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

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

DA and Drug Reinforcement “High” -10 10 20 30 40 -2 2 4 6 8 High (0-10) Change in Dopamine Bmax/kd (Placebo - MP) 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 raclopride D A D A D A m e t h y l p n i d a D A D A raclopride D A R R D A D A D A R R R R DA initiates and maintains responses to salient stimuli such as drugs

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

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

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

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

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

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

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

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?

Neutral: Subjects were asked to describe their family genealogy. 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

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

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

Relationship Between DA Changes and Self-Reports of Hunger and Desire for Food Induced by Food Cues -2 2 4 6 8 10 5 15 20 25 30 5 10 15 20 25 30 -2 2 4 6 8 Hunger Desire for Food % Change Bmax/kd p < 0.01

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 Cue-induced DA increases were associated with craving for drugs as well as for food, which highlights the automated (reflexes) nature of these responses 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

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