Models of addiction: role of dopamine and other neurobiological substrates

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 Motivation Reinforcement

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. each operant response Cocaine self administration

8. 2.0 1.8 1.6 1.4 1.2 Number of lever presses 1.0 0.8 0.6 0.4 0.2 0.0 0 120 240 360 480 600 Inter-lever-press interval (s) Lever-press responding for cocaine

9. Dopamine increases during drug taking 100 nM 0 120 240 360 480 Time (s)

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

11. * -5 0 5 10 Time (s) Learned associations are required 50 nM 25 nM

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

13. Dopamine increases during drug taking 50 nM 2 s

14. Lever approach Dopamine increases during drug taking 50 nM 2 s Phillips et al (2003) Nature422, 614-8

15. * * * * * * 6 * * 6 5 5 * 4 * 4 3 3 2 2 Number of lever presses Number of lever presses 1 1 0 Stimulated 0 3 Stimulated 3 2 2 1 1 0 0 Control Control -60 -30 0 30 60 0 120 240 360 480 600 Time (s) Inter-lever press interval (s) Dopamine triggers cocaine seeking

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

17. ? * * * …but how is cost-benefit decision making being altered? * * 6 5 4 3 Number of lever presses 2 1 0 3 Stimulated 2 1 0 Control -60 -30 0 30 60 Time (s) Subsecond dopamine release promotes reward seeking… • Cocaine feels better? • Cocaine costs less? …but what does this tell us about addiction? Phillips et al (2003) Nature422, 614-8

18. Decision making costs benefits benefits minus costs “desirability”

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

20. $3 3 2 -1 Would you buy a hotdog for three dollars?

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

22. What’s the alternative? $3 2 3 0 0 -1 0  

23. Have I eaten today? $3 2 3 0 2 -1 -2  

24. What about drugs?  1 0 0 0 +1 0  

25. Drugs feel really good but I get a hangover afterwards. 2 1 0 0 +1 0  

26. My friend got busted for drug possession 2 2 0 0 0 0  

27. I heard on the news that drugs are bad for me 2 3 0 0 -1 0  

28. My partner threatened to leave me if I used drugs 2 4 0 0 -2 0  

29. What happens to decision making during addiction? “Rational” decision maker Addict   2 3 0 0 -1 0 ? ?    

30. 1. Drugs are really good “Rational” decision maker Addict 2 3 0 0 4 3 0 0 -1 0 +1 0    

31. 2. I don’t care about the consequences “Rational” decision maker Addict 2 3 0 0 2 1 0 0 -1 0 +1 0    

32. 3. It feels really bad if I don’t take drugs “Rational” decision maker Addict 2 3 0 0 2 3 0 2 -1 0 -1 -2    

33. Opponency model of addiction

34. Opponency (negative reinforcement) model of addiction “Rational” decision maker Addict 2 3 0 0 1 3 0 4 -1 0 -2 -4    

35. Opponency model of addiction

36. Incentive sensitization model of addiction

37. Incentive sensitization model of addiction “Rational” decision maker Addict 2 3 0 0 4 3 0 0 -1 0 +1 0    

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

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

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

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

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

47. Incentive sensitization model of addiction “Rational” decision maker Addict 2 3 0 0 2 1 0 0 -1 0 2 – (⅓ x 3) = +1 0    

48. Loss of inhibitory control model of addiction “Rational” decision maker Addict 2 3 0 0 2 1 0 0 -1 0 +1 0    

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

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