Nora D. Volkow, M.D. Director National Institute on Drug Abuse National Institutes of Health

1. Overlapping Neuronal Circuits In ADDICTIONandOBESITY Nora D. Volkow, M.D. Director National Institute on Drug Abuse National Institutes of Health

2. Signals that Control: Reward Dopamine, Cannabinoids, Serotonin, Opioids Reward Dopamine, Cannabinoids, Serotonin, Opioids Ventral tegmental area (Reward) Ventral tegmental area (Reward) Homeostatic factors Leptin, Insulin,Ghrelin, PYY Food Consumption Drug Consumption Hypothalamus (Nutritional need) Hypothalamus

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

4. REWARD 10 8 6 4 NAcc 2 VP 0 -2 -10 0 10 20 30 40 RewardCircuit in Addiction and in Obesity “High” T Y R O S I N E T Y R O S I N E (0-10) Self-Reports D O P A D O P A D A D A DA D A DA D A D A D A D A methylphenidate D A raclopride D A D A Change in Dopamine D A D A raclopride D A R D A D A R R D A Bmax/kd(Placebo - MP) R R R Volkow et al., JPET 291(1):409-415, 1999.

5. P < .001 25 10 20 14% 8 15 % Change Bmax/Kd 6 10 4 3% 5 2 0 High Abuser Control Low Reactivity of Dopamine System to Drug Consumption in Actively Using Addicted Subjects Striatal Activation to Food Reward in Obese and Lean Ss Placebo MPH P < 0.001 Self-report High (1-10) Abuser Control Cocaine abuser High-BMI participants showed decreased response in caudate in response to consummatory food reward compared with low-BMI participants Active cocaine abusers showed a marked reduction in MPH-induced DA increases and in its reinforcing effects Control subject Stice et al., J Abnormal Psychology 2008.

6. Hipp DA Release NAc Auditory cue Amyg Memory Circuit in Addiction and in Obesity • In rats when a neutral stimuli is • repeatedly paired with the drug • (conditioned), it elicits DA • increases and reinstates • drug self- administration MEMORY/ LEARNING In training the cue was paired with cocaine In training the cue was not paired with cocaine Philipps et al Nature 422, 614-618. Here we tested if conditioned stimuli increase DA in addicted subjectsand its relationship to drug craving

7. 1.5 0 ml/g [11C]Raclopride Binding In Cocaine Abusers Viewing a Neutral and a Cocaine-Cue Video [11C]Raclopride Binding in Food Deprived Controls (n=16) During Neutral and Food Cues Neutral video Food Cue: Neutral: Subjects were asked to describe their family genealogy Viewing a video of cocaine scenes decreased specific binding of [11C]raclopride presumably from DA increases Bmax/Kd decreased with exposure to food-cues Volkow et al J Neuroscience 2006. Volkow, et al., Synapse 2002.

8. EXECUTIVE FUNCTION PFC ACG INHIBITORY CONTROL OFC SCC MOTIVATION/ DRIVE • Motivation & Executive • Control Circuits • In addicted subjects or in obese subjects, are the changes in DA function linked with disruption of frontal activity? • Used multiple tracers to evaluated in the same subject DA D2 receptors and brain glucose metabolism (marker of brain function). DA DA DA DA D2 Receptors DA DA DA DA signal Metabolism

9. 4.5 4 3.2 3 3.5 2.8 2.6 3 2.4 2.2 2.5 2 1.8 2 1.6 20 25 30 35 40 45 50 1.5 15 20 25 30 35 40 45 50 Dopamine D2 Receptors are Lower in Addiction Normal Controls Cocaine Abusers Cocaine Meth DA D2 Receptors (Ratio Index) DA D2 Receptor Availability Alcohol Bmax/Kd Heroin control addicted Volkow et al., Neurob Learning Memory 2002.

10. Obesity Obese Subjects 2.47 (Sd 0.36) Compulsive overeating shares many of the same characteristics as drug addiction Dopamine D2 Receptors [11C]raclopride DA D2 Receptors and BMI in Controls and Obese Subjects 65 60 • Obese subjects 55 • Control subjects 50 45 2 BMI 40 p < 0.002 Control Subjects 2.99 (Sd 0.41) 35 30 P < 0.008 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 Wang et al, Lancet 2001. Bmax/Kd 0 ml/gm

11. Cingulate Gyrus 90 70 70 80 65 65 60 60 70 Mol/100g/min 55 55 60 50 50 Medial Orbitofrontal 45 45 50 40 40 3.5 4.0 4.5 5.0 3.0 3.5 4.0 4.5 5.0 3.0 40 30 2.9 3 3.1 3.2 3.3 3.4 3.5 3.6 D2R (Bmax/Kd) Correlations Between D2 Receptors in Striatum & Brain Glucose Metabolism Relationship Between DAD2 Receptors (D2R) & Brain Metabolism in Obese Subjects CG Cocaine Abusers 65 60 55 PreF Striatum OFC 50 umol/100g/min 45 40 OFC r = 0.7, p < 0.001 35 30 2 2.2 2.4 2.6 2.8 3 3.2 3.4 1.8 DA D2 Receptors (Ratio Index) METH Abusers p < 0.005 OFC umol/100gr/min Low D2R in obese subjects is associated in with reduced metabolism in cingulate gyrus and medial orbitofrontal cortex r = 0.7, p < 0.005 Volkow et al., AJP 158(3):377-382, 2001. DA D2 Receptors (Bmax/kd)

12. Dopamine mediates behavioral responses in the Brain food intake Organs Tissues Cells Molecules HYP Glucose Peptides Neurohormones Amino acids Fatty acids work family friends community nature food sex tool-making sports music dance crafts art drugs work family friends community nature food Sex sports Music dance art drugs work family friends community nature food Sex sports music Dance Art drugs PFC NAc Amygdala Hippocampus Dorsal Striatum Motor Complex VTA/SN DOPAMINE Reward Motivation Action System (incentive, salience, learning, perseverance) Source: Volkow ND et al., in review, 2012. (Modified with permission from an unpublished presentation, courtesy of Dr. John Doyle)