1. The Neurobiology of Drug Addiction The Neurobiology of Drug Addiction Glen R. Hanson, Ph.D., D.D.S. Director, Utah Addiction Center Professor of Pharmacology and Toxicology, U of U Senior Advisor, NIDA Glen R. Hanson, Ph.D., D.D.S. Director, Utah Addiction Center Professor of Pharmacology and Toxicology, U of U Senior Advisor, NIDA

2. Drug Abuse and Addiction are Among the Most Serious Public HealthProblems Facing Our Society Drug Abuse and Addiction are Among the Most Serious Public HealthProblems Facing Our Society and Frequently Coexist with Other Mental and Physical Disorders and Frequently Coexist with Other Mental and Physical Disorders

3. Americans’ Views of the Seriousness of Health Problems (Top Ten of Thirty-Six Problems) 65% 68% 69% 71% 73% 74% 75% 78% 82% Stress Alcohol abuse Smoking Child abuse Violence HIV/AIDS Heart disease Drunk driving Cancer Drug abuse % saying “very serious problem” Harvard School of Public Health/Robert Wood Johnson Foundation/ICR, August 2000 Drug abuse Smoking HIV/AIDS Child abuse Violence Stress Cancer Drunk driving Heart disease Alcohol abuse

4. Two Decades of Neurobiological Research Have Brought Us A New Understanding of Drug Abuse and Addiction, Their Complexity and their Solutions Two Decades of Neurobiological Research Have Brought Us A New Understanding of Drug Abuse and Addiction, Their Complexity and their Solutions

5. We Know That Despite Their Many Differences, Virtually All Abused Substances Enhance Dopamine (neurotransmitter) Activity (particularly related to pleasure, motor, and cognitive function We Know That Despite Their Many Differences, Virtually All Abused Substances Enhance Dopamine (neurotransmitter) Activity (particularly related to pleasure, motor, and cognitive function For Example… Other pathways also involved!

6. Dopamine Pathways Functions reward (motivation) pleasure,euphoria motor function (fine tuning) compulsion perserveration decision making Serotonin Pathways Functions mood memory processing sleep cognition nucleus accumbens hippocampus striatum frontal cortex substantia nigra/VTA raphe

7. Neuronal structure (receiving) (sending)

8. /serotonin Vmat transporter stimulation DA/5HT How some drugs of abuse cause dopamine release: opioids narcotics (activate opioid receptors) nicotine (activate nicotine receptors) marijuana (activate cannabinoid receptors) caffeine alcohol (activate GABA receptors; an inhibitory transmitter) How some drugs of abuse cause dopamine release: opioids narcotics (activate opioid receptors) nicotine (activate nicotine receptors) marijuana (activate cannabinoid receptors) caffeine alcohol (activate GABA receptors; an inhibitory transmitter) Drug : cocaine ritalin vesicle Neuronal terminal

9. Release DA from vesicles and reverse transporter Drug Types: Amphetamines -methamphetamine -MDMA (Ecstasy) Vmat transporter serotonin/ DA/5HT

10. 0 0 100 200 300 400 500 600 700 800 900 1000 1100 0 0 1 1 2 2 3 3 4 4 5 hr Time After Amphetamine % of Basal Release DA DOPAC HVA Accumbens AMPHETAMINE 0 0 100 200 300 400 0 0 1 1 2 2 3 3 4 4 5 hr Time After Cocaine % of Basal Release DA DOPAC HVA Accumbens COCAINE 0 0 100 150 200 250 0 0 1 1 2 2 3 hr Time After Nicotine % of Basal Release Accumbens Caudate NICOTINE Source: Di Chiara and Imperato Effects of Drugs on Dopamine Release Much greater Activity than any Other drug of abuse -causes neurotoxicity

11. 0 0 50 100 150 200 0 0 60 120 180 Time (min) % of Basal DA Output NAc shell Empty Box Feeding Source: Di Chiara et al. FOOD Natural Rewards Elevate Dopamine Levels

12. Implication: Elucidation of the mechanism of drug addiction will help to understand other addictive and motivational behaviors/disorders Elucidation of the mechanism of drug addiction will help to understand other addictive and motivational behaviors/disorders

13. OFC SCC NAcc VP REWARD PFC ACG INHIBITORY CONTROL INHIBITORY CONTROL MOTIVATION/ DRIVE (saliency) MOTIVATION/ DRIVE (saliency) Brain Circuits Involved in Drug Addiction Brain Circuits Involved in Drug Addiction Hipp Amyg MEMORY/ LEARNING MEMORY/ LEARNING

