1. Common Brain Mechanisms in ADDICTION Common Brain Mechanisms in ADDICTION Nora D. Volkow, M.D. Director National Institute on Drug Abuse Nora D. Volkow, M.D. Director National Institute on Drug Abuse and OBESITY and OBESITY

2. Dopamine Neurotransmission VTA/SN nucleus accumbens nucleus accumbens frontal cortex frontal cortex 0 0 100 200 300 400 500 600 700 800 900 1000 1100 0 0 1 1 2 2 3 3 4 4 5 hr Time After Amphetamine % of Basal Release AMPHETAMINE 0 0 50 100 150 200 0 0 60 120 180 Time (min) % of Basal Release Empty Box Feeding Di Chiara et al. FOOD

3. Anatomy DA signal Dopamine Cell DA Transporters DA Receptors Metabolism Is DA Involved in Addiction and Obesity?

4. normal subject cocaine abuser (1 month post) cocaine abuser (4 months post) Effect of Cocaine Abuse on Dopamine D2 Receptors

5. 1.5 2 2.5 3 3.5 4 4.5 15 20 25 30 35 40 45 50 Cocaine Abusers Normal Controls DA D2 Receptors (Bmax/Kd) Age (years) DA D2 Receptors in Controls and in Cocaine Abusers (NMS) DA D2 Receptors in Controls and in Cocaine Abusers (NMS)

6. Dopamine D2 Receptors are Lower in Addiction DA D2 Receptor Availability control addicted Cocaine Heroin Alcohol DA Reward Circuits DA Reward Circuits DA Drug Abuser Non-Drug Abuser

7. 2nd D2R Vector Effects of Tx with an Adenovirus Carrying a DA D2 Receptor Gene into NAc in DA D2 Receptors 0 0 10 20 30 40 50 60 Percent Change in D2R 4 4 6 6 8 8 10 24 p < 0.0005 p < 0.005 p < 0.10 p < 0.005 1st D2R Vector 0 0 Null Vector -100 -80 -60 -40 -20 0 0 Time (days) 4 4 6 6 8 8 10 24 p < 0.001 % Change in Alcohol Intake p < 0.001 p < 0.01 0 0 Overexpression of DA D2 receptors reduces alcohol self-administration Overexpression of DA D2 receptors reduces alcohol self-administration Source: Thanos, PK et al., J Neurochem, 78, pp. 1094-1103, 2001. DA

8. Compulsive overeating shares many of the same characteristics as drug addiction. Obesity Do obese subjects have abnormal levels of D2-R? 10 severely obese subjects(BMI: 51±5 kg/m 2 ) 10 age-matched controls (BMI: 25±3 kg/m 2 )

9. Control Subjects 2.99 (Sd 0.41) 2 0 ml/gm Obese Subjects 2.47 (Sd 0.36) Dopamine D2 Receptors [ 11 C]raclopride Wang et al, Lancet 2001 P < 0.008

10. 20 25 30 35 40 45 50 55 60 65 1.8 2 2 2.2 2.4 2.6 2.8 3 3 3.2 3.4 3.6 3.8 p < 0.002 Obese subjects Control subjects DA D2 Receptors and BMI in Controls and Obese Subjects Bmax/Kd BMI p = 0.3

11. DA D2-R in Zucker Lean and Zucker Obese (fa/fa) Rats 0.00 100 200 300 400 500 600 700 LeanObese Weight (grams) 0.00 1.00 2.00 3.00 4.00 5.00 6.00 7.00 8.00 Lean (n=10) Obese (n=10) DA D2 Receptors Striatum/Cerebellum Thanos et al 2005 P < 0.05 0.00 100 200 300 400 500 600 LeanObese Locomotor Activity (beam crossings) P < 0.05 3 H-Spiperone Weight Locomotion D2-Receptors

12. Anatomy DA signal Dopamine Cell DA Receptors Metabolism What is the functional significance of low D2-R?

13. Correlations Between D2 Receptors in Striatum and Brain Glucose Metabolism Striatum CG PreF OFC 30 35 40 45 50 55 60 65 1.822.22.42.62.833.23.4 DA D2 Receptors (Ratio Index) OFC umol/100g/min r = 0.7, p < 0.001 30 40 50 60 70 80 90 2.933.13.23.33.43.53.6 OFC umol/100gr/min DA D2 Receptors (Bmax/kd) Cocaine Abusers Cocaine Abusers r = 0.7, p < 0.005 METH Abusers METH Abusers Salience Attribution Inhibitory Control control cocaine abuser

14. MP 85 0 µmole/100g/min Brain Activation with Methylphenidate Induced Cocaine Craving Placebo Orbitofrontal Activation Volkow et al Am J Psychiatry 1999 -30 -20 -10 0.0 10 20 30 0.02.04.06.08.010 micromol/100g/min (MP - Placebo) Self Report Craving r = 0.79, p < 0.0002

15. % Changes of feeling of hunger r = 0.84, p = 0.001 85 0 µmole/100g/min Neutral Stimuli Food Stimuli Wang et al, Neuroimage 2004 Orbitofrontal Activation Brain Activation with Food Stimuli

16. FOOD What Provides the Specificity? Drugs

17. 55 0 µmol/100g/min Control subjects Obese subjects Averaged FDG images What brain regions differ?

