Imaging the Addicted Brain

1. Imaging the Addicted Brain Nora D. Volkow, M.D. Director National Institute on Drug Abuse National Institutes of Health

2. 1100 AMPHETAMINE 1000 900 800 700 600 % of Basal Release 500 400 300 200 100 0 0 1 2 3 4 5 hr frontal cortex Time After Amphetamine FOOD 200 nucleus accumbens VTA/SN 150 100 % of Basal Release Empty 50 Feeding Box 0 0 60 120 180 Time (min) Di Chiara et al. Natural and Drug Reinforcers Increase Dopamine in NAc Drugs of abuse increase DA in the Nucleus Accumbens, which is believed to trigger the neuroadaptions that result in addiction

3. 10 10 8 8 6 6 4 4 Oral MPH (60 minutes) 2 2 m e t h y l p h e n i d a t e 0 40 50 10 20 30 0 0 -2 -10 0 10 20 30 40 Intravenous MPH (1 min) DA and the Rewarding Effects of Drugs in Humans (0-10) 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 Volkow et al., JPET 291:409-415, 1999. D A DA D A D A D A D A D A raclopride D A D A D A High (0-10) D A raclopride D A R D A D A R R D A R R R Change in DA (% change Bmax/Kd) DA increases induced by intravenous but not by oral administration of MPH were associated with the “high”. WHY?

4. 100 100 % Peak 80 80 60 60 40 40 "High" 20 "High" 20 Time (min) 0 0 40 0 30 10 20 50 60 70 80 0 10 20 30 40 50 60 70 80 [11C]Cocaine % Peak [11C]Methylphenidate

5. EXECUTIVE FUNCTION PFC INHIBITORY CONTROL OFC SCC REWARD NAcc MOTIVATION/ DRIVE Pharmacokinetics of Oral and iv MPH in Baboon Brain Oral (slow: NO “high”) iv (fast: intense “high”) 100 Hipp (peak concentration) 80 MP in Striatum ACG 60 Time (min) 40 20 MEMORY/ LEARNING Amyg VP 0 20 40 60 80 100 120 0 Thus the reinforcing effects of drugs are due to their ability to induce FAST DA increases that emulate phasic DA cell signaling (15-30 Hz), which are implicated in reward and conditioning rather than tonic DA cell signaling (2-10 Hz), which are implicated in cognitive, motivational and motoric systems. How are the different brain circuits regulated by Tonic and Phasic DA involved in addiction?

6. REWARD 10 8 6 4 NAcc 2 m e t h y l p h e n i d a t e VP 0 -2 -10 0 10 20 30 40 1. Reward Circuit in Addiction “High” T Y R O S I N E T Y R O S I N E (0-10) Self-Reports 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 Change in Dopamine D A D A raclopride D A R D A D A R R D A Bmax/kd(Placebo - MP) R R R Volkow et al., JPET 291(1):409-415, 1999.

7. 10 10 8 8 6 6 4 4 2 2 0 0 Controls Abusers Controls Abusers Self-Reports of Drug Effects After iv MPH in Controls (n=20) and in Detoxified Cocaine Abusers (n=20) Craving High Placebo MP 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.

8. Methylphenidate-induced Increases in Striatal DA in Controls and in Detoxified 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.

9. 50 40 30 20 Control Subjects 10 Putamen 0 P < 0.05 50 4 40 10 30 20 8 10 0 6 Alcoholic Subjects % Change Bmax/Kd Ventral Striatum 4 P < 0.003 2 0 0 DVR Controls (n=20) Alcoholics (n=20) Placebo MP Methylphenidate-induced Increases in Striatal DA in Controls and in Alcoholic Subjects p < 0.002 High (1-10) Controls Alcoholics Alcoholics had decreased DA release and decreased reinforcing responses to MP Volkow, ND et al., J Neuroscience 27(46), pp. 12700-12706, 2007.

10. MPH-induced Increases in Striatal DA in Controls (n=17) and in Active Cocaine Abusers (n=17) P < 0.001 25 10 20 8 15 % Change Bmax/Kd 6 10 4 5 2 14% 3% 0 Controls Abusers Placebo MPH P < 0.001 (1-10) Self-report High Control subject Controls Abusers Active cocaine abusers showed a marked reduction in MPH-induced DA increases and in its reinforcing effects Cocaine abuser Volkow et al., unpublished.

