A Team Science Approach to Nicotine Dependence Treatment Caryn Lerman, Ph.D. Center for Interdisciplinary Research on Nicotine Addiction

Continuum of Research Teams Investigator works largely independently on research problem in own lab Each group member brings expertise to address research problems Group members work on separate parts of research problem which later become integrated Data sharing or brainstorming varies from limited to frequent Each team member brings expertise to address common research problem Teams meet regularly to discuss team goals, individuals’ objectives and next steps Team shares leadership responsibility, decision authority, data and credit Level of Interaction and Integration LowHigh IndividualCollaboration Team Science

Team Science 1.Get the right people “on the bus”. 2.Develop a collective vision to address an important scientific, clinical, and or public health problem. 3.Identify a unifying theme that can/must be addressed from a multi-disciplinary perspective. 4.Generate a common conceptual model that links individual scientific projects to address the problem. 5.Develop a common vocabulary through cross-education of team members. 6.Meet often to facilitate synergy across projects and communicate goals and interests. 7.Support junior investigators in all aspects of career development.

Who to get on the bus? Team Science Essentials (smart is not sufficient) Creative Open (cognitive flexibility) Dependable Accessible team science takes extra time

Common vision: Elucidate the cellular, molecular and neural regulation of cognitive and affective responses that promote relapse, and translate findings to improve therapy for nicotine dependence ( ) Julie Blendy multi-PI CIRNA Center for Interdisciplinary Research on Nicotine Addiction (1999- )

Common Conceptual Model Cellular and genomic studies to identify potential targets Screening of novel compounds and repurposed meds Cognitive, neurobiological markers of medication effects A focus on the key clinical endpoint: relapse

A Translational Research Example Opioid genetic mechanisms in nicotine reward and relapse Exon1 *

Opioid Mechanisms in Nicotine Reward Nestler

Mouse Model of Nicotine Reward Preconditioning Day A B DRUG SALINE C C C C S S S S ?? Day 1 Pairing Days 2-8 Test Day Blendy Lab

Naloxone on Test Day Blocks Conditioned Rewarding Effects of Nicotine in 129/C57 B16 Mice Saline Nicotine (1.0mg/kg) Treatment on Test Day *p<.05 * Time on paired minus time on unpaired Walters et al, Neuron, 2005 Nicotine (2.0mg/kg) Nicotine on Pairing Days

The Human OPRM1 Gene PROMOTOR 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 relapse in smoking cessation treatment

Open Label Pharmacogenetic Trial of NRT (n=600*) Nicotine nasal spray x 8 wks Transdermal nicotine x 8 wks Follow-Up: EOT, 6-months, and 12-months Pre-treatment Assessment & Genotyping 95% retention rate *European ancestry only (n=420)

OR= 1.9, p=.01 OPRM1 Asn40Asp Variant is Associated with Response to Nicotine Replacement Therapy Treatment PhaseFollow-up Phase % quit Lerman et al., Pharmacogenomics, 2004 Normal Reduced activity

1.Do carriers of the OPRM1 G allele (loss of function) exhibit reduced nicotine reinforcement? 2. Does naltrexone reduce nicotine reinforcement—particularly in smokers with OPRM1 G allele? 3.Are females more sensitive to opioid system effects on nicotine reward? What is the Mechanism of Enhanced Therapeutic Response in Smokers with the OPRM1 Asp40 (G) allele?

Within Subject Design Day mg* Day 2 25mg* Day 4 50mg* 5-7 day Washout Study Phase 1Study Phase 2 Test Day Day 3 50mg* Day mg* Day 2 25mg* Day 3 50mg* Day 4 50mg* Observation Period *NTX or PLACEBO CO, medication compliance, side effects assessed in- person daily. *NTX or PLACEBO Nicotine choice paradigm N=60, genotype pre-screening, OPRM1 rare allele oversampled

Human Model of Nicotine Reward 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) 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 Associated with Reduced Nicotine Reward Subjective Ratings (nicotine minus denicotinized cigarette) p=.05p=.03 Normal activity Reduced activity Ray et al. Psychopharmacology, 2006

OPRM1 Genotype Predicts Nicotine Reinforcement in Females but not in Males number of nicotine puffs in 24 (across treatments) 24 P (genotype by gender interaction)= % of Puffs from Nicotine 50% Ray et al. Psychopharmacology, 2006

Naltrexone Does Not Reduce Nicotine Reward or Interact with OPRM1 Genotype number of nicotine puffs in 24 24

Using Targeted Genetic Mutations in the Mouse to Understand Human OPRM1 SNP (Blendy Lab) MolecularCellularImagingBehavioral Exon1 *

MOPR expression is decreased in A112G knock-in mice Mague et al, PNAS, 2009 (Blendy Lab) ©2009 by National Academy of Sciences Female G/G mice failed to show a conditioned place preference to morphine-paired environments (10 mg/kg)

2x2 factorial design in 24 smokers, 11C [carfentanil PET imaging]: (1)Nicotine: (nicotine vs. placebo) within subject (n=24) (2)OPRM1 genotype (AA vs. AG/GG) between subject (3) Healthy non-smoking controls (AA vs. AG/GG) (n=20) MOR Binding Availability as Mechanism for OPRM1 Association with Nicotine Reward Collaboration with Andy Newberg, Chaitan Divgi and Gur Lab

MOR Binding Potential by OPRM1 A118G Ray et al., PNAS, 2011

Summary: OPRM1 Cross-species MOR binding studies provide a platform for screening mu opioid receptor modulators OPRM1 G allele is protective for smoking MOR antagonist decreases nicotine reward G allele linked with reduced MOR mRNA and protein in mice; reduced MOR binding in humans Preclinical and clinical receptor studies Preclinical pharmacologyPharmacogenetic Clinical Trial Human behavioral pharmacology Transgenic, molecular pharmacology Human genetic, PET imaging OPRM1 G allele linked to reduced nicotine reward

Riju Ray Mary Falcone Rebecca Ashare Allison Gold Janet Audrain- McGovern Angela Pinto Susan Ware Paul Wileyto Freda Patterson Andrew Strasser Christopher Jepson Leah LaPrate Dan Heitjan Steve Siegel Jill Turner Monica Hilario Steve Mague M Casetllano Carrie Walters Heath Schmidt Robbie Schnoll Don Baldwin David Asch Ken Perkins Ze Wang John Detre Julie Blendy Ruben Gur James Loughead Kosha Ruparel Greg O’Donnel CIRNA Team

Thank you Funding Primary: NCI and NIDA Secondary: Pfizer, AstraZeneca