Transcript slides - Alcohol and Drug Abuse Institute

Conj 556 “Addiction: Mechanisms, Prevention,
Treatment”
Charles Chavkin
Department of Pharmacology
University of Washington
>150 faculty
Major grants from NIAAA, NIDA, and NIMH
UW Centers:
Addictive Behaviors Research Center
Alcohol and Drug Abuse Institute
Center for Drug Addiction Research
Center for Functional Genomics & HCV-Related Liver Disease
Center for Healthcare Improvement for Addictions, Mental
Illness and Medically Vulnerable Populations
Center for the Study of Health & Risk Behaviors
Fetal Alcohol and Drug Unit
Fetal Alcohol Syndrome Diagnostic & Prevention Network
Innovative Programs Research Group
Social Development Research Group
Societal structure and legal system
MACRO SCALE
Family structure and risky behaviors - initiation of drug use
Underserved populations at risk
INDIVIDUAL
College-age binge consumption, pre-addiction behaviors
Co-morbid psychiatric and addictive disorders
Sequelae of drug abuse: teratogenesis, HIV, HepC
Molecular pharmacology of abused drugs NEURONAL
Animal models of addictive behavior
What does it mean to be a ‘broadly trained’ scientist studying
the basis of addiction: mechanisms, prevention & treatment ?
What does it mean to be a ‘broadly trained’ scientist studying
the basis of addiction: mechanisms, prevention & treatment ?
What are the mechanisms of addictive drug action?
How do the drugs affect the brain to produce craving
and drug compulsion?
How does the underlying brain chemistry affect the
response to drugs?
-- molecular and neuronal basis of behavior
What does it mean to be a ‘broadly trained’ scientist studying
the basis of addiction: mechanisms, prevention & treatment ?
What are the risk factors controlling initiation?
What are the social factors sustaining drug use?
What are the external forces controlling relapse?
What is ‘harm reduction’, and who are ‘at-risk-youth’?
What are the social, biological and genetic factors
controlling addiction risk ?
What does it mean to be a ‘broadly trained’ scientist studying
the basis of addiction: mechanisms, prevention & treatment ?
How do we predict which interventions are likely to
be effective?
How do we design clinical trials that assess
treatment efficacies?
What new behavioral or pharmacological
interventions need to be considered?
What is Addiction? Compulsive, out-of-control drug use, despite
adverse consequences. Substance dependence/abuse. Specific DSM-IV
criteria.
• Voluntary intake
Euphoria
Tolerance
Physical dependence
Sensitization
readily reversible
• Involuntary - compulsive intake
cravings, obsession, self-destructive behavior
Addiction - high relapse risk
DSM-IV Criteria for Substance Dependence
A maladaptive pattern of substance use, leading to clinically
significant impairment or distress, as manifested by three (or more)
of the following, occurring at any time in the same 12-month period:
Tolerance
Withdrawal
Loss of intake control, Craving
Substance acquisition, use and recovery consumes a major
proportion of the affected person’s time
Reduction in alternative activities
Use is continued despite objective evidence of harm
What are the goals of this course? We want you to
understand the major Research themes:
Social forces that control access and initiation of drug use
Individual factors that confer vulnerability
Effective treatment options
Neurobiological effects on brain structure and function
Goals of the course con’t:
What does it mean to be broadly trained? Be able to
intelligently discuss the question:
“What would a CURE for addiction look like?”
What addictive substances will we be considering?
Alcohol
Psychostimulants (cocaine & amphetamine)
Marijuana and hashish
Opiates (heroin, morphine, oxycodone)
Others: nicotine, caffeine, inhalants, hallucinogens,
other prescription drugs…
Behaviors: gambling, over-eating, sex….
Basic Pharmacology of Alcohol (ethyl alcohol)
Non-potent compound: 80 mg/dL (0.08%)
Nonspecific compound:
(1) Potentiates the inhibitory effects of the transmitter GABA by altering the
conformation of the heteropentameric GABAA receptor and increases
Chloride ion entry into neurons.
(2) Inhibits the activation of NMDA-type glutamate receptors reducing
Sodium and Calcium ion entry into neurons.
Basic Pharmacology of Alcohol (con’t)
Acute: produces dose-dependent intoxication, loss of behavioral inhibition,
sedation, impaired judgment, slurred speech, ataxia. At higher doses: loss of
consciousness, anesthesia, coma, respiratory depression, cardiovascular
depression.
Chronic: hepatitis and cirrhosis, gastrointestinal bleeding, hypertension,
thiamine deficiency.