14. HOW DOES ADDICTION OCCUR? HOW DOES ADDICTION OCCUR?

15. Principles of Behavior Dynamics  Behavior Tracts Compete for Expression  Expression is Determined by (i) Dominance of Tracts, (ii) Strength of Prefrontal Cortex to Select, (iii) Relevance or saliency (orbitofrontal cortex)  Expression is Determined by (i) Dominance of Tracts, (ii) Strength of Prefrontal Cortex to Select, (iii) Relevance or saliency (orbitofrontal cortex) A A B C Prefrontal Cortex C C behavior expressed behavior expressed B B behavior expressed  Activation of Dopamine reward pathway initiates a behavior track  Activation of Dopamine reward pathway initiates a behavior track dopamine initiated (Miller & Cohen, Annu. Rev. Neurosci. 24 [2001] 167) Orbito- frontal cortex

16. Principles of Behavior Dynamics A A C B Prefrontal Cortex How does a behavior become an addiction? B B B B Addiction behavior expressed dopamine Orbito- frontal cortex

17. Prolonged Drug Use Changes the Brain and In Fundamental In Fundamental and Long-Lasting Ways Prolonged Drug Use Changes the Brain and In Fundamental In Fundamental and Long-Lasting Ways We Have Generated A Lot of Evidence Showing That… We Have Generated A Lot of Evidence Showing That…

18. We Have Evidence That These Changes Can Be Both Structural and Functional We Have Evidence That These Changes Can Be Both Structural and Functional AND…

19. Positron Emission Tomography BRAIN IMAGING Magnetic Resonance Imaging

20. control cocaine abuser Decreases in Metabolism in Orbito Frontal Cortex (OFC) Decreases in Metabolism in Orbito Frontal Cortex (OFC) Volkow et al. Am. J. Psychiatry 148, 621 Compromise assigning appropriate Value Compromise assigning appropriate Value

21. Source: McCann U.D. et al., The Journal of Neuroscience, 18(20), pp. 8417-8422, October 15, 1998. METH Suppresses Expression of DAT (note: duration of use/3-20 yrs; abstinent/ 1-4 yrs)

22. Comparison Subject METH Abuser Dopamine Transporter Loss After Heavy Methamphetamine Use (PET analysis) Source: Volkow, N.D. et al., Am J. Psychiatry, 158(3), pp. 377-382, 2001.

23. Dependence of Verbal Memory on Striatal DAT R = 0.70 p < 0.005 R = 0.70 p < 0.005 R = 0.64 p < 0.01 R = 0.64 p < 0.01 Interference recall Delayed recall Source: Volkow, N.D. et al., Am J. Psychiatry, 158(3), pp. 377-382, 2001. Compromises Cognitive Functions

24. MOTOR FUNCTION Slowed gait Impaired balance Impairment correlates with damage to dopamine system Impairment correlates with damage to dopamine system

25. Implication: Brain changes resulting from prolonged use of psychostimulants, such as methamphetamine may be reflected in compromised cognitive and motor functioning Brain changes resulting from prolonged use of psychostimulants, such as methamphetamine may be reflected in compromised cognitive and motor functioning

26. Is There Recovery? Good News: After 2 years some of the dopamine deficits are recovering Good News: After 2 years some of the dopamine deficits are recovering Bad News: Functional deficits persist Bad News: Functional deficits persist What does this mean???

27. Reward System in Addiction Cocaine Food Activity of Reward System METH Alcohol Ability to Experience Rewards Is Damaged Ability to Experience Rewards Is Damaged controls treated More Less

28. Get Rewired by Drug Use Get Rewired by Drug Use Their Brains…

29. INHERITED FACTORS (genetic vulnerability-not inevitability) INHERITED FACTORS (genetic vulnerability-not inevitability) Common strategy to investigate are Twin Studies Common strategy to investigate are Twin Studies

30. In General: Inheritability for Drug Abuse Ranges From 40-60% In General: Inheritability for Drug Abuse Ranges From 40-60% Some Variability Between Drugs Some Gender Variability

31. 17 22 r-SA r-candidate r-SA r-candidate 5 5 6 6 3 samples, > 2 labs 4 samples, > 3 labs >2 samples, >2 labs 3 samples, > 2 labs 4 samples, > 3 labs >2 samples, >2 labs Chromosomal Locations for Substance Abuse Vulnerability Loci Uhl et al Tr Genetics, updated June 03

32. Complex genetics Complex phenotypes (expressions) (Relation to Risk Factors?)

33. VULNERABILITY to What? Starting Drug Use? Liking Drugs More? Continuing Drug Use? Becoming Addicted? Specific to A Particular Drug? Starting Drug Use? Liking Drugs More? Continuing Drug Use? Becoming Addicted? Specific to A Particular Drug?