18. Regions that are More Active in Obese than Controls Right Hemisphere Left Hemisphere The specificity may be determined by an enhanced brain sensitivity to food as a reinforcer

19. The increased activity in somatosensory cortex for mouth, tongue and lips in obese subjects suggests that enhanced sensitivity in these regions, which are involved in the sensory processing of food may make them more vulnerable to the reinforcing properties of food The increased activity in somatosensory cortex for mouth, tongue and lips in obese subjects suggests that enhanced sensitivity in these regions, which are involved in the sensory processing of food may make them more vulnerable to the reinforcing properties of food The specificity for a particular drug or stimuli may be determined by an enhanced brain sensitivity to that particular reinforcer The specificity for a particular drug or stimuli may be determined by an enhanced brain sensitivity to that particular reinforcer

20. Addicted Brain Control Drive Saliency Memory STOP Non Addicted Brain GO Control Drive Saliency Memory

21. BNL PET Group (Support DOE, NIDA) F. Telang, R. MacGregor, P. Carter, D. Schlyer, C. Shea, J. Gatley, S. Dewey, C. Redvanly, P. King L. Caligiuri, G-J Wang, M. Franceschi, Y-S Ding, J. Logan, N. Volkow, J. Fowler, R. Ferrieri, C. Wong (not shown) D. Alexoff, C. Felder, N. Pappas, D. Franceschi, N. Netusil, V. Garza, R. Carciello, D. Warner, M. Gerasimov

22. Measuring Changes in Dopamine

23. -10010203040 -2 0 2 4 6 8 10 Self-Reports (0-10) Change in Dopamine Bmax/kd (Placebo - MP) “High” Increases in DA by iv Methylphenidate are Associated with its Reinforcing Effects

24. DA regulates food consumption in part by modulating its reinforcing properties through NAc DA increases in NAc during food expectation and food consumption. DA may also regulate food consumption through mechanisms other than rewarding circuits. DA deficient KO die of starvation unless DA is restored in dorsal striatum but not in NAc. What is the Role of Dopamine in the Motivation for Food Consumption in Humans?

25. MP or placebo are given 60’ prior to radiotracer and 45’ prior to neutral or food stimulation. Ten controls; 8 M and 2 F; 35 ± 8 years 4 scans with [11C]raclopride: Placebo and Neutral Stimulation Placebo and Food Stimulation MP (20 mg, po) and Neutral Stimulation MP (20 mg, po) and Food Stimulation DA MP DA MP was given to amplify stimuli induced DA increases

26. Brain Dopamine Response to Food Stimulation DA D2 Receptor Availability (Bmax/Kd) 2.5 3 3.5 4 Placebo/NeutralPlacebo/FoodMP/NeutralMP/Food p < 0.11 p < 0.02 p < 0.005 1.5 0 ml/g Sum images of 10 normal weight subjects ([ 11 C]raclopride) Volkow, et al, Synapse 2002

27. Relationship Between Changes in DA and Reports of Hunger and Desire for Food Induced by Food Stimulation when given with MP 0 0 5 5 10 15 20 25 30 -2 0 0 2 2 4 4 6 6 8 8 10 Hunger -2 0 0 2 2 4 4 6 6 8 8 10 0 0 5 5 15 20 25 30 Desire for Food % Change Bmax/kd p < 0.01

28. These results support the role of DA neurotransmission in dorsal striatum in mediating food motivation in human brain. Implication

29. Biology/Genes Environment Food Obesity Neurobiology/Metabolism

30. Brain Glucose Metabolism in Cocaine Abusers (n=20) and Controls (n=23) Brain Glucose Metabolism in Cocaine Abusers (n=20) and Controls (n=23) 40 45 50 55 60 ControlsAbusers micromol/100g/min 40 45 50 55 60 ControlsAbusers micromol/100g/min CG OFC CG P < 0.005 P < 0.01

31. MP-induced Increases in Metabolism OFC 1.00 1.05 1.10 1.15 1.20 1.25 1.30 Controls Abusers Baseline MP Rectal Gyrus/Brain -4.0 -2.0 0.0 2.0 4.0 6.0 8.0 10.0 -0.2 -0.1 0.0 0.1 0.2 0.3 Craving Rectal Gyrus (MP - Placebo) p < 0.005 Abusers > Controls p = 0.001 p < 0.01

32. Statistical Parameter Map of Metabolic Changes between Food and Neutral stimulation R Wang et al, Neuroimage 2004 Twelve normal weight subjects. Insula is a brain region modulating emotional responses to appetitive stimuli. Orbitofrontal cortex is a brain region involved with salience attribution.

33. Brain Dopamine Response to Food Stimulation (Bmax/Kd) 2.5 3 3.5 4 Placebo/Neutral MP/Food p < 0.005 1.5 0 ml/g Volkow, et al, Synapse 2002 -2 0 0 2 2 4 4 6 6 8 8 10 0 0 5 5 15 20 25 30 Desire for Food % Change Bmax/kd p < 0.01 NeutralFood

34. Addicted Brain Control Drive Reward Memory Output Non Addicted Brain Output Control Drive Reward Memory