Drug Abuse and Addiction Research EMERGING DIRECTIONS NAMI

1. Drug Abuse and Addiction Research EMERGING DIRECTIONS NAMI Donald R. Vereen, M.D., M.P.H. Special Assistant to the Director National Institute on Drug Abuse National Institutes of Health June 28, 2006

2. Addiction Medical NEUROTOXICITY OBESITY AIDS CANCERMENTAL ILLNESS DRUGS Economic Social HEALTH CARE COSTS PRODUCTIVITY LOSS ACCIDENTS HOMELESSNESS CRIME VIOLENCE

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

4. 2. ADDICTION IS A DEVELOPMENTAL DISEASE starts in adolescence and childhood 1.6% 1.4% 1.2% 1.0% % in each age group who develop first-time cannabis use disorder 0.8% Brain areas where volumes are smaller in adolescents than young adults. 0.6% 0.4% Sowell, E.R. et al., Nature Neuroscience, 2: 859-861, 1999 0.2% 0.0% 5 10 15 18 25 30 35 40 45 50 55 60 65 70 Age Age at cannabis use disorder as per DSM IV NIAAA National Epidemiologic Survey on Alcohol and Related Conditions, 2003

5. 3. ADDICTION INVOLVES MULTIPLE FACTORS Biology/Genes Environment DRUG Brain Mechanisms Addiction

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

7. 1-2 Min 3-4 5-6 6-7 7-8 8-9 9-10 10-20 20-30 Your Brain on Drugs Front of brain Back of brain YELLOWshows places in brain where cocaine goes (Striatum)

8. Effects of Drugs on Dopamine Levels striatum frontal cortex hippocampus substantia nigra/VTA nucleus accumbens Mounts Intromissions Ejaculations COCAINE AMPHETAMINE Accumbens 1100 Dopamine Pathways Principal “Pleasure” System of the Brain Accumbens 400 1000 900 DA 800 DA 300 700 600 % of Basal Release 500 200 % of Basal Release 400 300 100 200 100 0 0 0 1 2 3 4 5 hr 0 1 2 3 4 5 hr Time After Amphetamine Time After Cocaine Source: Di Chiara and Imperato Natural Rewards Elevate Dopamine Levels FOOD SEX 200 200 NAc shell 150 150 100 100 15 % of Basal DA Output 10 Empty DA Concentration (% Baseline) 50 Copulation Frequency Box Feeding 5 0 0 Scr Scr Scr Scr 0 60 120 180 Bas Female 1 Present Female 2 Present 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Time (min) Sample Number Di Chiara et al. Fiorino and Phillips

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

10. Dopamine D2 Receptors are Lower in Addiction DA DA DA DA DA DA DA DA DA DA DA DA Reward Circuits Non-Drug Abuser DA DA DA DA DA DA Reward Circuits Drug Abuser Cocaine Meth DA D2 Receptor Availability Alcohol Heroin control addicted

11. 4.5 4 3.5 3 2.5 2 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 (Bmax/Kd) Age (years)

12. 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 DA % Change in Alcohol Intake 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) Source: Thanos, PK et al., J Neurochem, 78, pp. 1094-1103, 2001.

14. OFC SCC Hipp NAcc VP Amyg Brain Circuits Involved in Drug Addiction EXECUTIVE FUNCTION PFC ACG INHIBITORY CONTROL REWARD MOTIVATION/ DRIVE MEMORY/ LEARNING Neurotransmitters and neuropeptides • Glutamate • Dopamine • Acethyl choline • GABA • CRF • Opiates • Serotonin • Cannabinoids

15. 2. ADDICTION IS A DEVELOPMENTAL DISEASE starts in adolescence and childhood 1.6% 1.4% 1.2% 1.0% % in each age group who develop first-time cannabis use disorder 0.8% Brain areas where volumes are smaller in adolescents than young adults. 0.6% 0.4% Sowell, E.R. et al., Nature Neuroscience, 2: 859-861, 1999 0.2% 0.0% 5 10 15 18 25 30 35 40 45 50 55 60 65 70 Age Age at cannabis use disorder as per DSM IV NIAAA National Epidemiologic Survey on Alcohol and Related Conditions, 2003

16. 3. ADDICTION INVOLVES MULTIPLE FACTORS Biology/Genes Environment DRUG Brain Mechanisms Addiction

17. Biology/Genes Environment DRUG Neurobiology Addiction

18. Biology/Genes Biology/ Environment Interaction Environment DRUG Addiction Addiction Involves Complex Interactions Between Biologicaland EnvironmentalVariables

19. Unexpected MP 70 Glucose Metabolism Was Greatly Increased By the Expectation of the Drug Expected MP 0 µmol/100g/min Source: Volkow, ND et al., Journal of Neuroscience, 23, pp. 11461-11468, December 2003.

20. 1. Experimentation Genes Non specific (i.e Externalizing disorders) Novelty seeking Environment: Drug Availability Alternative reinforcers Stress 2. Pharmacological Response Negative Positive Self limited Repeated use 3. Addiction

21. 1. Experimentation Genes: Non specific: Automedication Specific: sensitivity to reinforcers drug metabolism Environment: Drug availability Sensitization with stress Sensitization by prior drug exposure Alternative reinforcers 2. Pharmacological Response Negative Positive Self limited Repeated use 3. Addiction

22. 1. Experimentation 2. Pharmacological Response Genes: Specific plasticity Environment: drug availability stress prior drug exposure Negative Positive Self limited Repeated use 3. Addiction

23. Non Addicted Brain AddictedBrain Control Control STOP Saliency Saliency Drive Drive GO Memory Memory

24. ADDICTION TREATMENT Requires a Systems Approach DRUGS OF ABUSE social behavior neuronal circuits protein expression genome

25. Therapeutic Implications Suggested by Brain Imaging Studies • Multiprong approach that includes pharmacological and behavioral interventions: • (a) decrease the rewarding value of drugs, • (b) increase the value of non-drug reinforcers, • (c) weaken learned positive associations with drug and drug cues, • (d) strengthen frontal lobe function to provide self-control. • These interventions can be divided into those that • (a) interfere with the acute effects of the drug on DA, • (b) compensate for the chronic effects of long-term use of drugs.

26. Drugs that interfere with the binding of the drug to its target Drugs that block the DA receptors Drugs that interfere with the drug-induced DA increases Drugs that interfere with the postsynaptic responses to DA stimulation Treatments to Interfere with the Acute Effects of the Drug DA Transporter DA Receptors DA DA DA DA DA DA DA DA

27. Increase the amount of DA that is being released as a function of DA cell firing DA DA Increase DA D2 Receptors DA DA Interfere with conditioned responses Promote plasticity of dysfunctional brain circuits Treatments to Compensate for Chronic Effects Linked to Long-Term Use May Include Those That: DA Transporter DA Receptors DA DA DA DA DA DA DA DA

28. Decrease the rewarding value of drugs Increase the rewarding value of non-drug reinforcers CONTROL CONTROL REWARD DRIVE REWARD DRIVE MEMORY MEMORY CONTROL CONTROL Weaken learned positive associations with drugs and drug cues Strengthen frontal control REWARD DRIVE REWARD DRIVE MEMORY MEMORY Treating the ADDICTED Brain