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Drugs of Abuse

Drugs of Abuse. Americans’ Views of the Seriousness of Health Problems (Top 10 of 36 Problems). Drug abuse. 82%. Cancer. 78%. Drunk driving. 75%. Heart disease. 74%. % saying “very serious problem ”. HIV/AIDS. 73%. Violence. 71%. Child abuse. 69%. Smoking. 68%. Alcohol abuse.

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Drugs of Abuse

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  1. Drugs of Abuse

  2. Americans’ Views of the Seriousnessof Health Problems(Top 10 of 36 Problems) Drug abuse 82% Cancer 78% Drunk driving 75% Heart disease 74% % saying “very serious problem” HIV/AIDS 73% Violence 71% Child abuse 69% Smoking 68% Alcohol abuse 65% Stress 65% Harvard School of Public Health/Robert Wood Johnson Foundation/ICR, August 2000 Drug abuse Cancer Drunk driving Heart disease HIV/AIDS Violence Child abuse Smoking Alcohol abuse Stress

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

  4. 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!

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

  6. Neuronal structure (receiving) (sending)

  7. stimulation vesicle Neuronal terminal • Drug : • cocaine • ritalin transporter Vmat /serotonin • 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) DA/5HT

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

  9. Effects of Drugs on Dopamine Release COCAINE AMPHETAMINE Accumbens 1100 Accumbens 400 1000 900 DA 800 DA 300 DOPAC 700 DOPAC % of Basal Release HVA HVA 600 % of Basal Release 500 200 400 300 100 200 100 0 0 0 1 2 3 4 5 hr Time After Amphetamine Time After Cocaine 250 NICOTINE ETHANOL 250 Accumbens Dose (g/kg ip) 200 Accumbens 200 Caudate 0.25 0.5 150 % of Basal Release 1 2.5 % of Basal Release 150 100 0 2 3 hr 1 0 1 2 3 4 5 hr 100 0 0 0 1 2 3 4hr Time After Nicotine Time After Ethanol Much greater Activity than any Other drug of abuse -causes neurotoxicity Source: Di Chiara and Imperato

  10. FOOD SEX 200 200 NAc shell 150 150 DA Concentration (% Baseline) 100 100 15 % of Basal DA Output 10 Empty Copulation Frequency 50 Box Feeding 5 0 0 Scr Scr Scr Scr 0 60 120 180 Bas Female 1 Present Female 2 Present Mounts Time (min) Sample Number 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Intromissions Ejaculations Source: Di Chiara et al. Source: Fiorino and Phillips Natural Rewards Elevate Dopamine Levels

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

  12. Addiction and tolerance can be synonymous

  13. Pharmacodynamic mechanism of Tolerance

  14. Induction of Tolerance to Morphine

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

  16. Reward Pathways: Role of Opioids

  17. HOW DOES ADDICTION OCCUR?

  18. A Prefrontal Cortex C behavior expressed behavior expressed B C B Orbito- frontal cortex • Principles of Behavior Dynamics • Behavior Tracts Compete for Expression dopamine initiated • 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)

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

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

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

  22. BRAIN IMAGING Positron Emission Tomography Magnetic Resonance Imaging

  23. Decreases in Metabolism in Orbito Frontal Cortex (OFC) control cocaine abuser Volkow et al. Am. J. Psychiatry 148, 621

  24. 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. 8417-8422, October 15, 1998.

  25. 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. 377-382, 2001.

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

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

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

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

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

  31. Their Brains… Get Rewired by Drug Use

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

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

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

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

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

  37. 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)

  38. Genetics May Influence How Neurobiology Interacts With Environment

  39. Genetics Gene/EnvironmentInteraction Environment

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

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

  42. National ComorbiditySurvey (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?)

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

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

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

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

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

  48. Mechanism of action of amphetamine and cocaine

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

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

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