34. For Example- Contribution of Genetic Factors to: Nicotine- Liability to initiate=56% Transition to dependence=70% Smoking persistence= >50% (Lerman & Berrettine, Amer. J. Med. Gen. 54 (2003) 48)

35. Genetics May Influence How Neurobiology Interacts With Environment Genetics May Influence How Neurobiology Interacts With Environment

36. GeneticsGenetics EnvironmentEnvironment Gene/ Environment Interaction

37. PET Images: Dopamine Receptor Density PET Images: Dopamine Receptor Density Morelikely to self- administerCocaineMorelikely administerCocaine

38. Effect of Social Dominance on Cocaine Self -Administration * *.003.01.03.1 0.0 0.5 1.0 1.5 2.0 TOTAL INTAKE (mg/kg/session) Cocaine (mg/kg/injection) Subordinate Dominant Mean intake/session (mg/kg)

39. Addictive Disorders Often Co-Exist with or Predispose to Mental Disorders DSM IV Manual: D evotes ~ 100 pages to describing addiction and dependence disorders DSM IV Manual: D evotes ~ 100 pages to describing addiction and dependence disorders Discusses substance abuse as a confound to diagnosis and Tx Discusses substance abuse as a confound to diagnosis and Tx

40. National Comorbidity Survey (NCS) Nearly half of individuals with a past year substance use disorder also had a mental disorder Mental disorders found to be most prevalent included affective disorders, anxiety disorders, personality disorders, and psychotic disorders Nearly half of individuals with a past year substance use disorder also had a mental disorder Mental disorders found to be most prevalent included affective disorders, anxiety disorders, personality disorders, and psychotic disorders (Note: can we have parity for mental health with- out considering drug abuse?) (Note: can we have parity for mental health with- out considering drug abuse?)

41. Common Underlying Neurobiological Factors Can Be: Common Underlying Neurobiological Factors Can Be: Structural/anatomical (same regions and pathways) Structural/anatomical (same regions and pathways) Neurochemical (imbalance of neurotransmitters) Neurochemical (imbalance of neurotransmitters) Genetic (inherited factors that compromise function) Genetic (inherited factors that compromise function)

42. Because of this overlap, drugs of abuse can cause symptoms that mimic most forms of mental illness Because of this overlap, drugs of abuse can cause symptoms that mimic most forms of mental illness

43. Drug Disorder Cocaine and Methamphetamine Schizophrenia, paranoia, anhedonia, compulsive behavior Schizophrenia, paranoia, anhedonia, compulsive behavior Stimulants Anxiety, panic attacks, mania and sleep disorders Anxiety, panic attacks, mania and sleep disorders LSD, Ecstasy & psychedelics Delusions and hallucinations Alcohol, sedatives, sleepaids & narcotics Alcohol, sedatives, sleepaids & narcotics Depression and mood disturbances Depression and mood disturbances PCP & Ketamine Antisocial behavior

44. Some drugs of abuse have a mechanism of action similar to that of drugs used as psychotherapeutic agents Some drugs of abuse have a mechanism of action similar to that of drugs used as psychotherapeutic agents Significance: rationale for self-administration Significance: rationale for self-administration

45. Serotonin/dopamine synaptic terminal Synaptic vesicle Postsynaptic target Activate transmitter receptors Causes an effect transporter Prozac, Ritalin, & Cocaine block

46. Chronic use of some of these drugs of abuse may alter the way the brain functions, making persons particularly susceptible to mental illness Chronic use of some of these drugs of abuse may alter the way the brain functions, making persons particularly susceptible to mental illness

47. Double People With Comorbid Mental and Addictive Disorders Have a Brain Disease People With Comorbid Mental and Addictive Disorders Have a Brain Disease Double Mental Disorder Mental Disorder Addictive Disorder Addictive Disorder Comorbid Disorders Comorbid Disorders

48. Role of Stress and Trauma

49. The Stress Hormone Cycle Hypothalamus Pituitary Gland Pituitary Gland Adrenal Glands Adrenal Glands Kidneys CRF ACTH CORTISOL Stress Responses CRF: Corticotropin Releasing Factor CRF: Corticotropin Releasing Factor

50. DRUG USE (Self-Medication) STRESSSTRESS CRFCRF AnxietyAnxiety CRFCRF AnxietyAnxiety What Role Does Stress Play In Initiating Drug Use? What Role Does Stress Play In Initiating Drug Use?

51. Prolonged DRUG USE AbstinenceAbstinence RELAPSERELAPSECRFCRF AnxietyAnxiety What Happens When A Person Stops Taking A Drug? What Happens When A Person Stops Taking A Drug?