11. Hipp DA Release NAc Auditory cue Amyg 2. Memory/conditioning • In rats when a neutral stimuli is • repeatedly paired with the drug • (conditioned), it elicits DA • increases and reinstates • drug self- administration MEMORY/ LEARNING 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

12. [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

13. 3.50 3.00 2.50 2.00 Change in Craving (Pre - Post) 30 20 10 0 -10 -20 -30 -40 Relationship between Cue-Induced Decreases in [11C]raclopride Binding and Cocaine Craving Putamen Neutral 2.5 P < 0.002 Cue-induced increases in DA were associated with craving Cocaine-Cues 2.0 1.5 P < 0.01 1.0 P < 0.05 0.50 Bmax/Kd 0.0 -0.50 % Change Bmax/Kd Caudate Putamen Volkow et al J Neuroscience 2006

14. EXECUTIVE FUNCTION PFC ACG INHIBITORY CONTROL OFC SCC MOTIVATION/ DRIVE • 3. Motivation & Executive • Control Circuits • Here we tested if, in addicted subjects, changes in DA function were linked with disruption of frontal activity as assessed by multiple tracer studies that evaluated in the same subject dopamine D2 receptors and brain glucose metabolism (marker of brain function). DA DA DA DA D2 Receptors DA DA DA DA signal Metabolism

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

16. 4.5 4 3.2 3 3.5 2.8 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 DA D2 Receptors (Ratio Index) Bmax/Kd Age (years) Volkow et al., Neuropsychopharmacology 14(3):159-168, 1996.

17. 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 % Change in Alcohol Intake DA -40 p < 0.01 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.

18. Impulsive rats have lower D2R in striatum and are more vulnerable to compulsive cocaine intake than non impulsive rats. WHY?????? Compulsive cocaine SA Impulsive rats have lower D2 receptors in striatum than non impulsive rats High impulsivity predicts compulsive cocaine-taking Dalley JW et al., Science 315, 1267 (2007). Belin D et al., Science 320, 1352 (2008).

19. 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.

20. 90 80 70 60 50 40 30 2.9 3 3.1 3.2 3.3 3.4 3.5 3.6 Correlations Between D2 Receptors in Striatum and Brain Glucose Metabolism Cocaine Abusers 65 60 55 OFC CG 50 umol/100g/min 45 PreF Striatum 40 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 DA D2 Receptors (Ratio Index) METH Abusers OFC umol/100gr/min r = 0.7, p < 0.005 control cocaine abuser DA D2 Receptors (Bmax/kd) Volkow et al., AJP 158(3):377-382, 2001.

21. 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 0.95 0.90 0.85 0.80 0.75 4.2 4.4 4.6 4.8 5.0 4.0 DA D2 Receptors and Relationship to Brain Metabolism in Subjects with Family History for Alcoholism Volkow et al. Arch Gen Psychiatry 2006. OFC Relative metabolism CG Relative metabolism Correlations between Metabolism and D2R P <0.005 D2R (Bmax/Kd) D2R were associated with metabolism in PREFRONTAL regions the disruption of which results in impulsivity and compulsivity

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

23. David Alexoff, Karen Apelskog, Helene Benveniste,Anat Biegon, Elisabeth Caparelli, Pauline Carter, Stephen Dewey,Congwu Du, Richard Ferrieri, Joanna Fowler, Andrew Gifford, Rita Goldstein, Nils Hanik,Fritz hennm Jacob Hooker, Bud Jayne, Kun-eek Kil, Sunny Kim, Payton King, Nelly Klein,Hai-Dee Lee, Jean Logan, Jeming Ma,Martine Mirrione, Lisa Muench, Alicia Reid, Colleen Shea, Wynne Schiffer, Hanno Schieferstein, Matthias Schonberger, David Schlyer, Mike Schueller,Elena Shumay, Peter Thanos, Dardo Tomasi, Frank Telang, Paul Vaska, Nora Volkow, Gene-Jack Wang, Donald Warner, Chris Wong, Youwen Xu, Wei Zhu http://www.bnl.gov/CTN/: supported by DOE-OBER and NIH Mike Rich

24. Source: Dr. Eric Kandel/Columbia University

25. Drug addicted subjects have evidence of DA dyfunction (tonic and phasic) that is associated with disrupted activity in prefrontal activity (OFC, CG and DLPF). • Decreased tonic DA signaling results in impaired prefrontal function including disrupted executive control. • Enhanced phasic DA signaling to conditioned stimuli further inhibits prefrontal striatal regulation triggering compulsive drug seeking and consuming behavior.