1. Models of addiction: role of dopamine and other neurobiological substrates Paul E. M. Phillips, Ph.D. Department of Psychiatry and Behavioral Sciences Department of Pharmacology

2. Mesostriatal, mesolimbic and mesocortical dopamine pathways

3. Dopamine is reward? Hedonia Reinforcement Motivation

4. Direct action of psychostimulants on dopamine transmission

5. Drugs of abuse increase extracellular dopamine Di Chiara & Imperato, 1988

6. Effects of cocaine on dopamine transmission measured with high temporal resolution Cocaine

7. Cocaine self administration each operant response

8. 0120240360480600 Inter-lever-press interval (s) 0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 Number of lever presses Lever-press responding for cocaine

9. Dopamine increases during drug taking 0120240360480 100 nM Time (s)

10. E (V vs Ag/AgCl) app Dopamine increases to cocaine-related cues 50 nM 2 s

11. 25 nM 50 nM Learned associations are required * -50510 Time (s)

12. Post-response encodes reward expectation Maintenance Reinstatement ns * Extinction * 0 50 100 150 [DA] (nM)

13. Dopamine increases during drug taking 2 s 50 nM

14. Dopamine increases during drug taking 2 s 50 nM Phillips et al (2003) Nature 422, 614-8 Lever approach

15. Dopamine triggers cocaine seeking 0 1 2 3 Control 0120240360480600 Inter-lever press interval (s) Number of lever presses 0 1 2 3 4 5 6 * * * * * Stimulated -60-3003060 Time (s) Number of lever presses 0 1 2 3 Control * * * * * Stimulated 0 1 2 3 4 5 6

16. “Ectopic” dopamine triggers behavioral switching 100 nM 60 s

17. Subsecond dopamine release promotes reward seeking… Phillips et al (2003) Nature 422, 614-8 -60-3003060 Time (s) Number of lever presses 0 1 2 3 Control * * * * * Stimulated 0 1 2 3 4 5 6 …but what does this tell us about addiction? …but how is cost-benefit decision making being altered? Cocaine feels better? Cocaine costs less?

18. Decision making costs “desirability” benefits minus costs

19. Would you buy a hotdog for a dollar? $1 2 1 +1

20. Would you buy a hotdog for three dollars? $3 2 3

21. $3 4 3 +1 Would you buy a steak for three dollars?

22. What’s the alternative? $3 2300 0 

23. Have I eaten today? $3 2302 -2 

24. What about drugs? 1000 +10  

25. Drugs feel really good but I get a hangover afterwards. 2100 +10 

26. My friend got busted for drug possession 2200 00  

27. I heard on the news that drugs are bad for me 2300 0 

28. My partner threatened to leave me if I used drugs 2400 -20 

29. What happens to decision making during addiction? 2300 0  ??  “Rational” decision makerAddict  

30. 1. Drugs are really good 2300 0  +10  “Rational” decision makerAddict 4300

31. 2. I don’t care about the consequences 2300 0  +10  “Rational” decision makerAddict 2100

32. 3. It feels really bad if I don’t take drugs 2300 0  -2  “Rational” decision makerAddict 2302

33. Opponency model of addiction

34. Opponency (negative reinforcement) model of addiction 2300 0  -2-4  “Rational” decision makerAddict 1304

35. Opponency model of addiction

36. Incentive sensitization model of addiction

37. 2300 0  +10  “Rational” decision makerAddict 4300

38. Taste reactivity as a measure of hedonia/aversion Berridge, 2000

39. Taste reactivity as a measure of hedonia/aversion Berridge, 2000

40. Taste reactivity as a measure of hedonia/aversion Berridge, 2000

41. Taste reactivity is not altered after dopamine depletion Berridge et al, 1989

42. Cannon & Palmiter, 2003 Reward preference in the absence of dopamine

43. Cannon & Palmiter, 2003 Reward preference in the absence of dopamine

44. Nucleus accumbens dopamine lesions suppress responding for higher efforts Salamone et al, 2003

45. Zhang et al, 2003 Salamone et al, 2003 Dopamine modulates cost-benefit analysis to acquire rewards

46. How does dopamine effect the decision-making process? D = desirability B = benefits C = costs D = B - C D = B - αC where 0 < α < 1 and α is a function of dopamine (high DA → low α)

47. Incentive sensitization model of addiction 2300 0  2 – (⅓ x 3) = +10  “Rational” decision makerAddict 2100

48. Loss of inhibitory control model of addiction 2300 0  +10  “Rational” decision makerAddict 2100

49. Baker et al, 2003 Glutamate levels are reduced in the nucleus accumbens following repeated cocaine exposure

50. Baker et al, 2003 Restoration of glutamate levels in the nucleus accumbens prevents reinstatement of drug seeking

51. Aberrant learning models of addiction 2300 0  +10  “Rational” decision makerAddict 4300

52. Habit model of addiction

53. Ito et al, 2002

54. Rescorla-Wagner model for Pavlovian learning Dayan & Abbott, 2001

55. Temporal Difference (TD) learning

56. Schultz et al, 1997 Dopamine neurons carry a reward prediction error signal

57. Berns et al, 2001

58. McClure et al, 2003

61. Temporal Difference (TD) learning in addiction 50 nM 2 s

62. Aberrant learning models of addiction 2300 0  +10  “Rational” decision makerAddict 4300