. cocaine is more effective in engaging the striatum (Samaha et al.,2004)

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

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

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

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 more effective in engaging the striatum (Samaha et al.,2004)

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

27. Rapidly infused i.v. nicotine is more effective 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 H. Crombag S. Ferguson A-N. Samaha