NATIONAL INSTITUTE ON DRUG ABUSE

1. Dopamine’s Role in DRUG CRAVING Nora D. Volkow, M.D. Director, National Institute on Drug Abuse NIAAA NIDA National Institute Alcohol Abuse and Alcoholism NATIONAL INSTITUTE ON DRUG ABUSE

2. 1100 AMPHETAMINE 1000 900 800 % of Basal Release 700 600 500 400 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. High (0-10) 10 8 6 Change in Dopamine Bmax/kd (Placebo - MP) 4 2 m e t h y l p h e n i d a t e 0 -2 -10 0 10 20 30 40 DA and Drug Reinforcement “High” T Y R O S I N E T Y R O S I N E D O P A D O P A D A D A DA D A DA D A D A D A D A D A raclopride D A D A D A D A raclopride D A R D A D A R R D A R R R DA initiates and maintains responses to salient stimuli such as drugs

4. The mechanism(s) underlying the intense desire for the drug when addicted subjects are exposed to drug cues (places, people and paraphernalia linked with the drug), is still unknown. Since DA is involved with reward and with prediction of reward, it could underlie craving

5. Background In rodents when a neutral stimuli is repeatedly paired with the drug (conditioned), it elicits DA increases. DA Release NAc Auditory cue In training the cue was paired with cocaine In training the cue was not paired with cocaine Philipps et al Nature 422, 614-618

6. 1. Subjects Eighteen cocaine abusers Inclusion criteria: DSM- IV criteria for cocaine dependence active use for at least the prior 6 months free-base or crack at least "four grams" a week Exclusion criteria: past or present neuro and psychiatric diseases other than cocaine dependence past or present endocrinological disease head trauma with loss of consciousness current medical illness

7. 2. Subjects Gender 17 males, 1 female Age 43 6 years Ethnicity 15 AA, 3 Caucasians Education 13 2 years of education Years used 15 7 years Route 18 smoked cocaine Dose used 2.8 1.6 grams a day Last used 2 1.4 days (range 1 & 6 days) Cigarette smokers 15 current smokers

8. Methods: Videos The neutral video featured non-repeating segments of nature scenes The cocaine-cue video featured non repeating scenes that simulated purchase, preparation, and smoking of cocaine Videos were shown 10 min prior to radiotracer injection for a total of 40 min

9. 5.00 5.00 4.50 4.50 4.00 4.00 3.50 3.50 3.00 3.00 2.50 2.50 2.00 2.00 Self-reports of craving during the neutral and the cocaine-cue video Neutral Video Cocaine-Cue Video P < 0.01 Cocaine Craving Cocaine Craving (1-7) After After Before Before Cocaine cues increased self reports of cocaine craving in cocaine abusers Source: Volkow, ND et al., Journal of Neuroscience, 26(24):6583-6588, 2006.

10. Caudate Putamen 2.5 2.5 2.0 2.0 1.5 1.5 (Pre - Post) Change in Craving 1.0 1.0 0.50 0.50 0.0 0.0 30 20 10 0 -10 -20 -30 -40 30 20 10 0 -10 -20 -30 -40 -0.50 -0.50 % Change Bmax/Kd Relationship between Cue-Induced Decreases in [11C]raclopride Binding and Cocaine Craving Cue-induced increases in DA were associated with craving P < 0.05 P < 0.002 Source: Volkow, ND et al., Journal of Neuroscience, 26(24):6583-6588, 2006.

11. Craving of Food Why is it that the sight of food can elicit the desire for it even when we are not hungry? Are the responses to cues similar to those that triggered the cocaine in cocaine abusers?

12. Ten healthy food deprived controls (15-18 hours food deprivation) tested under neutral and food cue conditions Neutral:Subjects were asked to describe their family genealogy. Food Cues:The food-cue featured non repeating presentation of favorite foods that had been heated to enhance smell Stimuli were presented 10 min prior to radiotracer injection for a total of 40 min

13. 10 8 4 6 4 2 3.5 0 -2 0 5 10 15 20 25 30 3 2.5 Brain Dopamine Response to Food Stimulation Neutral Food 1.5 0 ml/g (Bmax/Kd) p < 0.005 Desire for Food MP/Food Placebo/Neutral % Change Bmax/kd p < 0.01 Source: Volkow, et al., Synapse 2002.

14. 1.5 4 3.5 0 ml/g (Bmax/Kd) p < 0.005 3 2.5 MP/Food Placebo/Neutral [11C]Raclopride Binding in Food Deprived Controls During Neutral and Food Cues Neutral Bmax/Kd decreased with exposure to food-cues presumably from DA increases Food Cue Source: Volkow, et al., Synapse 2002.

15. 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 DA Changes and Self-Reports of Hunger and Desire for Food Induced by Food Cues Desire for Food Hunger % Change Bmax/kd p < 0.01

16. Both drug as well as food cues increased DA in dorsal striatum (brain region involved with initiation of action and with learning of habits), suggesting that drugs usurp physiological processes DA activation of DS may underlie the “desire” (wanting) that result in the readiness to engage in the behaviors necessary to procure the desired object whether it’s a drug or food Cue-induced DA increases were associated with craving for drugs as well as for food, which highlights the automated (reflexes) nature of these responses

17. Funded by DOE and NIH 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