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New Directions in the Prevention and Treatment of Tobacco Addiction

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There is a need to develop new treatment models that can be ... Wileyto, Wade Berrettini, Carrie Walters, Christopher Jepson, Andrew Newberg, Chetan Divgi ... – PowerPoint PPT presentation

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Title: New Directions in the Prevention and Treatment of Tobacco Addiction


1
Nicotine Dependence Treatment From Mouse to Man
to Medicine Team Science PENN TTURC
Abramson Cancer Center

2
Overview of Presentation
  • Mission, Conceptual Framework, and Integration of
    Transdisciplinary Center
  • Highlights of Team Science
  • Nicotine-Opioid Interactions
  • Obesity and Nicotine Dependence

3
Nicotine 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.

4
TTURC2 ResearchMission Statement
To translate discoveries in basic neuroscience,
pharmacology, genetics, and behavioral science to
improve treatment for nicotine dependence.
5
Pharmacology
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
6
Transdisciplinary 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

7
Translational Model of Tobacco Dependence
Treatment
  • Animal Models
  • Nanoparticles for delivery
  • Mouse genetic models
  • Mouse behavioral models
  • Neurobiology

Discovery -------------------Development----------
------Delivery
8
UPENN TTURC Team Science Highlights

9
Opioid Mechanisms in Nicotine Reward
Nestler, 2005
10
Conditioned Place Preference
Day 1
Pairing Days 2-8
??
Test Day
11
Naloxone 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
12
The 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

13
Open 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
14
OPRM1 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
15
What 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?

16
Study Population (n60) OPRM1 Asn40/Asn40
n30OPRM1 Asp40/ n30All European
ancestrysmoke gt10 cpd
17
Within 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
18
Nicotine 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
19
Reduced 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
20
OPRM1 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
21
Naltrexone Does Not Reduce Nicotine Reward or
Interact with OPRM1 Genotype
number of nicotine puffs in 24
24
Ray et al. Psychopharmacology, 2006
22
Using Targeted Genetic Mutations in the Mouse to
Understand Human OPRM1 SNP (Blendy)
Molecular
Cellular
Imaging
Behavioral
23
Examine 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
24
Nicotine 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

25
6-Month Prolonged Abstinence by Treatment
P.03
P.04
Non-obese Obese Low High
Dependence
BMI
Lerman et al. Annals of Internal Medicine, 2004
26
Reinforcing Value of Nicotine Mouse-Human
Research
27
Relative 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
28
Nicotine 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.
29
Conditioned Place Preference for Nicotine
30
mRNA for Mu Opioid and Leptin Receptors
Normal High Fat
Normal High Fat
31
Team Science
  • Identify the right disciplines
  • Identify the right people
  • Issues in publication
  • Issues in promotion and tenure

32
Acknowledgements!
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
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