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NicotineNicotine Dependence p
Treatment: From M t M tMouse to Man to
Medicine
Caryn Lerman, Ph.D. yTransdisciplinary Tobacco Use Research Center UPENNUPENN
About this presentation
Dr Lerman presented this onDr. Lerman presented this on December 1, 2009, as the Distinguished Lecture of the Institute for HealthLecture of the Institute for Health Research and Policy and the Center for Clinical and Translational Research atClinical and Translational Research at the University of Illinois at Chicago. The UIC CCTS is supported by the NationalUIC CCTS is supported by the National Center for Research Resources, Award No UL1RR029879 For moreNo. UL1RR029879. For more information, see www.ihrp.uic.edu.
Our Challenge
• 1 in 5 Americans is tobacco dependent.p• Current FDA-approved medications are
successful for only 1 in 3 smokers.successful for only 1 in 3 smokers.
Tobacco Use Research Center P50 (1999- 2014)Scientific Mission
To translate discoveries inTo translate discoveries in neuroscience, pharmacology, genetics and behavioral sciencegenetics and behavioral science to improve treatment for nicotine dependencedependence
Treatment Development for Tobacco Dependence
Target Identification (Discovery)
Transcriptional Profiling
Human Genetics
Initial Target ValidationProof of
MechanismInitial Target Validation(Development)Imaging
Mechanism Testing in
Rodents and Humans
Early Human Screening Models
Behavioral Pharmacology
Cost-Effectiveness
AnalysisTargeted Therapy
PharmacogeneticsTargeted Therapy
Trials
Nicotine Addiction is a Chronic, Relapsing Brain Disease
Lerman et al. Nature Reviews Drug Discovery, 2007
Nicotine-related Brain Reward Pathway
COMT
COMT val158met Polymorphism Predicts Smoking Relapse in Independent StudiesSmoking Relapse in Independent Studies
Odds Ratio
Case-Control Study (n=785)
Prospective Clinical Trial (n=290)
3.2
3
3.5Ratio (n 785)
OR (relapse v. quit)
(n 290)
OR (current v. former smoker)
2.5
3P=0.03 P=0.03
1.45 1 4
1.82
1.01 1.01
1.45 1.4
1
1.5
met/met val/met val/val met/met val/met val/val
Colilla et al., Pharmacogenetics and Genomics, 2005
met/met val/met val/val met/met val/met val/val
COMT is a Potential Therapeutic Targetp g
• Methylation enzyme involved in the inactivation of dopamineof dopamine
• Common functional val158met variant (1 in 4 are val/val)are val/val)
• Val allele is associated with an increase in COMT activity and corresponding decrease in dopamine in frontal cortex
• Carriers of the val allele exhibit deficits in cognitive functioncognitive function
Hypothesis: Nicotine deprivation will produce cognitive deficits in smokers with val/val genotypes, an effect that may prompt
smoking relapse to reverse deficits.