Teratogenicity: fetal alcohol spectrum disorders.
Major molecular pharmacological questions for Ethanol:
How does its binding affect receptor functioning?
Do different receptor isoforms differ in sensitivity?
How does ethanol tolerance occur?
Can a specific antagonist be designed based on an understanding
of ethanol action?
Neural Systems level question:
How does ethanol activate the dopamine-reward pathways to
cause changes in the brain that result in addiction?
Basic Pharmacology of Psychostimulants (cocaine &
methamphetamine, dextroamphetamine, methylphenidate)
Indirect acting sympathomimetics: block the reuptake of the
neurotransmitters: dopamine, norepinephrine and serotonin
NT reuptake
Nerve terminal
Vesicular repackaging
Vesicular fusion and
transmitter release
Basic Pharmacology of Psychostimulants (con’t)
Acute: arousal, euphoria, agitation, restlessness, insomnia,
anorexia, tachycardia, hyperthermia, seizures. Chronic:
psychotic delusions and paranoia.
dopamine - euphoria, motor control, sexual arousal
norepinephrine - affect, arousal, euphoria, learning
serotonin - affect, appetite, sleep, sexual behavior,
anxiety, pain
Major molecular pharmacological questions for
Psychostimulants:
How do cocaine and amphetamine affect synaptic plasticity
leading to long term potentiation (LTP) and cellular events
underlying learning?
How do the effects on dopamine, norepinephrine and
serotonin contribute to the reinforcing and addictive effects
of these drugs?
Can these insights be used to develop new therapeutics able
to block or reverse the addictive effects of
psychostimulants?
Basic Pharmacology of Marijuana and hashish
Marijuana D9Tetrahydrocannabinol (THC) is the Active
alkaloid from the cannabis plant
• Currently the most commonly used illegal drug in US
• Anandamide is the endogenous ligand
• Binds and activates abundant G-protein coupled
receptors in brain (CB1 and CB2); reduces neuronal
excitability by:
- increasing K+ conductance and
- decreasing Ca+ + conductance
•
Rimonabant (Sanofi) is a specific antagonist
Major molecular pharmacological questions for THC:
How does THC tolerance occur?
How will rimonabant or related CB1 antagonists be incorporated
as therapeutics?
Neural Systems level question:
How does THC activate the dopamine-reward pathways to cause
effects resulting in addiction?
Basic Pharmacology of Opiates (heroin, morphine, oxycodone)
•
Mu (), Kappa (), and Delta () type opioid receptors
• Mu receptor activation induces euphoria, Kappa receptor
activation produces dysphoria
• Enkephalins, Endorphins and Dynorphins are the endogenous
ligands that are released during stress to induce analgesia,
immobility (sedation), euphoria or dysphoria.
•
Naloxone, Naltrexone, and Nalmefene are Mu antagonists
• Methadone and Buprenorphine are weak mu agonists used in
opiate addiction treatment.
Major molecular pharmacological questions for Opiates:
How does tolerance occur?
What are the mechanisms of withdrawal?
Neural Systems level question:
How does morphine activate the dopamine-reward pathways to
cause changes in the brain resulting in addiction?
How does the dysphoria induced by kappa receptor activation
affect the motivation to use drugs of abuse?
These are the basic ‘drug facts’ that every addiction
researcher should know.
More detail: see Wikipedia
Addiction is a chronic relapsing disorder. What can we
learn about the molecular pharmacology of relapse?
Drug consumption
What are the neurobiological mechanisms controlling relapse?
tolerance
Compulsive, out-of-control drug use,
despite adverse consequences.
withdrawal
crash
time
relapse
Stress or Cue driven
Stress releases endogenous opioids - drives relapse
Kappa opioid antagonists block stress-induced relapse
buprenorphine is a kappa antagonist.
Dynorphins
Endogenous opioid peptides first detected in early 1970’s
1973 Goldstein first detected dynorphin in pituitary extracts
1979 & 1981 Goldstein reported the sequence of dynorphin A
1982 Numa cloned and sequenced the dynorphin precursor
signal seq
Neoendorphin
Dynorphin A
Dynorphin B
neo
Dyn-A
YGGFLRKYPK
YGGFLRRIRPKLKWDNQ
YGGFLRRQFKVVT
Dynorphins act at kappa opioid receptors
Dyn-B
How do the dynorphins modulate behavior?
QuickTime™ and a
Motion JPEG OpenDML decompressor
are needed to see this picture.
