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

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)

More Facts about Alcoholism

• • • •

Often comorbid with depression and anxiety disorders Initial diagnosis is typically in one’s 20’s 30 - 40% 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

• • • •

Often comorbid with depression and anxiety disorders Initial diagnosis is typically in one’s 20’s 30 - 40% 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 This is Not Good!

www.monitoringthefuture.org

28 20 10

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

Portland Profile: from Oregon Partnership, 2005

Brain Reward Circuitry

Santiago Ram ón y Cajal (1852-1934)

Most psychotherapeutic drugs act on either transporters or receptors Transporters Receptors

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

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

Risk Factors for Alcoholism or Drug Dependence

GENETIC G X E Interaction ENVIRONMENTAL

Risk Factors for Alcoholism or Drug Dependence

GENETIC Specific genes G X E Interaction ENVIRONMENTAL Family, Peers Workplace Comorbidity Early onset

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

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

Drug-related phenomena contributory to addiction

• • • • •

Initial response to intoxication Tolerance to intoxicating effects Changes in rewarding effects Pathological effects on brain Withdrawal symptoms

Dopamine D2 Receptors and Response to Intravenous Methylphenidate unpleasant 3.8

3.6

3.4

3.2

3 2.8

2.6

2.4

pleasant unpleasant neutral pleasant Volkow, Hitzemann et al.

Subjects with low receptor availability report MP as pleasant

"Sylvia" - Nicole Hollander

"Sylvia" - Nicole Hollander

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

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

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

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

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

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

Consumption of 10% EtOH (g/kg) [Bachmanov, unpublished]

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

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

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)

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

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 60 40 20 0 4 6 8 10 Time (days) 24 Alcohol Intake 0 -20 -40 -60 -80 -100 Thanos et al. J Neurochem 78:1094 (2001) 0 4 6 8 10 12 Time (days) 20 24

Chronic Effects of Alcohol

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

WSP mice were bred to have severe alcohol withdrawal

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

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

Selective Breeding for High Drinking in the Dark

25% of mice now exceed .010% BAL

Risk Factors for Alcoholism or Drug Dependence

GENETIC Specific genes G X E Interaction ENVIRONMENTAL Family, Peers Workplace Comorbidity Early onset

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

Types of Alcohol Dependence

Type II

Early onset Impulsivity Aggression

Type I

Stress sensitive Anxiety Depression

Mild Course Non-familial

Stress

Genes

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

One Gene Variant Leads to Higher Brain Acetaldehyde

Alcohol Acetaldehyde

ALDH 2-1

Acetate Alcohol ACETALDEHYDE

ALDH 2-2

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.

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

Treatment of Alcoholism

• • • •

12-Step programs (AA) Cognitive-behavioral therapy Motivational enhancement therapy Drugs (combined with therapy)

PROJECT MATCH

(1988-1998)

• • •

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):1671-98

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):1671-98

Drugs Approved for Use

• • •

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

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

• • • • •

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

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

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

More Factoids about Alcoholism

• • •

Nearly one-quarter of alcoholics achieved natural recovery (without treatment) Natural recovery was stable for 5+ years) 20% of the time (i.e., lasted In two studies, most change occurred before starting treatment Dawson et al., (2005) Addiction. 100(3):281-92

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%

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

Collaborators

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