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

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

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

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

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)

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

2nd D2R Vector Effects of Tx with an Adenovirus Carrying a DA D2 Receptor Gene into NAc in DA D2 Receptors Percent Change in D2R p < p < p < 0.10 p < st D2R Vector 0 0 Null Vector Time (days) p < % Change in Alcohol Intake p < p < 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 , DA

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 )

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

p < Obese subjects Control subjects DA D2 Receptors and BMI in Controls and Obese Subjects Bmax/Kd BMI p = 0.3

DA D2-R in Zucker Lean and Zucker Obese (fa/fa) Rats LeanObese Weight (grams) Lean (n=10) Obese (n=10) DA D2 Receptors Striatum/Cerebellum Thanos et al 2005 P < LeanObese Locomotor Activity (beam crossings) P < H-Spiperone Weight Locomotion D2-Receptors

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

Correlations Between D2 Receptors in Striatum and Brain Glucose Metabolism Striatum CG PreF OFC DA D2 Receptors (Ratio Index) OFC umol/100g/min r = 0.7, p < OFC umol/100gr/min DA D2 Receptors (Bmax/kd) Cocaine Abusers Cocaine Abusers r = 0.7, p < METH Abusers METH Abusers Salience Attribution Inhibitory Control control cocaine abuser

MP 85 0 µmole/100g/min Brain Activation with Methylphenidate Induced Cocaine Craving Placebo Orbitofrontal Activation Volkow et al Am J Psychiatry micromol/100g/min (MP - Placebo) Self Report Craving r = 0.79, p <

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

FOOD What Provides the Specificity? Drugs

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

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

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

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

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

Measuring Changes in Dopamine

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

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?

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

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

Relationship Between Changes in DA and Reports of Hunger and Desire for Food Induced by Food Stimulation when given with MP Hunger Desire for Food % Change Bmax/kd p < 0.01

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

Biology/Genes Environment Food Obesity Neurobiology/Metabolism

Brain Glucose Metabolism in Cocaine Abusers (n=20) and Controls (n=23) Brain Glucose Metabolism in Cocaine Abusers (n=20) and Controls (n=23) ControlsAbusers micromol/100g/min ControlsAbusers micromol/100g/min CG OFC CG P < P < 0.01

MP-induced Increases in Metabolism OFC Controls Abusers Baseline MP Rectal Gyrus/Brain Craving Rectal Gyrus (MP - Placebo) p < Abusers > Controls p = p < 0.01

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.

Brain Dopamine Response to Food Stimulation (Bmax/Kd) Placebo/Neutral MP/Food p < ml/g Volkow, et al, Synapse Desire for Food % Change Bmax/kd p < 0.01 NeutralFood

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