Research
The Yale-SCOR is organized around research projects and cores. To learn more, explore the tabs below.
Research Projects
Project 1
The primary aims of Project 1 are to identify the brain areas regulated by noradrenergic agents and nicotinic drugs under conditions related to stress-reactivity, and to determine whether stimulation of the noradrenergic system can decrease stress reactivity and dopamine dependent behaviors in a hypercholinergic model of increased stress reactivity in male and female mice. This project will also determine whether the effects of noradrenergic agents on anxiety and nicotine reinforcement depend on expression of nicotinic acetylcholine receptors, the primary target of nicotine in the brain.
Principal Investigator:
Marina Picciotto, Ph.D.
Charles B.G. Murphy Professor of Psychiatry
Professor of Pharmacology and of Neurobiology
Yale University School of Medicine
Co-Investigator:
Yann S. Mineur, Ph.D.
Research Scientist in Psychiatry
Yale University School of Medicine
Medications that target the noradrenergic system are important therapeutics for depression and anxiety disorders. More recently, clinical studies have shown that the α2-noradrenergic receptor (α2AR) agonist guanfacine can decrease stress-induced smoking relapse during acute abstinence, suggesting that targeting the noradrenergic system may aid in smoking cessation through effects on stress pathways in the brain. Acetylcholine (ACh), like the nicotine in tobacco, acts at nicotinic acetylcholine receptors (nAChRs) to regulate behaviors related to anxiety and depression. We therefore investigated interactions between guanfacine and ACh signaling in tests of anxiolytic and antidepressant efficacy in female and male C57BL/6J mice, focusing on the amygdala as a potential site of noradrenergic/cholinergic interaction. The antidepressant-like effects of guanfacine were blocked by shRNA-mediated knockdown of α2AR in amygdala. Knockdown of the high-affinity β2 nAChR subunit in amygdala also prevented antidepressant-like effects of guanfacine, suggesting that these behavioral effects require ACh signaling through β2-containing nAChRs in this brain area. Ablation of NE terminals prevented the anxiolytic- and antidepressant-like effects of the nicotinic partial agonist cytisine, whereas administration of the cholinesterase antagonist physostigmine induced a depression-like phenotype that was not altered by knocking down α2AR in the amygdala. These studies suggest that ACh and NE have opposing actions on behaviors related to anxiety and depression and that cholinergic signaling through β2-containing nAChRs and noradrenergic signaling through α2a receptors in neurons of the amygdala are critical for regulation of these behaviors.
RATIONALE:
The a2A-noradrenergic agonist guanfacine can decreases stress-induced smoking in female, but not male, human smokers. It is not known whether these effects are due to effects on mood regulation and/or result from nicotinic-cholinergic interactions.
OBJECTIVES:
The objective of the study was to determine whether there are sex differences in the effect of guanfacine in tests of anxiolytic and antidepressant efficacy in mice at baseline and in a hypercholinergic model of depression induced by the acetylcholinesterase inhibitor physostigmine.
METHODS:
The effects of guanfacine were measured in the light/dark box, tail suspension, and the forced swim test in female and maleC57BL/6J mice. In parallel, electrophysiological properties were evaluated in the prefrontal cortex, a critical brain region involved in stress responses. c-fos immunoreactivity was measured in other brain regions known to regulate mood.
RESULTS:
Despite a baseline sex difference in behavior in the forced swim test (female mice were more immobile), guanfacine had similar, dose-dependent, antidepressant-like effects in mice of both sexes (optimal dose, 0.15 mg/kg). An antidepressant-like effect of guanfacinewas also observed following pre-treatment with physostigmine. A sex difference in the paired-pulse ratio in the prefrontal cortex (PFC) (male, 1.4; female, 2.1) was observed at baseline that was normalized by guanfacine. Other brain areas involved in cholinergic control of depression-like behaviors, including the basolateral amygdala and lateral septum, showed sex-specific changes in c-fos expression.
