The Neurobiology of Drug Addiction

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1 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

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

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

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

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

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

7 Neuronal structure (receiving) (sending)

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

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

10 % of Basal Release Effects of Drugs on Dopamine Release Accumbens AMPHETAMINE Much greater DA Activity than DOPAC any HVA Other drug of abuse -causes neurotoxicity hr Time After Amphetamine % of Basal Release Accumbens COCAINE DA DOPAC HVA hr Time After Cocaine % of Basal Release hr Time After Nicotine NICOTINE Accumbens Caudate % of Basal Release Source: Di Chiara and Imperato 0 Accumbens ETHANOL Dose (g/kg ip) hr Time After Ethanol

11 Natural Rewards Elevate Dopamine Levels % of Basal DA Output Empty FOOD Box Feeding NAc shell Time (min) DA Concentration (% Baseline) Sample Number Scr Scr Bas Female 1 Present SEX Scr Mounts Intromissions Ejaculations Scr Female 2 Present Copulation Frequency Source: Di Chiara et al. Source: Fiorino and Phillips

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

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

14 HOW DOES ADDICTION OCCUR?

15 Principles of Behavior Dynamics Prefrontal Cortex Orbitofrontal cortex 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) Activation of Dopamine reward pathway initiates a behavior track (Miller & Cohen, Annu. Rev. Neurosci. 24 [2001] 167) A B C dopamine initiated behavior expressed C B

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

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

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

19 BRAIN IMAGING Positron Emission Tomography Magnetic Resonance Imaging

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

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

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

23 Dependence of Verbal Memory on Striatal 15 Interference recall DAT 15 Delayed recall Number of words R = 0.70 p < Number of words Compromises Cognitive Functions R = 0.64 p < Dopamine transporter Dopamine transporter (Bmax/Kd) (Bmax/Kd) Source: Volkow, N.D. et al., Am J. Psychiatry, 158(3), pp , 2001.

24 MOTOR FUNCTION Slowed gait Impaired balance 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

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

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

28 Their Brains Get Rewired by Drug Use

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

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

31 Chromosomal Locations for Substance Abuse Vulnerability Loci samples, > 2 labs r-sa 4 samples, > 3 labs r-candidate Uhl et al Tr Genetics, updated June 03 >2 samples, >2 labs

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?

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

36 Genetics Gene/ Environment Interaction Environment

37 PET Images: Dopamine Receptor Density More likely to self- administer Cocaine

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

39 Addictive Disorders Often Co-Exist with or Predispose to Mental Disorders DSM IV Manual: Devotes ~ 100 pages to describing addiction and dependence disorders 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 (Note: can we have parity for mental health with- out considering drug abuse?)

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

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

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

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

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

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

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

48 Role of Stress and Trauma

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

50 Anxiety DRUG USE (Self-Medication) CRF What Role Does Stress Play In Initiating Drug Use? CRF STRESS Anxiety

51 Anxiety RELAPSE Prolonged DRUG USE What Happens When A Person Stops Taking A Drug? CRF Abstinence

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

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

54 Use the Science

55 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 Prefrontal Cortex Orbitofrontal cortex A B C dopamine initiated behavior expressed C B

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

59 Principles of Behavior Dynamics Prefrontal Cortex Orbitofrontal cortex A B C dopamine initiated behavior expressed C B

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

61 Principles of Behavior Dynamics Prefrontal Cortex Orbitofrontal cortex A B C dopamine initiated behavior expressed C B

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

63 Principles of Behavior Dynamics Prefrontal Cortex Orbitofrontal cortex A B C dopamine initiated behavior expressed C B

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

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

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

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

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

69 Relieve stress-related drug abuse CRF antagonist Anxiety RELAPSE Prolonged DRUG USE CRF Abstinence

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

Understanding Addiction and Its Impact on the Brain. SDSMA Webinar Matthew Stanley, DO

Understanding Addiction and Its Impact on the Brain SDSMA Webinar Matthew Stanley, DO Estimated Economic Cost to Society Due to Substance Abuse and Addiction: Illegal drugs: Alcohol: Tobacco: $181 billion/year