Title: New Directions in the Prevention and Treatment of Tobacco Addiction
1Nicotine Dependence Treatment From Mouse to Man
to Medicine Team Science PENN TTURC
Abramson Cancer Center
2Overview of Presentation
- Mission, Conceptual Framework, and Integration of
Transdisciplinary Center
- Highlights of Team Science
- Nicotine-Opioid Interactions
- Obesity and Nicotine Dependence
3Nicotine Dependence Treatment
- Despite progress in tobacco control research,
almost one quarter of Americans continue to smoke.
- FDA-approved medications are effective for only a
fraction of smokers. As many as 70 of smokers
respond poorly or not at all to these therapies.
- There is a need to develop new treatment models
that can be readily translated to the clinical
setting to maximize the effectiveness of nicotine
dependence treatment.
4TTURC2 ResearchMission Statement
To translate discoveries in basic neuroscience,
pharmacology, genetics, and behavioral science to
improve treatment for nicotine dependence.
5Pharmacology
Genetics
Physiology
Molecular Neurobiology
Neuro-Imaging
TTURC
Improve Treatments for Nicotine Dependence and
Reduce Tobacco Use
Computational Biology
Policy
Informatics
Communication
Medicine
Psychiatry
Behavioral Science
Research Disciplines
6Transdisciplinary Model of Tobacco Dependence
Treatment
- Intermediate Markers
- Nicotine reward
- Abstinence effects
- Psychological
- Hormonal
- Neurocognitive
- Treatment
- Opioid Antagonists
- Atomoxetine
- Modafinil
- NRT, Bupropion
- Outcomes
- Abstinence
- Relapse Curves
7Translational Model of Tobacco Dependence
Treatment
- Animal Models
- Nanoparticles for delivery
- Mouse genetic models
- Mouse behavioral models
- Neurobiology
Discovery -------------------Development----------
------Delivery
8UPENN TTURC Team Science Highlights
9 Opioid Mechanisms in Nicotine Reward
Nestler, 2005
10Conditioned Place Preference
Day 1
Pairing Days 2-8
??
Test Day
11Naloxone on Test Day Blocks Conditioned Rewarding
Effects of Nicotine in 129/C57 B16 Mice
Treatment on Test Day
Time on paired minus time on unpaired
Nicotine (1.0mg/kg)
Nicotine (2.0mg/kg)
Saline
Nicotine on Pairing Days
plt.05
Walters et al, Neuron, 2005
12The Human OPRM1 Gene
PROMOTOR EXON 1 EXON 2 EXON 3 EXON
4 3UTR
A118G
- Includes a common Exon 1 functional Asn40Asp
(A118G) mis-sense single nucleotide polymorphism
(SNP) - The Asp40 variant alters mRNA expression relative
to the wildtype Asn40 - The Asp40 variant is present in 25-30 of persons
of European ancestry
13Open Label Trial of Nicotine Patch vs. Nicotine
Nasal Spray (n600)
Orientation Screening
Pre-treatment Assessment Genotyping
NS 7 sessions group counseling
TN 7 sessions group counseling
95 retention rate
Follow-Up EOT, 6-months, and 12-months
14OPRM1 Asn40Asp Variant is Associated with
Response to Nicotine Replacement Therapy
CO-verified abstinence
Follow-up Phase
Treatment Phase
OR 1.9, p.01
Lerman et al. Pharmacogenomics Journal, 2004
15What is the Mechanism of Enhanced Therapeutic
Response in Smokers with the OPRM1 Asp40 (G)
allele?
- Do carriers of the OPRM1 G allele (loss of
function) exhibit reduced nicotine reinforcement? - 2. Does naltrexone reduce nicotine
reinforcementparticularly in smokers with OPRM1
G allele? - Are females more sensitive to opioid system
effects on nicotine reward?
16Study Population (n60) OPRM1 Asn40/Asn40
n30OPRM1 Asp40/ n30All European
ancestrysmoke gt10 cpd
17Within Subject Design
Study Phase 1
Study Phase 2
NTX or PLACEBO
NTX or PLACEBO
Day 1 12.5mg
Day 2 25mg
Day 4 50mg
Day 3 50mg
Day 1 12.5mg
Day 2 25mg
Day 3 50mg
Day 4 50mg
5-7 day Washout
Observation Period
Observation Period
Test Day
Test Day
- CO, medication compliance, side effects assessed
in-person daily.
