Transcript Document

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 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
More Facts about Alcoholism
•
•
•
•
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
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 Ramón 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
GXE
ENVIRONMENTAL
Interaction
Risk Factors for Alcoholism or
Drug Dependence
GENETIC
Specific
genes
GXE
ENVIRONMENTAL
Family, Peers
Interaction
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
DA D2 receptor availability
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
Subjects with low receptor
availability report MP as pleasant
Volkow, Hitzemann et al.
"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
C57/58
Castle’s
Japan-NZ
Swiss
Mouse
strain
family tree
1683 SNPs
in 102
inbred
strains
Little’s DBA+
Petkov PM et al.
(2004) Genome
Res 14:1806
Wild-derived
Bagg
Consumption of 10% EtOH
(g/kg) [Bachmanov,
unpublished]
Inbred strain data are highly repeatable
Wahlsten, Finn, Bachmanov & Crabbe, in preparation
Strains
showing
high
withdrawal
(X axis)
show low
ethanol
drinking
(Y axis)
Metten et al. (1998) Mammalian Genome 9:983
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
A viral vector
containing the DRD2
gene was infused
into the nucleus
accumbens
% Increase in D2R
Effects of Increasing Brain Dopamine D2
Receptors on Rat Alcohol Drinking
D2 Receptors
60
40
20
0
4
6 8 10
Time (days)
24
Null Vector
Alcohol Intake
0
-20
-40
-60
-80
-100 0
Thanos et al. J Neurochem 78:1094 (2001)
4 6 8 10 12
20
Time (days)
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)
Withdrawal Severity
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
GXE
ENVIRONMENTAL
Family, Peers
Interaction
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
Stresssensitive
Anxiety
Depression
Mild Course
Non-familial
Stress
Genes
ACETALDEHYDE
ADH
ALCOHOL
ALDH
ACETATE + CO2
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
Acetate
ALDH 2-1
Alcohol
ACETALDEHYDE
Acetate
ALDH 2-2
~ 50% of Asians (Japanese, Chinese, Korean)
have the ALDH2-2 version of ALDH, a slowworking 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 – GABAB
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 (GABAB 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 (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
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
University of Texas
Bob Hitzemann
Pamela Metten
Steve Boehm
University of Illinois
Justin Rhodes