CONCLUSIONS:
Guanfacine has a robust antidepressant-like effect and can reverse a depression-like state induced by increased acetylcholine (ACh) signaling. These data suggest that different brain areas are recruited in female and male mice, despite similar behavioral responses to guanfacine.
Project 2
The primary aims of Project 2 are to use PET brain imagining to determine 1) if there are sex differences in dopamine release in healthy tobacco smokers, 2) whether noradrenergic agents differentially attenuate dopamine release between male and female tobacco smokers, and, 3) the relationship between changes in dopamine release and reward, negative affect and inhibitory control.
Principal Investigator:
Kelly P. Cosgrove, Ph.D.
Associate Professor of Psychiatry and of Diagnostic Radiology
Yale University School of Medicine
Cosgrove, KP, Wang, S, Kim, S-J, McGovern, E, Nabulsi, N, Gao, H, Labaree, D, Tagare, H, Sullivan, J, and Morris, ED (2014). Sex-Differences in the Brain's Dopamine Signature of Cigarette Smoking. Journal of Neuroscience,34(50):16851-5. PubMed PMID:25505336; PubMed Central PMCID: PMC4261105. https://pubmed.ncbi.nlm.nih.gov/25505336/
Cigarette smoking is a major public health danger. Women and men smoke for different reasons and cessation treatments, such as the nicotine patch, are preferentially beneficial to men. The biological substrates of these sex differences are unknown. Earlier PET studies reported conflicting findings but were each hampered by experimental and/or analytical limitations. Our new image analysis technique, lp-ntPET (Normandin et al., 2012; Morris et al., 2013; Kim et al., 2014), has been optimized for capturing brief (lasting only minutes) and highly localized dopaminergic events in dynamic PET data. We coupled our analysis technique with high-resolution brain scanning and high-frequency motion correction to create the optimal experiment for capturing and characterizing the effects of smoking on the mesolimbic dopamine system in humans. Our main finding is that male smokers smoking in the PET scanner activate dopamine in the right ventral striatum during smoking but female smokers do not. This finding-men activating more ventrally than women-is consistent with the established notion that men smoke for the reinforcing drug effect of cigarettes whereas women smoke for other reasons, such as mood regulation and cue reactivity. lp-ntPET analysis produces a novel multidimensional endpoint: voxel-level temporal patterns of neurotransmitter release ("DA movies") in individual subjects. By examining these endpoints quantitatively, we demonstrate that the timing of dopaminergic responses to cigarette smoking differs between men and women. Men respond consistently and rapidly in the ventral striatum whereas women respond faster in a discrete subregion of the dorsal putamen.
Guanfacine, a noradrenergic alpha2a agonist, reduced tobacco smoking in a 4-week trial and in animal models has been shown to reduce cortical dopamine release, which is critically involved in the reinforcing effect of tobacco smoking. We measured amphetamine-induced extrastriatal dopamine release before and after treatment with guanfacine with [11C]FLB457, a dopamine D2/D3 receptor radiotracer, and positron emission tomography (PET). Sixteen tobacco smokers had one set of [11C]FLB457 PET scans on the same day, one before and one at 2.5-3 h after amphetamine (0.4-0.5 mg/kg, PO). A subset (n=12) then underwent guanfacine treatment (3 mg/day for 3 weeks) and the set of scans were repeated.
[11C]FLB457-binding potential (BPND) was measured pre- and post amphetamine in extrastriatal brain regions. The fractional change in BPND after vs before amphetamine (Δ BPND) is an indirect measure of DA release and was compared between the untreated and guanfacine-treated conditions. Guanfacine treatment attenuated amphetamine-induced DA release; however, the change was due to a global 8% decrease in baseline BPND from the untreated to the guanfacine-treated condition. Chronic guanfacine treatment reduced [11C]FLB457 BPND in tobacco smokers, suggesting an increase in dopaminergic tone. Guanfacine-induced normalization of dopamine signaling may be an important mesocortical mechanism contributing to its ability to aid in tobacco smoking cessation.
