The Neurobiology of Free Will In

1. The Neurobiology of Free Will In ADDICTIVE DISORDERS Nora D. Volkow, M.D. Director 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. Self-Reports (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 Volkow et al., JPET 291(1):409-415, 1999.

4. REWARD NAcc VP • 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)

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

6. Methylphenidate-induced Increases in Striatal DA in Controls and in Cocaine Abusers 35 Placebo MP 30 25 20 15 10 5 0 Normal Control Cocaine Abuser 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.

7. Hipp MEMORY/ LEARNING DA Release NAc Auditory cue Amyg 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. 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 subjectsand its relationship to drug craving

8. [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.

9. 3.50 3.00 Putamen 2.50 2.5 2.00 2.0 1.5 Change in Craving (Pre - Post) 1.0 0.50 0.0 30 20 10 0 -10 -20 -30 -40 -0.50 Relationship between Cue-Induced Decreases in [11C]raclopride Binding and Cocaine Craving Cue-induced increases in DA were associated with craving Neutral P < 0.002 Cocaine-Cues P < 0.01 P < 0.05 Bmax/Kd Caudate Putamen % Change Bmax/Kd Volkow et al J Neuroscience 2006.

10. EXECUTIVE FUNCTION PFC ACG INHIBITORY CONTROL OFC SCC 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

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

12. 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.

13. 4.5 4 3.2 3 3.5 2.8 DA D2 Receptors (Ratio Index) 2.6 3 2.4 2.2 2.5 2 1.8 2 1.6 20 25 30 35 40 45 50 1.5 15 20 25 30 35 40 45 50 DA D2 Receptors in Controls and in Cocaine Abusers (NMS) Normal Controls Cocaine Abusers Bmax/Kd Age (years) Volkow et al., Neuropsychopharmacology 14(3):159-168, 1996.

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

15. 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 2nd D2R Vector p < 0.0005 50 p < 0.0005 40 p < 0.005 p < 0.005 30 Percent Change in D2R 20 p < 0.10 10 0 Null Vector 6 10 4 8 24 0 0 -20 DA DA -40 p < 0.01 % Change in Alcohol Intake DA DA p < 0.01 DA -60 DA p < 0.001 DA -80 DA p < 0.001 p < 0.001 -100 0 4 6 8 10 24 Time (days) Thanos, PK et al., J Neurochem, 78, pp. 1094-1103, 2001.

16. 60 55 50 45 40 Controls Abusers 60 55 50 45 40 Controls Abusers Brain Glucose Metabolism in Cocaine Abusers (n=20) and Controls (n=23) CG CG micromol/100g/min P < 0.01 OFC micromol/100g/min P < 0.005 Volkow et al., AJP 156:19-26, 1999.

17. 90 Cocaine Abusers 65 60 55 CG OFC 80 50 umol/100g/min 45 PreF Striatum 40 70 r = 0.7, p < 0.001 35 OFC 30 1.8 2 2.2 2.4 2.6 2.8 3 3.2 3.4 60 DA D2 Receptors (Ratio Index) 50 40 30 2.9 3 3.1 3.2 3.3 3.4 3.5 3.6 control cocaine abuser Correlations Between D2 Receptors in Striatum and Brain Glucose Metabolism Volkow et al., Synapse 14(2):169-177, 1993. METH Abusers OFC umol/100gr/min r = 0.7, p < 0.005 DA D2 Receptors (Bmax/kd) Volkow et al., AJP 158(3):377-382, 2001.

18. 1.30 1.25 1.20 1.15 1.10 1.05 1.00 0.950 0.900 4.0 4.2 4.4 4.6 4.8 5.0 1.05 1.00 0.950 0.900 0.850 0.800 0.750 4.0 4.2 4.4 4.6 4.8 5.0 DA D2 Receptors and Relationship to Brain Metabolism in Subjects with Family History for Alcoholism Relative metabolism OFC Relative metabolism CG Correlations between Metabolism and D2R P <0.005 D2R (Bmax/Kd) DA D2R were associated with metabolic activity in OFC, CG and dorsolateral prefrontal cortex Volkow et al. Arch Gen Psychiatry 2006.

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

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

21. 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