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

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

hr Time After Amphetamine % of Basal Release AMPHETAMINE Time (min) % of Basal Release Empty Box Feeding Di Chiara et al. FOOD VTA/SN nucleus accumbens nucleus accumbens frontal cortex frontal cortex Dopamine Neurotransmission

TYROSINE DA DOPA DA DA DA DA TYROSINE DA DOPA DA DA DA DA DA DA DA DA DA DA R R R R R R Self-Reports (0-10) Change in Dopamine Bmax/kd (Placebo - MP) “High” Reward Circuit in Addiction and in Obesity raclopride DA Volkow et al., JPET 291(1): , NAcc VP REWARD methylphenidate

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

Hipp Amyg MEMORY/ LEARNING MEMORY/ LEARNING Philipps et al Nature 422, In training the cue was paired with cocaine In training the cue was not paired with cocaine Memory Circuit in Addiction Memory Circuit in Addiction and in Obesity 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 Here we tested if conditioned stimuli increase DA in addicted subjects and its relationship to drug craving Here we tested if conditioned stimuli increase DA in addicted subjects and its relationship to drug craving DA Release NAc Auditory cue

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

DA signal Motivation & Executive Control Circuits ACG OFC SCC INHIBITORY CONTROL INHIBITORY CONTROL EXECUTIVE FUNCTION EXECUTIVE FUNCTION PFC MOTIVATION/ DRIVE MOTIVATION/ DRIVE 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 D2 Receptors Metabolism

Dopamine D2 Receptors are Lower in Addiction DA D2 Receptor Availability Cocaine Alcohol Heroin Meth control addicted Volkow et al., Neurob Learning Memory DA D2 Receptors (Ratio Index) Bmax/Kd Normal Controls Cocaine Abusers

Compulsive overeating shares many of the same characteristics as drug addiction Obesity 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 P < DA D2 Receptors and BMI in Controls and Obese Subjects p < Obese subjects Control subjects Bmax/Kd BMI p = 0.3

Correlations Between D2 Receptors in Striatum & Brain Glucose Metabolism Striatum CG PreF OFC umol/100g/min r = 0.7, p < Cocaine Abusers DA D2 Receptors (Ratio Index) OFC umol/100gr/min DA D2 Receptors (Bmax/kd) r = 0.7, p < METH Abusers Volkow et al., AJP 158(3): , Relationship Between DAD2 Receptors (D2R) & Brain Metabolism in Obese Subjects p < D2R (Bmax/Kd) Medial Orbitofrontal Cingulate Gyrus  Mol/100g/min Low D2R in obese subjects is associated in with reduced metabolism in cingulate gyrus and medial orbitofrontal cortex

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