The Neurobiology of Free Will In National Institute on Drug Abuse ADDICTIVE DISORDERS Nora D. Volkow, M.D. Director National Institute on Drug Abuse

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 Self-Reports (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 Volkow et al., JPET 291(1):409-415, 1999.

Reward Circuit In laboratory animals repeated exposure to the drug NAcc VP REWARD Reward Circuit In laboratory animals repeated exposure to the drug results in enhanced responses to it (sensitization) that have been hypothesized to underlie addiction. Here we tested if, in humans addicted to cocaine, there is an enhancement of DA release and of the reinforcing effects of the drug. For this purpose we compared the changes in DA and the behavioral effects of intravenous MP between cocaine abusers (n=20) and controls (n=20)

Self Reports of Drug Effects After iv MP in Controls and in Cocaine Abusers High Craving Placebo MP 2 4 6 8 10 2 4 6 8 10 P < 0.001 P <0.001 Self Report Self Report Craving (0-10) (0-10) Controls Abusers Controls Abusers Cocaine abusers showed decreased drug induced increases in rewarding responses and enhanced drug craving Volkow et al., Nature 386:830-833, 1997.

Methylphenidate-induced Increases in Striatal DA in Controls and in Cocaine Abusers Normal Control Cocaine Abuser Placebo MP 5 10 15 20 25 30 35 P < 0.003 % Change Bmax/Kd 21% 9% Controls (n = 20) Abusers (n = 20) Cocaine abusers showed decreased DA increases and reduced reinforcing responses to MP Volkow et al., Nature 386:830-833, 1997.

In rats when a neutral stimulus is repeatedly paired with the drug Hipp Amyg MEMORY/ LEARNING 2. Memory circuit In rats when a neutral stimulus is repeatedly paired with the drug (conditioned), it elicits DA increases and reinstates drug self- administration. 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 Here we tested if conditioned stimuli increase DA in addicted subjects and its relationship to drug craving

Volkow et al. J Neuroscience 2006. [11C]Raclopride Binding In Cocaine Abusers (n=18) Viewing a Neutral and a Cocaine-Cue Video Neutral video Viewing a video of cocaine scenes decreased specific binding of [11C]raclopride presumably from DA increases Volkow et al. J Neuroscience 2006.

Cue-induced increases in DA were associated with craving Relationship between Cue-Induced Decreases in [11C]raclopride Binding and Cocaine Craving -0.50 0.0 0.50 1.0 1.5 2.0 2.5 -40 -30 -20 -10 10 20 30 Putamen Neutral P < 0.002 Cocaine-Cues Change in Craving (Pre - Post) 2.00 2.50 3.00 3.50 P < 0.01 Bmax/Kd P < 0.05 Caudate Putamen % Change Bmax/Kd Volkow et al J Neuroscience 2006. Cue-induced increases in DA were associated with craving

Motivation & Executive Control Circuits ACG OFC SCC INHIBITORY CONTROL EXECUTIVE FUNCTION PFC MOTIVATION/ DRIVE Motivation & Executive Control Circuits DA is involved not only with reward and prediction of reward but also with motivation and executive function via its regulation of frontal activity. Here we tested if, in addicted subjects, changes in DA function were linked with disruption of frontal activity as assessed by brain glucose metabolism. We assessed the relationship between DA markers and frontal activity in cocaine (n=20) and in methampethamine abusers (n =20) and controls

Adapted from: Volkow et al., J Clin Invest 111(10):1444-1451, 2003. Dopamine Measures Obtained DA D2 Receptors Anatomy DA DA DA DA DA DA DA signal Metabolism Dopamine Synapse Adapted from: Volkow et al., J Clin Invest 111(10):1444-1451, 2003.

Volkow et al., Synapse 14(2): 169-177, 1993. Effect of Cocaine Abuse on Dopamine D2 Receptors normal subject cocaine abuser (1 month post) cocaine abuser (4 months post) Volkow et al., Synapse 14(2): 169-177, 1993.