(Pliakas et al., 2001)
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Dynorphin WT
nor-BNI treated
(10 mg/kg i.p.)
Dynorphin KO
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Immobility (sec)
Immobility (sec)
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Vehicle treated
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Day 1
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Trial
McLaughlin et al, 2003
Forced swim stress-induced analgesia is blocked by prodynorphin gene
disruption
Day 1
Day 2
McLaughlin et al, 2003
Dynorphin is a stress hormone; stress affects drug abuse risk; how
does dynorphin release affect cocaine reward?
Day: 1
2
3
Preference test, 30 min
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Forced swim stress exposure
Cocaine conditioning, 30 min
Vehicle conditioning, 30 min
McLaughlin et al, 2003
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Forced swim stress potentiation of cocaine conditioned-place
preference (CPP) mediated by endogenous dynorphins
Prodynorphin gene knockout
Similar block with KOR-/-
Q u ic k T im e ™ a n d a
TI FF ( L Z W ) d e c o m p r e s s o r
a r e n e e d e d t o s e e t h is p ic t u r e .
QuickTime™ and a
TIFF (LZW) decompressor
are needed to see this pic ture.
Q u ic k T im e ™ a n d a
TI FF ( L Z W ) d e c o m p r e s s o r
a r e n e e d e d t o s e e t h is p ic t u r e .
Drug Box Preference (post-pre, sec)
Extinction
Footshock
Cocaine Prime
Control
norBNI
preference
KOR-/-
Redila, unpublished observations
Kappa opioid receptor activation by endogenous
dynorphins during repeated forced swim, chronic social
stress, footshock, and chronic pain produces:
• Stress-induced immobility
• Stress-induced analgesia
• Stress-induced potentiation of cocaine-CPP
• Stress-induced reinstatement of craving
• blocked by norBNI, prodyn-/-, KOR-/-
Since KOR activation produces dysphoria in humans and
aversion in rodents, how does it potentiate reward
mechanisms?
Hypothetical model to explain negative reinforcement
prior to cocaine training
Pre cocaine
Post cocaine
Dm
Dm
(DA, NE + 5HT?)
Stressed
Normal
D m is the hypothetical rewarding valence of cocaine
U50488 (5mg/kg)
time
cocaine (15 mg/kg)
cpp
Kappa receptor activation prior to cocaine potentiates
(McLaughlin et al, 2006)
Does swim stress create KOR dependent
dysphoria?

Cannot use classical CPA conditioning because
of the swim

Pair swim with a smell (olfactory cue); test in a
different environment with access to smell
Olfactory cue
Where in the brain are dynorphins acting to produce
their behavioral effects? (how is the stress-circuit organized?)
What cell types mediate the effects, (immunohistochemistry)
What signal transduction mechanisms are involved, and
How is the processing within the neuronal circuit
affected? (electrophysiology)
Activated kappa opioid receptors are phosphorylated at serine369 by G-protein receptor kinase.
Phosphoselective antibody KOR-P developed to identify sites of
dynorphin action in brain.
Increased KOR-P in
GFAP-ir astrocytes
and
GABAergic neurons
in nAcc
a
b
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Saline **
NorBNI
Odorant
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(+)Stress
Time in "Stress" Side (sec)
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Odorant Aversion Score (sec)
NorBNI
Odorant
(-)Stress
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Odorant-Cocaine Pairing
Preference Score (sec)
Odorant Aversion Score (sec)
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Shock
No Shock
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(+/+)
(-/-)
Prodynorphin
Saline
NorBNI
Land et al, unpublished
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CRF CRF + NorBNI
KORp
SA
CRF
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Aversion Score (sec)
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65Kda
CRF+ KOR
NorBNI (-/-)
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200m
50 m
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Aversion score (sec)
% of Control KORp-IR
a
Saline
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CRF
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Dyn (+/+)
Dyn (-/-)
Behavioral stress (forced swim, social defeat,
neuropathic pain) induce dynorphin release
and KOR activation following CRF-R2
receptor activation.
Dynorphin/KOR activation seems to encode the
aversive (dysphoric) component of chronic
stress by p38 MAPK activation.
Stress/CRF activates dynorphin-KOR systems
broadly in the CNS
Therapeutically, KOR antagonism may potentially
reduce stress-induced addictive drug craving
and reduce relapse risk.
Thanks:
Jay McLaughlin
Ben Land
Mei Xu
Van Redila
Julia Lemos
Mike Bruchas
Shuang Li
Megumi Aita
Dan Messinger
Erica Melief