Project 3
The primary aim of Project 3 is to conduct a Phase II double-blind, placebo-controlled study to examine gender differences in the effect of noradrenergic agents to 1) counteract stress-induced effects on smoking behavior and smoking-related reinforcement in the laboratory and 2) improve clinical outcomes during a subsequent brief smoking cessation treatment. In addition, Project 3 will examine potential gender differences in mechanisms underlying stress precipitated smoking lapse and smoking-related reinforcement (e.g., craving, mood, cardiovascular reactivity, HPA axis reactivity, catecholamines, cognitive function).
Principal Investigator:
Sherry A. McKee, Ph.D.
Professor of Psychiatry
Yale University School of Medicine
Stress and pre-frontal cognitive dysfunction have key roles in driving and maintaining smoking, however, there are no current therapeutics for smoking cessation which attenuate the effects of stress on smoking and enhance cognition. Central noradrenergic pathways are involved in stress-induced reinstatement to nicotine in animal models and in the prefrontal executive control of adaptive behaviors. Using a novel translational approach, we report for the first time that guanfacine 1) significantly reduced smoking behavior and craving using a well-validated laboratory analog of stress-precipitated smoking, 2) increased prefrontal activity associated with improved attention and self-control during a cognitive control task, and 3) reduced smoking and improved retention during a subsequent treatment period. Our findings are consistent with preclinical results that guanfacine rescues stress-precipitated decrements in self-control, and support further development of guanfacine as a potential pharmacotherapy for stress-precipitated relapse in smoking cessation.
Preclinical findings support a role for α1-adrenergic antagonists in reducing nicotine-motivated behaviors, but these findings have yet to be translated to humans. The current study evaluated whether doxazosin would attenuate stress-precipitated smoking in the human laboratory. Using a well-validated laboratory analogue of smoking-lapse behavior, this pilot study evaluated whether doxazosin (4 and 8 mg/day) versus placebo attenuated the effect of stress (vs neutral imagery) on tobacco craving, the ability to resist smoking and subsequent ad-libitum smoking in nicotine-deprived smokers ( n=35). Cortisol, adrenocorticotropin, norepinephrine, epinephrine, and physiologic reactivity were assessed. Doxazosin (4 and 8 mg/day vs placebo) decreased cigarettes per day during the 21-day titration period. Following titration, doxazosin (4 and 8 mg/day vs placebo) decreased tobacco craving. During the laboratory session, doxazosin (8 mg/day vs placebo) further decreased tobacco craving following stress versus neutral imagery. Doxazosin increased the latency to start smoking following stress, and reduced the number of cigarettes smoked. Dosage of 8 mg/day doxazosin increased or normalized cortisol levels following stress imagery and decreased cortisol levels following neutral imagery. These preliminary findings support a role for the noradrenergic system in stress-precipitated smoking behavior, and support further development of doxazosin as a novel pharmacotherapeutic treatment strategy for smoking cessation.
Core A: Scientific and Administrative Core
The Yale-SCOR Scientific and Administrative Core provides overall interdisciplinary scientific planning and coordination, fiscal and administrative oversight, and personnel management for the Yale-SCOR’s projects. The Scientific and Administrative Core manages a centralized core battery of assessments to maximize the scientific gain from projects, coordinates research collaborations within our Yale-SCOR and across SCORs, and provides pilot funding to advance women’s health with regard to tobacco use.