DA D2 Receptors in Controls and in Cocaine Abusers (NMS) Normal Controls Cocaine Abusers 1.5 2 2.5 3 3.5 4 4.5 15 20 25 30 35 40 45 50 DA D2 Receptors (Ratio Index) 1.6 1.8 2 2.2 2.4 2.6 2.8 3 3.2 Bmax/Kd 20 25 30 35 40 45 50 Age (years) Volkow et al., Neuropsychopharmacology 14(3):159-168, 1996.

Dopamine D2 Receptors are Lower in Addiction DA Cocaine DA DA DA DA DA DA DA DA DA DA DA Reward Circuits Meth Non-Drug Abuser DA D2 Receptor Availability Reward Circuits DA Drug Abuser Alcohol Heroin Adapted from Volkow et al., Neurobiology of Learning and Memory 78:610-624, 2002. control addicted

Effects of Tx with an Adenovirus Carrying a DA D2 Receptor Gene into NAc in DA D2 Receptors Overexpression of DA D2 receptors reduces alcohol self-administration 60 1st D2R Vector p < 0.0005 2nd D2R Vector 50 p < 0.0005 40 p < 0.005 p < 0.005 Percent Change in D2R 30 20 p < 0.10 10 Null Vector 4 6 8 10 24 -20 DA DA % Change in Alcohol Intake -40 DA p < 0.01 DA p < 0.01 DA -60 DA p < 0.001 DA DA -80 p < 0.001 p < 0.001 -100 4 6 8 10 24 Thanos, PK et al., J Neurochem, 78, pp. 1094-1103, 2001. Time (days)

Brain Glucose Metabolism in Cocaine Abusers (n=20) and Controls (n=23) CG 40 45 50 55 60 Controls Abusers CG micromol/100g/min P < 0.01 OFC 40 45 50 55 60 Controls Abusers micromol/100g/min Volkow et al., AJP 156:19-26, 1999. P < 0.005

DA D2 Receptors (Ratio Index) Correlations Between D2 Receptors in Striatum and Brain Glucose Metabolism 30 35 40 45 50 55 60 65 1.8 2 2.2 2.4 2.6 2.8 3 3.2 3.4 DA D2 Receptors (Ratio Index) OFC umol/100g/min r = 0.7, p < 0.001 Cocaine Abusers Striatum CG PreF OFC Volkow et al., Synapse 14(2):169-177, 1993. 30 40 50 60 70 80 90 METH Abusers control cocaine abuser umol/100gr/min OFC r = 0.7, p < 0.005 2.9 3 3.1 3.2 3.3 3.4 3.5 3.6 DA D2 Receptors (Bmax/kd) Volkow et al., AJP 158(3):377-382, 2001.

DA D2 Receptors and Relationship to Brain Metabolism in Subjects with Family History for Alcoholism 0.900 0.950 1.00 1.05 1.10 1.15 1.20 1.25 1.30 Relative metabolism OFC 4.0 4.2 4.4 4.6 4.8 5.0 0.750 0.800 0.850 0.900 0.950 1.00 1.05 Relative metabolism CG Correlations between Metabolism and D2R P <0.005 4.0 4.2 4.4 4.6 4.8 5.0 D2R (Bmax/Kd) DA D2R were associated with metabolic activity in OFC, CG and dorsolateral prefrontal cortex Volkow et al. Arch Gen Psychiatry 2006.

GO Non-Addicted Brain Addicted Brain STOP Memory Memory Drive Drive Saliency Control Drive OFC Saliency NAc Memory Amygdala Control CG Drive Memory Saliency STOP GO Adapted from: Volkow et al., J Clin Invest 111(10):1444-1451, 2003.

STOP GO Medications for Relapse Prevention Drive Addicted Brain Strengthen reinforcing effects of non-drug reinforcers Addicted Brain Drive Control Saliency Memory GO STOP Saliency Drive Control Memory Non-Addicted Brain Strengthen inhibitory control Strengthen prefrontal-striatal communication Interfere with conditioned memories (craving) Counteract stress responses that lead to relapse Adapted from: Volkow et al., J Clin Invest 111(10):1444-1451, 2003.

Brookhaven PET Group 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