Why do Some Become Addicted? Directions from Current Research

1. Why do Some Become Addicted? Directions from Current Research John Crabbe, Ph.D. Portland Alcohol Research Center Dept. of Behavioral Neuroscience Oregon Health & Science University VA Medical Center Supported by NIAAA, NIDA, and the VA

6. Facts About Alcoholism and Drug Dependence • Chronic, relapsing brain diseases • About 5% of the adult population is dependent on alcohol (9% on illicit drugs, and this ignores smoking!) • Men have higher incidence than women • Socioeconomic and ethnic factors don’t affect risk for alcoholism (one exception)

7. More Facts about Alcoholism • Often comorbidwith depression and anxiety disorders • Initial diagnosis is typically in one’s 20’s • 30 - 40% of 12th graders (10% of 8th graders) report having 5 or more drinks in a row during the past 2 weeks • The earlier one starts serious drinking or drug use, the higher the risk of dependence

8. More Facts about Alcoholism This is Not Good! • Often comorbid with depression and anxiety disorders • Initial diagnosis is typically in one’s 20’s • 30 - 40% of 12th graders (10% of 8th graders) report having 5 or more drinks in a row during the past 2 weeks • The earlier one starts serious drinking or drug use, the higher the risk of dependence

9. www.monitoringthefuture.org 28 20 10

10. Use of any illicit drug in last month www.monitoringthefuture.org

11. Portland Profile: from Oregon Partnership, 2005

15. Brain Reward Circuitry

16. Santiago Ramón y Cajal (1852-1934)

17. Transporters Receptors Most psychotherapeutic drugs act on either transporters or receptors

18. Brain Cells Communicate Using Chemical Neurotransmitters Glutamate (excitatory) GABA(inhibitory) Reward pathways uses these plus Dopamine, Serotonin, Acetylcholine

19. Brain Dysregulation in Addiction (CNS activity, mood, behavior) Normal Addicted Koob & LeMoal, Neurobiology of Addiction, 2006

20. Risk Factors for Alcoholism or Drug Dependence GENETIC G X E Interaction ENVIRONMENTAL

21. GENETIC ENVIRONMENTAL Specific genes Family, Peers Workplace Comorbidity Early onset Risk Factors for Alcoholism or Drug Dependence G X E Interaction

22. Data Supporting Genetic Influences • 4-fold increased risk in close relatives (e.g. children, siblings) • Identical vs fraternal twins • Adopted away children still have a 4-fold increase in risk • Work with genetic animal models

23. Behaviors are complex genetic traits MULTIGENIC: Several genes contribute POLYGENIC: Each gene exerts only a small influence Such traits are quantitative (distributed continuously) rather than qualitative (all-or-none) in populations This implies that diagnostic categories are genetically and etiologically heterogeneous

24. Drug-related phenomena contributory to addiction • Initial response to intoxication • Tolerance to intoxicating effects • Changes in rewarding effects • Pathological effects on brain • Withdrawal symptoms

25. 3.8 3.6 3.4 3.2 3 2.8 2.6 2.4 Dopamine D2 Receptors and Response to Intravenous Methylphenidate DA D2 Receptors (Bmax/Kd) unpleasant DA D2 receptor availability pleasant unpleasant neutral pleasant Subjects with low receptor availability report MP as pleasant Volkow, Hitzemann et al.

26. "Sylvia" - Nicole Hollander

27. "Sylvia" - Nicole Hollander

28. Advantages of the Mouse for Genetic Studies • Mice are mammals whose biology is very similar to humans • The mouse and human genetic maps are very similar (~ 80%) • Therefore, finding or manipulating an important gene in mice tells us where to look in humans, and for what

30. Advantages of the Mouse for Genetic Studies • Mice are mammals whose biology is very similar to humans • The mouse and human genetic maps are very similar (~ 80%) • Therefore, finding or manipulating an important gene in mice tells us where to look in humans, and for what

31. Many Genes on Mouse Chromosome 16 are found on Human Chromosomes 3 and 21

32. Advantages of the Mouse for Genetic Studies • Mice are mammals whose biology is very similar to humans • The mouse and human genetic maps are very similar (~ 80%) • Therefore, finding or manipulating an important gene in mice tells us where to look in humans, and for what

34. C57BL/6 (B6) is a high alcohol drinking strain while DBA/2J (D2) are abstainers B6 D2

35. C57/58 Castle’s Japan-NZ Swiss Little’s DBA+ Bagg Wild-derived Mouse strain family tree 1683 SNPs in 102 inbred strains Petkov PM et al. (2004) Genome Res 14:1806

36. Consumption of 10% EtOH (g/kg) [Bachmanov, unpublished]

37. Inbred strain data are highly repeatable Wahlsten, Finn, Bachmanov & Crabbe, in preparation

38. Strains showing high withdrawal (X axis) show low ethanol drinking (Y axis) Metten et al. (1998) Mammalian Genome 9:983

39. Mice with a single GABA-A receptor subunit gene (α2) deleted drank less alcoholand had less severe alcohol withdrawal Boehm et al, Biochem Pharmacol 68:1581 (2004)

40. Studies with Knocked out or Over-expressed Genes • More than 50 genes mutated in mice have been studied for alcohol drinking • About 1/3 decrease drinking • About 1/3 increase drinking • About 1/3 have no effect Crabbe, Phillips, et al. in preparation

41. 60 0 40 -20 20 -40 -60 -80 -100 Effects of Increasing Brain Dopamine D2 Receptors on Rat Alcohol Drinking D2 Receptors A viral vector containing the DRD2 gene was infused into the nucleus accumbens % Increase in D2R 0 6 10 4 8 24 Time (days) Alcohol Intake Null Vector % Decrease in Drinking 0 4 6 8 10 12 20 24 Time (days) Thanos et al. J Neurochem 78:1094 (2001)

42. Chronic Effects of Alcohol

43. Errors Maze-Bright Maze-Dull Selection Generation Parental Population Plomin, Nat Rev Neurosci (2001); adapted from Tryon, J Comp Psychol (1940)

44. WSP mice were bred to have severe alcohol withdrawal Withdrawal Severity

45. Rhodes et al., Physiol Behav 84:53 (2005)

46. Mice drank to intoxication Rhodes et al., Genes Brain Behav, in press

47. Selective Breeding for High Drinking in the Dark 25% of mice now exceed .010% BAL

48. GENETIC ENVIRONMENTAL Specific genes Family, Peers Workplace Comorbidity Early onset Risk Factors for Alcoholism or Drug Dependence G X E Interaction

49. Serotonin Transporter Polymorphism and Depression Caspi et al., Science 301:386 (2003)

50. Type I Stress- sensitive Anxiety Depression ImpulsivityAggression Types of Alcohol Dependence Type II Mild Course Non-familial Early onset Stress Genes