Sherry A. McKee, Ph.D. (Principal Investigator)
Professor of Psychiatry
Yale University School of Medicine
The Yale-SCOR has developed a themed issue titled “Innovations in Translational Sex and Gender-Sensitive Tobacco Research" for Nicotine & Tobacco Research published in April 2015. This issue brings together leading tobacco use researchers to report innovative findings on gender/sex differences in factors maintaining tobacco use and how these findings are being translated to treatments. The articles in this issue span preclinical, clinical, laboratory, and epidemiologic methods to advance our knowledge related to gender and tobacco in three important areas of research: (a) the influence of ovarian hormones and menstrual cycle on smoking behavior; (b) stress, negative affect, and withdrawal; and (c) smoking cessation treatments. In conjunction with the publication of the issue, we organized a 4 hour workshop at the recent conference for the Society of Research on Nicotine & Tobacco to educate the tobacco research community on the importance of examining sex and gender differences.
- Commentary: Innovations in Translational Sex and Gender-Sensitive Tobacco Research. Sherry A. McKee, Andrea H. Weinberger
- Sex Differences in Hormonal Responses to Stress and Smoking Relapse: A Prospective Examination. Mustafa al’Absi, Motohiro Nakajima, Sharon Allen, Andrine Lemieux, Dorothy Hatsukami
- Influence of Menstrual Cycle Phase on Neural and Craving Responses to Appetitive Smoking Cues in Naturally Cycling Females. Teresa R. Franklin, Kanchana Jagannathan, Reagan R. Wetherill, Barbara Johnson, Shannon Kelly, Jamison Langguth, Joel Mumma, Anna Rose Childress
- Increasing Progesterone Levels Are Associated With Smoking Abstinence Among Free-Cycling Women Smokers Who Receive Brief Pharmacotherapy. Michael E. Saladin, Erin A. McClure, Nathaniel L. Baker, Matthew J. Carpenter, Viswanathan Ramakrishnan, Karen J. Hartwell, Kevin M. Gray
- Systematic and Meta-Analytic Review of Research Examining the Impact of Menstrual Cycle Phase and Ovarian Hormones on Smoking and Cessation. Andrea H. Weinberger, Philip H. Smith, Sharon S. Allen, Kelly P. Cosgrove, Michael E. Saladin, Kevin M. Gray, Carolyn M. Mazure, Cora Lee Wetherington, Sherry A. McKee
- Nicotine Withdrawal Increases Stress-Associated Genes in the Nucleus Accumbens of Female Rats in a Hormone-Dependent Manner. Oscar V. Torres, Joseph A. Pipkin, Patrick Ferree, Luis M. Carcoba, Laura E. O’Dell
- Gender and Stimulus Control of Smoking Behavior. Stuart G. Ferguson, Mai Frandsen, Michael S. Dunbar, Saul Shiffman
- Gender Differences in Responses to Cues Presented in the Natural Environment of Cigarette Smokers. Jennifer M. Wray, Kevin M. Gray, Erin A. McClure, Matthew J. Carpenter,Stephen T. Tiffany, Michael E. Saladin
- Sex Differences in Acute Relief of Abstinence-Induced Withdrawal and Negative Affect due to Nicotine Content in Cigarettes. Kenneth A. Perkins, Joshua L. Karelitz
- Sex Differences in Time Perception During Smoking Abstinence. Rebecca L. Ashare, Joseph W. Kable
- Financial Incentives for Smoking Cessation Among Depression-Prone Pregnant and Newly Postpartum Women: Effects on Smoking Abstinence and Depression Ratings. Alexa A. Lopez, PhD, Joan M. Skelly, MS, Stephen T. Higgins, PhD
- Gender Differences in Medication Use and Cigarette Smoking Cessation: Results From the International Tobacco Control Four Country Survey. Philip H. Smith, Karin A. Kasza, Andrew Hyland, Geoffrey T. Fong, Ron Borland, Kathleen Brady, Matthew J. Carpenter, Karen Hartwell, K. Michael Cummings, Sherry A. McKee
- Nicotine Concentrations With Electronic Cigarette Use: Effects of Sex and Flavor. Cheryl Oncken, Mark D. Litt, Lynn D. McLaughlin, Nausherwan A. Burki
- Gender Differences in a Randomized Controlled Trial Treating Tobacco Use Among Adolescents and Young Adults With Mental Health Concerns. Judith J. Prochaska, Sebastien C. Fromont, Danielle E. Ramo, Kelly C. Young-Wolff, Kevin Delucchi, Richard A. Brown, Sharon M. Hall
- Targeting the Noradrenergic System for Gender-Sensitive Medication Development for Tobacco Dependence Terril L. Verplaetse, Andrea H. Weinberger, Philip H. Smith, Kelly P. Cosgrove,Yann S. Mineur, Marina R. Picciotto, Carolyn M. Mazure, Sherry A. McKee
- Protecting Children From Smoke Exposure in Disadvantaged Homes. Neneh Rowa-Dewar, Colin Lumsdaine, Amanda Amos
INTRODUCTION:
Converging clinical and biological evidence suggest sex is an important factor when selecting a pharmacological intervention for smoking cessation. The current investigation used network meta-analyses to estimate sex differences in the comparative efficacy of transdermal nicotine (TN), varenicline, and sustained release (SR) bupropion for smoking cessation.