Imaging-Based Target Validation
Prospective genotyping
met/met: n=11
val/met: n=12
val/val: n=10
Smokers scanned on two occasions (counterbalanced): (1)
ki l (2) >14 hsmoking as usual vs. (2) >14 hrs. abstinent (confirmed with CO)
Fractal N-back (Working Memory Task)
0 – back Press the button when you 1 – back Press the button when the pict re is the same as the one immediatel
Participant responds to stimuli based on 3 rules:
see the target picture picture is the same as the one immediately before
2 – back Press the button when the picture is the same as the one two before
3 – back Press the button when the picture is the same as the one three before
Brain Signature of Abstinence Effect on Cognitive Function in COMT val/val group
Dorsolateral prefrontal cortex
Genotype x abstinence effect (p=0.0005)
•Brain activation in smokers with val/val genotypes is reduced in abstinence during performance of difficult cognitive task•Reduced activation is liked with slower performance in val/val
Loughead et al, Molecular Psychiatry, 2009
Reduced activation is liked with slower performance in val/val group at higher task difficulty (p=0.03)
Tolcapone as a “Tool Compound” for Proof of Mechanism Studyfor Proof of Mechanism Study
• Inhibitor of COMT in central• Inhibitor of COMT in central nervous system
• FDA-approved for the treatment of Parkinson’streatment of Parkinson s Disease
• Cognitive enhancing effects
Phase I Safety Study of Tolcapone in Smokers
•Short-term (7-day) treatment with tolcaponeCorrect response time (ms) on treatment with tolcapone 200mg t.i.d. is safe and well tolerated by smokers
Correct response time (ms) on working memory task
1520
VALMET
•Tolcapone (v. placebo) decreased speed of 0
510
MET
pperformance in val/val group, but not the met/met group
-20-15-10-5
•Reversal of dopaminergic d fi it i l/ l
-25-20
n=8 n=8deficit in val/val group may reduce abstinence-induced cognitive deficits
Phase II Study of Tolcapone in Smokers
Reversal of abstinence-induced cognitive deficits by tolcapone will provide “proof of mechanism”
Day 14 – 27 WASH-OUT
PLACEBO/TOLCAPONE® TOLCAPONE®/PLACEBO
Medication run up Medication run up
Day 1 - 9 Day 28 - 37Day 10 - 13 Day 38 - 41
3.5 days mandatory 3.5 days mandatory abstinence
abstinence (CO confirmed)
abstinence
fMRI Scan fMRI Scan
Correct Reaction Time ± 1 SE Faster (lower) reaction700
800
Correct Reaction Time ± 1 SE Faster (lower) reaction time on the N-back
400
500
600 working memory task predicts 7-day quit
200
300
400
success (p=.01; r2=.15)
0
100
Relapsers Abstainers Relapsers Abstainers
Variable Beta T p Model R2
Sex -0.015 0.104 .92 .01Baseline cigs. per day 0.437 3.049 .005 .15Baseline 3-Back performance -0.030 -0.166 .87 .25Abstinent 3-Back performance -0.482 -2.651 .013 .40
Summary: COMTCOMT val allele is risk
factor for nicotine dependence
Cognitive deficits are a core symptom of dependence and
predict relapse
Smokers with val/val genotype have altered brain function and cognitive deficits inbrain function and cognitive deficits in
abstinenceProof of mechanism experiments (tolcapone)
val
C t b h i l ti d h l i idConvergent behavioral, genetic, and pharmacologic evidence would support COMT as a therapeutic target for tobacco
dependence
Treatment Development for Tobacco Dependence
Target Identification (Discovery)
Transcriptional Profiling
Human Genetics
Initial Target ValidationProof of
MechanismInitial Target Validation(Development)Imaging
Mechanism Testing in
Rodents and Humans
Early Human Screening Models
Behavioral Pharmacology
Cost-Effectiveness
AnalysisTargeted Therapy
PharmacogeneticsTargeted Therapy
Trials
Opioid Mechanisms in Nicotine Reward
Nestler
Mouse Model of Nicotine Reward
Preconditioning DayA B
Day 1
A B
C
S
A B
C
S Pairing Days 2-8
A BC
S
A BC
S ??Test Day
Work by Julie Blendy
Naloxone on Test Day Blocks Conditioned Rewarding Effects of Nicotine in 129/C57 B16 MiceEffects of Nicotine in 129/C57 B16 Mice
400.00500.00
Saline
Treatment on Test Day*
n
100 00200.00300.00 Naloxone
s tim
e on
-100.000.00
100.00
red
min
usnp
aire
d
400 00-300.00-200.00
me
on p
air un
-500.00-400.00
SalineNicotine
(1.0mg/kg)Tim
Nicotine (2.0mg/kg)
Nicotine on Pairing Days*p<.05
Walters et al, Neuron, 2005
Nicotine on Pairing Days
The Human OPRM1 GenePROMOTOR EXON 1 EXON 2 EXON 3 EXON 4 3’UTR
A118G
•The human OPRM1 gene includes a common Exon 1 Asn40Asp (A118G) mis-sense single nucleotide polymorphism (SNP).
