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

2. Healthy Heart Diseased Heart Decreased Heart Metabolism in Heart Disease Patient ADDICTION IS A DISEASE OF THE BRAIN as other diseases it affects the tissue function Control Cocaine Abuser Decreased Brain Metabolism in Drug Abuse Patient Sources: From the laboratories of Drs. N. Volkow and H. Schelbert High Low

3. ADDICTION INVOLVES MULTIPLE FACTORS Addiction DRUG Brain Mechanisms Biology/Genes John Smith James Smith Ann Jones John Jones Mary Hill Walter Jones James Hill Susan Adams Alice Price Thomas JonesWilliam Price Richard Hill Steven Adams Allison Fields Mary Walters Alice Benson Rebecca Wilson ThomasSmith John Smith EdwardSmith AnneCook JaneWalker John Walker JaneJones Susan Edwards JamesCook Beth Bryson JonathanCook Edward Bryson Amy Mason Beth Carter Environment

4. Anatomy DA signal Dopamine Cell DA Transporters DA Receptors Metabolism Brain Dopamine System

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

6. 2nd D2R Vector 0 10 20 30 40 50 60 Percent Change in D2R 4 6 8 10 24 p < 0.0005 p < 0.005 p < 0.10 p < 0.005 1st D2R Vector 0 N ull Vector - 100 - 80 - 60 - 40 - 20 0 Time (days) 4681024 p < 0.001 % Change in Alcohol Intake p < 0.001 p < 0.01 0 Overexpression of DA D2 receptors reduces alcohol self-administration Overexpression of DA D2 receptors reduces alcohol self-administration Thanos, PK et al., J Neurochem, 78, pp. 1094-1103, 2001. DA Effects of Tx with an Adenovirus Carrying a DA D2 Receptor Gene into NAc in DA D2 Receptors

7. Becomes Subordinate Stress remains Individually Housed Group Housed Morgan, D. et al. Nature Neuroscience, 5: 169-174, 2002. * * S.003.01.03.1.1 0 10 20 30 40 50 Reinforcers (per session) Cocaine (mg/kg/injection) Dominant Subordinate Becomes Dominant No longer stressed Isolation Can Change Neurobiology Effects of a Social Stressor on Brain DA D2 Receptors and Propensity to Administer Drugs

8. ADDICTION CONTRIBUTES TO MANY SERIOUS MEDICAL CONSEQUENCES Mental Illness Cancer Infectious Diseases (HIV, HCV) Cardiac Pulmonary Learning Disorders Obesity Cerebrovascular (strokes) Trauma (accidents)

9. Partial Recovery of Brain Dopamine Transporters in Methamphetamine (METH) Abuser After Protracted Abstinence Normal Control METH Abuser (1 month detox) METH Abuser (14 months detox) 0 3 ml/gm Source: Volkow, ND et al., Journal of Neuroscience 21, 9414-9418, 2001. ADDICTION CAN BE TREATED

10. HIV Seroconversion at 18 Months By Receipt of Treatment 0 0 5 5 10 15 20 25 Rate of Seroconversion (%) Treatment Status No treatment Partial treatment Continuous treatment Source: Metzger, D. S., Woody, G. E., McLellan, A. T., O’Brien, C. P., Druley, P., Navaline, H., De Philipps, D., Stolley, P., & Abrutyn, E. (1993). Human immunodeficiency virus seroconversion among intravenous drug users in- and out-of-treatment: An 18-month prospective follow-up. Journal of Acquired Immune Deficiency Syndromes, 6, 1049-1056. Among IDUs the Most Effective HIV/AIDS Prevention Strategy is Drug Abuse Treatment

11. Medications for Relapse Prevention Addicted Brain Drive Control Saliency Memory GO Strengthen prefrontal- striatal communication Strengthen prefrontal- striatal communication Executive function/ Inhibitory control Executive function/ Inhibitory control Interfere with conditioned memories (craving) Interfere with conditioned memories (craving) Teach new memories Counteract stress responses that lead to relapse Counteract stress responses that lead to relapse Interfere with drug’s reinforcing effects Interfere with drug’s reinforcing effects Vaccines Enzymatic degredation Naltrexone DA D3 antagonists CB 1 antagonists Vaccines Enzymatic degredation Naltrexone DA D3 antagonists CB 1 antagonists Biofeedback Modafinil Bupropion Stimulants Biofeedback Modafinil Bupropion Stimulants Antiepileptic GVG N-acetylcysteine Antiepileptic GVG N-acetylcysteine Cycloserine CRF antagonists Orexin antagonists CRF antagonists Orexin antagonists STOP Drive Control Memory Non-Addicted Brain Saliency Adenosine A2 antagonists DA D3 antagonists Adenosine A2 antagonists DA D3 antagonists

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

13. Cocaine abusers, when directed, can inhibit cue-induced craving and decrease limbic activity No-Inhibition (NI) 2 4 6 8 10 NICI Self-report Craving (1-10) *** Before After p u < 0.001 Cognitive-Inhibition (CI)

14. ACG OFC SCC Hipp NAcc VP Amyg REWARD INHIBITORY CONTROL INHIBITORY CONTROL MEMORY/ LEARNING MEMORY/ LEARNING EXECUTIVE FUNCTION EXECUTIVE FUNCTION PFC MOTIVATION/ DRIVE MOTIVATION/ DRIVE MULTIPLE BRAIN CIRCUITS ARE INVOLVED IN ADDICTION

15. Mapping Drug Risk Factors in a Community Poor family support Drug availability Poverty Crime What are the neurobiological factors that mediate social stressors as a risk factor for drug abuse?