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Why do Some Become Addicted? Directions from Current Research John Crabbe, Ph.D. Portland Alcohol Research Center Dept. of Behavioral Neuroscience Oregon.

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Presentation on theme: "Why do Some Become Addicted? Directions from Current Research John Crabbe, Ph.D. Portland Alcohol Research Center Dept. of Behavioral Neuroscience Oregon."— Presentation transcript:

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

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6 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) Facts About Alcoholism and Drug Dependence

7 Often comorbid with depression and anxiety disorders Initial diagnosis is typically in one’s 20’s % of 12 th graders (10% of 8 th 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 More Facts about Alcoholism

8 Often comorbid with depression and anxiety disorders Initial diagnosis is typically in one’s 20’s % of 12 th graders (10% of 8 th 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 More Facts about Alcoholism This is Not Good!

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10 Use of any illicit drug in last month

11 Portland Profile: from Oregon Partnership, 2005

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15 Brain Reward Circuitry

16 Santiago Ramón y Cajal ( )

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

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

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

20 G X E Interaction Risk Factors for Alcoholism or Drug Dependence GENETICENVIRONMENTAL

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

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 Dopamine D2 Receptors and Response to Intravenous Methylphenidate DA D2 receptor availability pleasant unpleasantneutral DA D2 Receptors (Bmax/Kd) unpleasant pleasant Subjects with low receptor availability report MP as pleasant Volkow, Hitzemann et al.

26 "Sylvia" - Nicole Hollander

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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

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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

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

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

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

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

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

39 Olsen et al, Biochem Pharmacol 68: 2004 Schematic of a GABA-A receptor

40 Deleting the α 2 receptor subunit gene

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

42 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

43 Effects of Increasing Brain Dopamine D2 Receptors on Rat Alcohol Drinking % Increase in D2R Time (days) Time (days) % Decrease in Drinking Null Vector 0 D2 Receptors Alcohol Intake A viral vector containing the DRD2 gene was infused into the nucleus accumbens Thanos et al. J Neurochem 78:1094 (2001)

44 Chronic Effects of Alcohol

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

46 WSP mice were bred to have severe alcohol withdrawal Withdrawal Severity

47 Keir & Morrow, Molec Brain Res 25:200 (1994) Genetic predisposition to mild alcohol withdrawal increases the numbers of specific GABA receptor subunits WSR - WSP

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

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

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

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

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

53 Type II Mild Course Non-familial Stress Type I Types of Alcohol Dependence Genes Stress- sensitive Anxiety Depression Impulsivity Aggression Early onset

54 ACETALDEHYDE ALCOHOL ACETATE + CO 2 ALDH2-2 is a clear example of a single gene that unequivocally affects alcoholism risk ADHALDH

55 One Gene Variant Leads to Higher Brain Acetaldehyde Alcohol Acetaldehyde Acetate ALDH 2-1 Alcohol ACETALDEHYDE Acetate ~ 50% of Asians (Japanese, Chinese, Korean) have the ALDH2-2 version of ALDH, a slow- working version. These individuals have much lower rates of alcoholism. ALDH 2-2

56 DISULFIRAM (Antabuse ® ) Inhibits aldehyde dehydrogenase activity Leads to increased acetaldehyde after drinking alcohol Antabuse has for many years helped some to stop drinking Antabuse has recently shown efficacy in a cocaine clinical trial

57 Treatment of Alcoholism 12-Step programs (AA) Cognitive-behavioral therapy Motivational enhancement therapy Drugs (combined with therapy)

58 PROJECT MATCH ( ) Compared outcome efficacy for patients matched to treatments based on a priori hypotheses about 11 client attributes Treatment was for 12 weeks; follow-ups continued for years 12-Step programs, CBT and MET were compared Project MATCH secondary a priori hypotheses. Project MATCH Research Group. Addiction 1997 Dec;92(12):

59 PROJECT MATCH Each of the three methods helped about 20% of those treated There were a few matching effects, and they were weak Project MATCH secondary a priori hypotheses. Project MATCH Research Group. Addiction 1997 Dec;92(12):

60 Drugs Approved for Use Disulfiram (Antabuse) Opioid antagonists Naloxone (Narcan) Naltrexone (Trexan, Revia) Nalmefene (Revex) Acamprosate (Campral) Glutamate – GABA B receptor antagonist

61 The COMBINE Study 11-site clinical trial Naltrexone, acamprosate, or both Medical management vs a combined behavioral intervention Placebo controlled, double-blind About 1400 patients Completed, data expected Fall 2005

62 Other Drugs/Herbs Currently in Use SSRIs (Prozac) Serotonin 3 receptor antagonist Ondansetron (Zofran) Evening primrose Ginseng St. John's Wort Milk Thistle Combinations of the above

63 Ongoing Clinical Trials (NIAAA) Gabapentin (Neurontin: mechanism also unknown) Neurontin + Revia Bupropion (Wellbutrin: mechanism also unknown) NIAAA feels that the biggest problem is getting treatment providers to agree to use drug therapies

64 Ongoing Clinical Trials (NIAAA) Rimonabant (CB1 antagonist) Baclofen (GABA B antagonist) Namenda (memantine: a glutamate antagonist) Kudzu Topamax (topiramate: glutamate? GABA? Na + channels? Ca ++ channels?) Topamax + ondansetron

65 Nearly one-quarter of alcoholics achieved natural recovery (without treatment) Natural recovery was stable (i.e., lasted for 5+ years) 20% of the time In two studies, most change occurred before starting treatment Dawson et al., (2005) Addiction. 100(3): More Factoids about Alcoholism

66 Conclusions Deciding to enter alcoholism treatment may be the most important step There is no strong evidentiary basis for matching patients to particular therapies Different psychotherapeutic approaches are about equally effective, with 1-year success rates of about 20-25%

67 More Conclusions Our understanding of the addicted brain continues to improving There is extensive, but not total, genetic comorbidity among the addictions Genetic studies, particularly with animal models, are leading us to specific brain circuits and specific risk genes, which will lead us to a new generation of drugs

68 Collaborators OHSU-VA Medical Center John Belknap Bob Hitzemann Pamela Metten University of Illinois Justin Rhodes University of Texas Steve Boehm

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