METHODS:
Systematically searched previously published reviews and databases (Medline, PsycINFO, Embase) of randomized, double-blind, placebo-controlled trials of bupropion-SR, TN, and varenicline for cigarette smoking cessation in primary care/general community samples were included.
RESULTS
Thirty-two studies met all criteria and 28 (88%) were included in the final analyses, representing 14 389 smokers (51% female). Results of the full sample (women and men combined) mirrored those from a Cochrane Tobacco Addiction Group network meta-analysis of smoking cessation pharmacotherapy, showing VAR>TN=BUP. All medications improved quit rates over placebo for both women and men. Relative to placebo, varenicline efficacy was similar for women and men. Significant sex differences were evident when comparing varenicline versus TN and varenicline versus bupropion. For women, varenicline was more efficacious than TN (RR = 1.41; 95% CI = 1.12,1.76) and bupropion (RR = 1.38; 95% CI = 1.08,1.77). For men, outcomes for those treated with TN and bupropion were similar to those treated with varenicline. There were no differences in efficacy when comparing bupropion versus TN.
CONCLUSIONS:
The advantage of varenicline over bupropion SR and TN is greater for women than men. Clinicians should strongly consider varenicline as the first option treatment for women. Among men, the advantage of varenicline over TN or bupropion is less clear.
IMPLICATIONS:
This study provides information for the sex-informed treatment of nicotine addiction among cigarette smokers. Relative to placebo, women and men achieved similar outcomes when treated with varenicline; however the advantages of varenicline over transdermal patch and bupropion were greater for women compared to men.
Science has come a long way with regard to the consideration of sex differences in clinical and preclinical research, but one field remains behind the curve: human statistical genetics. The goal of this commentary is to raise awareness and discussion about how to best consider and evaluate possible sex effects in the context of large-scale human genetic studies. Over the course of this commentary, we reinforce the importance of interpreting genetic results in the context of biological sex, establish evidence that sex differences are not being considered in human statistical genetics, and discuss how best to conduct and report such analyses. Our recommendation is to run stratified analyses by sex no matter the sample size or the result and report the findings. Summary statistics from stratified analyses are helpful for meta-analyses, and patterns of sex-dependent associations may be hidden in a combined dataset. In the age of declining sequencing costs, large consortia efforts, and a number of useful control samples, it is now time for the field of human genetics to appropriately include sex in the design, analysis, and reporting of results.
Core B: Service Core
The Yale-SCOR Service Core provides research resources to Yale-SCOR projects including human subjects involvement, centralized recruitment, data management, and statistical support. Core B also provides coordinated, central expertise on the design and implementation of all projects, including pilot projects as well as quality control of data and innovative analytic strategies. Importantly, the Service Core provides mentorship to trainees and early stage investigators, translates and disseminates findings generated by the SCOR-related projects, and provides a national resource for the study of women’s health and tobacco use.