52. Stress Reliably Reinstates Drug Seeking in Rats Saline Nicotine Nicotine-trained rats Footshock Saline Cocaine Footshock Water Alcohol Footshock Cocaine-trained rats Alcohol-trained rats 0 0 20 40 60 80 100 Responses Inactive Lever Active Lever Saline Heroin Footshock Heroin-trained rats * * * * * * * * 0 0 20 40 60 80 100 Responses From: Psychopharmacology, 1996, 1998, 1999 ; J. Neurosci. 1996

53. CRF 1 Receptor Antagonist Attenuates Stress-Induced Reinstatement of Drug Seeking CRF 1 Receptor Antagonist Attenuates Stress-Induced Reinstatement of Drug Seeking Alcohol-trained rats From: Shaham et al. Psychopharmacology 1998; Le et al. Psychopharmacology, 2000 CP-154,526 Dose (mg/kg, SC) Intermittent Footshock No stress Heroin-trained rats Cocaine-trained rats 0 0 15 * 30 * 0 0 15 30 45 60 Responses (3 hr) * * 0 0 15 30 * 0 0 15 30 45 60 Responses (1 hr) 0 0 15 30

54. Use the Science

55. We Are Capitalizing on Basic Science Discoveries in the Design Of Behavior Therapies and Medications To Treat Addiction We Are Capitalizing on Basic Science Discoveries in the Design Of Behavior Therapies and Medications To Treat Addiction

56. Objectives of Intervention: Rearrange dominance of behavior tracks  contingency management (vouchers)  motivational enhancement  therapeutic communities

57. Principles of Behavior Dynamics A A B C Prefrontal Cortex C C behavior expressed behavior expressed B B behavior expressed dopamine initiated Orbito- frontal cortex

58. Strengthen prefrontal cortex influence (change thinking process) Strengthen prefrontal cortex influence (change thinking process)  cognitive and cognitive behavioral tx (unlearn old habits-suppress; learn new skills)  cognitive and cognitive behavioral tx (unlearn old habits-suppress; learn new skills)  assertiveness training (suppress and express)  assertiveness training (suppress and express)

59. Principles of Behavior Dynamics A A B C Prefrontal Cortex C C behavior expressed behavior expressed B B behavior expressed dopamine initiated Orbito- frontal cortex

60. Alter function of orbitofrontal (saliency) cortex Alter function of orbitofrontal (saliency) cortex  motivational therapy  family therapies

61. Principles of Behavior Dynamics A A B C Prefrontal Cortex C C behavior expressed behavior expressed B B behavior expressed dopamine initiated Orbito- frontal cortex

62. Recovery of function (frontal and obito- frontal cortex) Recovery of function (frontal and obito- frontal cortex)  all treatments that keep brain away from drugs for extended time  all treatments that keep brain away from drugs for extended time

63. Principles of Behavior Dynamics A A B C Prefrontal Cortex C C behavior expressed behavior expressed B B behavior expressed dopamine initiated Orbito- frontal cortex

64. Alleviate underlying psychiatric disorder Alleviate underlying psychiatric disorder  administer: Antidepressants for depression Ritalin for ADHD Sedatives for anxiety  administer: Antidepressants for depression Ritalin for ADHD Sedatives for anxiety

65. Targets of Medication Methadone, LAAM and Buprenorphine Activate opioid receptors Nicotine gum/patch Activate nicotinic receptors Naloxone Block opioid receptors

66. Vmat transporter stimulation DA How some drugs of abuse cause dopamine release: opioids narcotics (activate opioid receptors) nicotine (activate nicotine receptors) How some drugs of abuse cause dopamine release: opioids narcotics (activate opioid receptors) nicotine (activate nicotine receptors) vesicle Neuronal terminal

67. Psychostimulants Enhancing GABA-ergic inhibition (baclofen-muscle relaxant; anti-seizure- Tiagabine) Enhancing GABA-ergic inhibition (baclofen-muscle relaxant; anti-seizure- Tiagabine) Cannabinoid antagonist (rimonabant)

68. Principles of Behavior Dynamics A A B C Prefrontal Cortex C C behavior expressed behavior expressed B B behavior expressed dopamine initiated Orbito- frontal cortex GABA and cannabinoid systems critical for function GABA and cannabinoid systems critical for function

69. Relieve stress-related drug abuse CRF antagonist Prolonged DRUG USE AbstinenceAbstinence RELAPSERELAPSECRFCRF AnxietyAnxiety

70. Science is helping to improve our strategies and successes Science is helping to improve our strategies and successes To be successful, treatment is a Lifetime Process To be successful, treatment is a Lifetime Process Consequence: There is no “ cure ”… Consequence: There is no “ cure ”…