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Common Brain Mechanisms in ADDICTI O N

Common Brain Mechanisms in ADDICTI O N. and O BESITY. Nora D. Volkow, M.D. Director National Institute on Drug Abuse. 1100. AMPHETAMINE. 1000. 900. 800. 700. % of Basal Release. 600. 500. 400. frontal cortex. 300. 200. 100. 0. 0. 1. 2. 3. 4. 5 hr.

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Common Brain Mechanisms in ADDICTI O N

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

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

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

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

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

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

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

  8. Obesity Compulsive overeating shares many of the same characteristics as drug addiction. Do obese subjects have abnormal levels of D2-R? 10 severely obese subjects (BMI: 51±5 kg/m2) 10 age-matched controls (BMI: 25±3 kg/m2)

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

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

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

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

  13. 90 80 70 60 50 40 30 2.9 3 3.1 3.2 3.3 3.4 3.5 3.6 control cocaine abuser Correlations Between D2 Receptors in Striatum and Brain Glucose Metabolism Inhibitory Control Cocaine Abusers 65 60 55 OFC 50 umol/100g/min CG 45 40 PreF Striatum r = 0.7, p < 0.001 35 30 1.8 2 2.2 2.4 2.6 2.8 3 3.2 3.4 OFC DA D2 Receptors (Ratio Index) METH Abusers Salience Attribution OFC umol/100gr/min r = 0.7, p < 0.005 DA D2 Receptors (Bmax/kd)

  14. Brain Activation with Methylphenidate Induced Cocaine Craving 85 30 20 10 0.0 -10 -20 0 -30 0.0 2.0 4.0 6.0 8.0 10 µmole/100g/min Placebo Orbitofrontal Activation (MP - Placebo) micromol/100g/min MP Self Report Craving r = 0.79, p < 0.0002 Volkow et al Am J Psychiatry 1999

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

  16. What Provides the Specificity? Drugs FOOD

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

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

  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 specificity for a particular drug or stimuli may be determined by an enhanced brain sensitivity to that particular reinforcer

  20. Non Addicted Brain AddictedBrain Control Control STOP Saliency Drive Drive Saliency GO Memory 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. Self-Reports (0-10) 10 8 6 Change in Dopamine Bmax/kd (Placebo - MP) 4 2 0 -2 -10 0 10 20 30 40 Increases in DA by iv Methylphenidate are Associated with its Reinforcing Effects “High”

  24. What is the Role of Dopamine in the Motivation for Food Consumption in Humans? • 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.

  25. MP DA DA DA DA DA DA DA DA DA DA DA DA DA DA DA DA DA DA DA DA DA DA DA 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 MP was given to amplify stimuli induced DA increases MP or placebo are given 60’ prior to radiotracer and 45’ prior to neutral or food stimulation.

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

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

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

  29. Biology/Genes Environment Food Neurobiology/Metabolism Obesity

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

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

  32. Statistical Parameter Map of Metabolic Changes between Food and Neutral stimulation R • 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. Wang et al, Neuroimage 2004

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

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

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