•G allele associated with reduced mRNA expression and protein levels and is present in 25-30% of persons of European ancestry
Hypothesis: Smokers with G allele will have a lower liability to l i ki ti t t trelapse in smoking cessation treatment
Open Label Pharmacogenetic Trial of NRT (TTURC 1, n=600*)( , )
Pre-treatment Assessment & Genotyping
Nicotine nasal TransdermalNicotine nasal spray x 8 wks
Transdermal nicotine x 8 wks
95%
Follow-Up: EOT, 6-months, and 12-months
retention rate
p , ,
*European ancestry only (n=420)
OPRM1 Asn40Asp Variant is Associated with Response to Nicotine Replacement Therapy p p py
60Treatment Phase Follow-up Phase% quit
41.5
52.450
60AA n=238GA GG n=82
Normal
Reduced activity
30
2226.8
33.329.8 31
30
40activity
22
12.51516.215.5
10
20
0All Patch Spray All Patch Spray
OR= 1.9, p=.01 Lerman et al., Pharmacogenomics J, 2004
What is the Mechanism of Enhanced Therapeutic Response in Smokers with the OPRM1 Asp40 (G) allele?Response in Smokers with the OPRM1 Asp40 (G) allele?
1. Do carriers of the OPRM1 G allele (loss of function) exhibit reduced nicotine reinforcement?
2. Does naltrexone reduce nicotine reinforcement particularly in smokersreinforcement—particularly in smokers with OPRM1 G allele?
3. Are females more sensitive to opioid system effects on nicotine reward?
Study Population (n=60)Study Population (n 60)
OPRM1 AA n=30OPRM1 AA n 30OPRM1 AG/GG n=30All European ancestrysmoke >10 cpdsmoke >10 cpd
Within Subject Designj g
Day 1 Day 2 Day 4
Study Phase 1 Study Phase 2Day 3 Day 1 Day 2 Day 3 Day 4
*NTX or PLACEBO *NTX or PLACEBOy
12.5mg*
y25mg*
y50mg*
5-7 day Washout
y50mg*
y12.5mg*
y25mg*
y50mg*
y50mg*
Observation Observation
Test Day Test Day
Observation Period
Observation Period
• CO, medication compliance, side effects assessed in person
• CO, medication compliance, side effects assessed in personassessed in-person
daily.assessed in-person daily.
Nicotine choice paradigm Nicotine choice paradigmNicotine choice paradigm Nicotine choice paradigm
Human Model of Nicotine Reward
• 2 hour deprivation period (to standardize i h i d i iexposure without inducing serious
withdrawal symptoms)
• Initial (blinded) exposure to 4 puffs of Quest cigarettes: denic. (.05 mg) vs nic. (.6 mg)
• Assess subjective effects
• Self-administer 4 puffs from either cigarette at 30 minute intervals in 6 trials over a 3-hour period
• Outcome measure is number of nicotine puffs chosen out of 24 = relative reinforcing value of nicotine
Reduced Activity OPRM1 Allele is A i t d ith R d d Ni ti R dAssociated with Reduced Nicotine Reward
Subjective Ratings (nicotine minus denicotinized cigarette)
1 61.8
2 AA(n=30)G*
Normal activity
11.21.41.6 G*
(n=30)Reduced activity
0.40.60.8
1
00.2
Satisfaction Strengthgp=.05 p=.03
Ray et al. Psychopharmacology, 2006
OPRM1 Genotype Predicts Nicotine Reinforcement in Females but not in Males
number of nicotine puffs in 24 (across treatments)
20AA n=30
24
75% of Puffs from Nicotine75% of Puffs from Nicotine
19.65
18 1815
GA GG n=30
13.58
5
10
50%
0Males Females