- CO, medication compliance, side effects assessed
in-person daily.
Nicotine choice paradigm
Nicotine choice paradigm
18Nicotine Choice Paradigm
- Smoke own brand cigarette following arrival to
the clinic - 2 hour deprivation period (to standardize
exposure without inducing serious withdrawal
symptoms) - Initial (blinded) exposure to 4 puffs of Quest
cigarettes denic. (.05 mg) vs nic. (.6 mg) with
30-minute interval. Assess subjective effects - Self-administer 4 puffs from either cigarette at
30 minute intervals over a 2-hour period - Standardized puffing procedure no differences
in smoking topography - Outcome measure is number of nicotine puffs
chosen out of 16 relative reinforcing value of
nicotine
Paradigm validated by Ken Perkins (1996, 1999,
2002). nicotine choices sensitive to
differences in deprivation and predicts abstinence
19Reduced Activity OPRM1 Allele is Associated with
Reduced Nicotine Reward
Subjective Ratings (nicotine minus
denicotinized cigarette)
Normal activity
Reduced activity
p.05
p.03
Ray et al. Psychopharmacology, 2006
20OPRM1 Genotype Predicts Nicotine Reinforcement in
Females but not in Males
number of nicotine puffs in 24 (across
treatments)
24
75 of Puffs from Nicotine
50
P (genotype by gender interaction).036
Ray et al. Psychopharmacology, 2006
21Naltrexone Does Not Reduce Nicotine Reward or
Interact with OPRM1 Genotype
number of nicotine puffs in 24
24
Ray et al. Psychopharmacology, 2006
22Using Targeted Genetic Mutations in the Mouse to
Understand Human OPRM1 SNP (Blendy)
Molecular
Cellular
Imaging
Behavioral
23Examine MOR Binding as Mechanism for Observed
OPRM1 Association with Nicotine Reward
2x2 Factorial Design (1) nicotine vs. denic cig
(within subject) (2) OPRM1 genotype
- Hypotheses
- Reduced baseline MOR binding availability
associated with Asp40 allele - Nicotine increases MOR binding in Asn40 but not
Asp40 group - Exploratory analysis of estradiol levels and MOR
binding by OPRM1
In collaboration with Radiologists Andy Newberg
and Chetan Divgi
24Nicotine Reward in Obese Smokers From the
Clinic to the Laboratory
- About 20 of smokers are also obese
-
- Obesity and tobacco use may act synergistically
to increase morbidity and mortality risks - Little is known about smoking behavior and
cessation in obese individuals
256-Month Prolonged Abstinence by Treatment
P.03
P.04
Non-obese Obese Low High
Dependence
BMI
Lerman et al. Annals of Internal Medicine, 2004
26Reinforcing Value of Nicotine Mouse-Human
Research
27Relative Rewarding Value of Nicotine in Obese and
Non-obese Smokers
Mean of nicotine puffs
70 of puffs from nicotine
(SD3.6)
48 of puffs from nicotine
(SD4.6)
(n20)
(n17)
P .002 in linear regression model controlling
for pre-choice CO, cigs/day, own brand, dependence
28Nicotine Reward in Obese and Lean Mice
- At 5 weeks of age, mice (6 per group) were fed
either high fat chow or normal chow for 15 weeks - On avg. obese mice gained 13.5 grams (28 body
fat) compared to 5.0 grams (18 fat) for
leanmice - Nicotine reward tested using conditioned place
paradigm - mRNA samples tested for mu-opioid and leptin
receptors
Work by Julie Blendy, Ph.D.
29Conditioned Place Preference for Nicotine
30mRNA for Mu Opioid and Leptin Receptors
Normal High Fat
Normal High Fat
31Team Science
- Identify the right disciplines
- Identify the right people
- Issues in publication
- Issues in promotion and tenure
32Acknowledgements!
The following scientists contributed to the
research findings in this presentation..
University of Pennsylvania Julie Blendy, Riju
Ray, Janet Audrain, Margaret Rukstalis, Paul
Wileyto, Wade Berrettini, Carrie Walters,
Christopher Jepson, Andrew Newberg, Chetan
Divgi University of Pittsburgh Ken Perkins UCSF
Neal Benowitz