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Why do Some Become Addicted? Directions from Current Research

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Presentation on theme: "Why do Some Become Addicted? Directions from Current Research"— 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 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 comorbid with depression and anxiety disorders Initial diagnosis is typically in one’s 20’s % 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 % 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

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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 (1852-1934)

17 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 Risk Factors for Alcoholism or Drug Dependence
GENETIC Specific genes G X E Interaction 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 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
2.4 2.6 2.8 3 3.2 3.4 3.6 3.8 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

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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

35 Mouse strain family tree
Bagg Swiss Japan-NZ C57/58 Castle’s Little’s DBA+ 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 Schematic of a GABA-A receptor
Olsen et al, Biochem Pharmacol 68: 2004 Schematic of a GABA-A receptor

40 Deleting the α2 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 Boehm et al, Biochem Pharmacol 68:1581 (2004)

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

44 Chronic Effects of Alcohol

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

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 Keir & Morrow, Molec Brain Res 25:200 (1994)

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

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

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

54 ACETALDEHYDE ALCOHOL ACETATE + CO2 ADH ALDH
ALDH2-2 is a clear example of a single gene that unequivocally affects alcoholism risk

55 One Gene Variant Leads to Higher Brain Acetaldehyde
Alcohol Acetaldehyde Acetate ALDH 2-1 Alcohol ACETALDEHYDE Acetate ALDH 2-2 ~ 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.

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 – GABAB 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 (GABAB antagonist) Namenda (memantine: a glutamate antagonist) Kudzu Topamax (topiramate: glutamate? GABA? Na+ channels? Ca++ channels?) Topamax + ondansetron

65 More Factoids about Alcoholism
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):281-92

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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