P (genotype by gender interaction)=.036Ray et al. Psychopharmacology, 2006
Estrogen Modulation of MOR Binding
Zubieta et al., J Neuroscience, 2006
Naltrexone Does Not Reduce Nicotine Reward or Interact with OPRM1 Genotype
number of nicotine puffs in 24
20
AA24
18.23
18.83
116.38
15
AG/GG
15.5516.38
5
10
0Naltrexone Placebo
Ray et al. Psychopharmacology, 2006
Using Targeted Genetic Mutations in the Mouse to Understand Human OPRM1 SNP (Blendy)( y)
Exon1*
Molecular Cellular Imaging Behavioral
MOPR expression is decreased in A112G knock-in mice
Female G/G mice failed to show a conditioned place preference to morphine-
paired environments (10 mg/kg)
Mague, Isiegas, Huang, Liu-Chen, Lerman, Blendy 2009©2009 by National Academy of Sciences
MOR Binding as Mechanism for Observed OPRM1 Association with Nicotine Reward
2x2 Factorial Design: (1) iv nicotine vs. saline
Association with Nicotine Reward MOR Binding Potential (BP) in Nicotine vs. Placebo Session
BP(within subject); (2) OPRM1 genotype (stratified by sex)
4
5
planic
N=4 (2 sessions/subject)
BP
(stratified by sex)
2
3nic
0
1
0rVST lVST rNAC lNAC rTHAL lTHAL rACC lACC OCC
VST=ventral striatum; NAC-nucleus accumbens; THAL=thalamus; ACC=anterior cingulate cortex; OCC=occipital cortex (reference region)
P=.18 P=.03 P=.14 P=.10 P=.07
ACC=anterior cingulate cortex; OCC=occipital cortex (reference region)
Nicotine abstinence-induced rCBF changes by OPRM1 Genotype g y yp
Hot color means greater in delta rCBF the AA subgroup. The color bar indicates the range of t-values displayed. Spatial location of each slice is indicated by the number in the upper left corner of the slice image and also is labeled by the white lines (for axial slices) and the green lines (for the sagittal slices).
Wang, Ray, Faith, Wileyto, Detre, Lerman, Neuroscience Letters, 2008; J. Neuroscience, 2007
Summary of OPRM1 Work
MOR antagonist blocks nicotine CPP in mice
Preclinical: Blendy Lab Clinical: Lerman Lab
Human OPRM1 G allele associated with quit successnicotine CPP in mice associated with quit success
Nicotine reward reduced in f l G ll l i s
Female mice with equivalent of human OPRM1 G show
female G allele carriersreduced morphine CPP
Smokers with G allele show MOR expression reduced in mice with G allele
less CBF change in nicotine abstinence
P ll l M H t d Eff t Ni ti MOR Parallel Mouse-Human study: Effects on Nicotine on MOR Binding in Males and Females
Treatment Development for Tobacco Dependence
Target Identification (Discovery)
Transcriptional Profiling
Genome-wide Association
Initial Target Validation Proof of M h iInitial Target Validation
(Development)Imaging Mechanism Testing in
Rodents and Humans
Early Human Screening Models
Behavioral Pharmacology
Cost-Effectiveness
AnalysisTargeted TherapyPharmacogenetics and
Targeted Therapy
Targeted Therapy Trials
Can we predict who will benefit from different Can we predict who will benefit from different treatments for smoking cessation?treatments for smoking cessation?treatments for smoking cessation?treatments for smoking cessation?
Nicotine Dependent Smokers Nicotine Dependent Smokers Alter Alter SmokingSmoking to Maintain Nicotine Levels:to Maintain Nicotine Levels:Smoking Smoking to Maintain Nicotine Levels:to Maintain Nicotine Levels:
Nicotine removal (i.e. metabolism)
Nicotine intake (i.e. smoking)
NICOTINENICOTINE COTININECOTININE 3’Hydroxycotinine3’Hydroxycotinine
Active Inactive Inactive
NICOTINENICOTINE COTININE COTININE 3 Hydroxycotinine3 Hydroxycotinine
CYP2A6 CYP2A6CYP2A6 CYP2A6
CYP2A6 Gene Mutations Alter Dependence Phenotypesp yp
Genetically slow metabolizers smoke fewer cigs/day and are
less dependent
CYP2A6 genotype alters enzyme activity and
metabolite ratiop
Malaiyandi et al., Molecular Psychiatry, 2006
Nicotine Metabolic Profile Benowitz et al
NICOTINE-1’-N-OXIDE NORNICOTINENICOTINE
9.8% 0.4%
NICOTINE
4.4%9.8%
NICOTINEGLUCURONIDE
~ 80%4.2% CYP2A6
COTININETRANS-3’-
HYDROXYCOTININE
TRANS-3’-
HYDROXYCOTININECOTININE
13 0% 33 6%
COTININE
GLUCURONIDE COTININE N OXIDETRANS-3’
13.0% 33.6%
GLUCURONIDE COTININE-N-OXIDE NORCOTININE HYDROXYCOTININE
GLUCURONIDE12.6% 2.4% 2% 7.4%
Nicotine Metabolite Ratio is a Phenotypic Measure of CYP2A6 ActivityMeasure of CYP2A6 Activity
• The ratio of nicotine metabolites: i i /3’h d i icotinine/3’hydroxycotinine
• A stable measure of nicotine metabolism rate derived from smoking
• Independent of time since last cigarettep g• Can be measured in plasma, urine or saliva• Reflects both genetic and environmental• Reflects both genetic and environmental
influences on nicotine clearance
Easy to perform in clinical practice
Nicotine Metabolite Ratio Predicts Therapeutic Response to Nicotine Patch
End of Treatment 6-Month Follow-up% Quit
Clinical Pharmacology & Therapeutics, 2006
OR=.72 (.57-.91) p=006)
3-HC: Cotinine Ratio in QuartilesSlow Fast Slow Fast
Nicotine Metabolite Ratio Predicts Response to Nicotine Patch: Independent Validation (n=568)
% QUITPharmacology, Biochem and Behavior, 2009
OR=.54 [95% CI:.36-.82], p=.003
Nicotine Metabolite Ratio Predicts Therapeutic Response to Bupropion (n=414)
% Quit
p p p p ( )
40 Placebo •Decreased quitOR=4.59 (1.5-13.6), p=.006
25
3230 30
3432
30
35Bupropion
Decreased quit rates also observed with placebo
20
15
20
25•Increased liability to relapse in fast metabolizers is10
5
10metabolizers is reversed by bupropion
01st Qrtl 2nd Qrtl 3rd Qrtl 4th Qrtl
Slow Fast
•Fast metabolizers are candidates for b i
Patterson et al., Clinical Pharmacology & Therapeutics, 2008
Slow Fast bupropion
Algorithm for Use of Nicotine Metabolite Ratio to Personalize Smoking Cessation Treatmentto Personalize Smoking Cessation Treatment
Plasma saliva or urinePlasma, saliva or urine Nicotine metabolite ratio
Slo F tSlow Metabolizer
Fast Metabolizer
Nicotine Patch Bupropion or Varenicline
Low costLow toxicity
Higher costGreater toxicity
Summary: Nicotine Metabolism
CYP2A6 gene linked with dependence
phenotypes
Nicotine metabolite ratio is a stable measure of CYP2A6
activity
Genetically slow metabolizers respond well to transdermal nicotine; fast metabolizerstransdermal nicotine; fast metabolizers
respond well to bupropion
Targeted therapy based on nicotine metabolite ratio can be cost-effective
Evidence from prospective targeted therapy trial will support
t l ti t ti
Test kit in development through industry
ll b titranslation to practice collaboration
Summary and Implications y p•Genetics and neuroimaging provide powerful new tools forprovide powerful new tools for probing the biobehavioral basis of nicotine dependencep
•A better understanding of behavior-biology linkages will leadbehavior biology linkages will lead to better treatments and tests to personalize treatment to individual smokers
•Reductions in tobacco use will have a significant public health impact
AcknowledgementsAcknowledgementsCOMT and NeuroimagingCOMT and NeuroimagingR.C. Gur, Loughead, Wileyto, Detre, WangNi ti O i id I t tiNicotine Opioid InteractionsBlendy, Berrettini, Ray, Perkins, Strasser, Jepson
Nicotine MetabolismSchnoll Wileyto PattersonSchnoll, Wileyto, Patterson Rachel Tyndale (U Toronto) Neal Benowitz (UCSF)FundingFundingNCI, NIDA, Commonwealth of PA