Research

The Yale-SCOR is organized around research projects and cores. To learn more, explore the tabs below.

Project 1: Acetylcholine-Norepinephrine Interactions and Their Implications for the Effects of Nicotine in Reinforcement and Stress Reactivity

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.

Marina Picciotto, PhD

Principal Investigator:
Marina Picciotto, Ph.D.
Charles B.G. Murphy Professor of Psychiatry
Professor of Pharmacology and of Neurobiology
Yale University School of Medicine

Yann Mineur, MSc, PhD

Co-Investigator:
Yann S. Mineur, Ph.D.
Research Scientist in Psychiatry
Yale University School of Medicine

Recent Findings

Mineur YS, Taylor SR, Picciotto MR. Calcineurin downregulation in the amygdala is sufficient to induce anxiety-like and depression-like behaviors in C57BL/6J male mice. Biol Psychiatry. 2014 Jun 15;75(12):991-8. PubMed PMID: 24742621; PubMed Central PMCID: PMC4037359.

BACKGROUND: The calcium-dependent phosphatase calcineurin is highly expressed in the amygdala, a brain area important for behaviors related to mood disorders and anxiety. Organ transplant patients are administered the calcineurin inhibitor cyclosporine A (CsA) chronically and demonstrate an increased incidence of anxiety and mood disorders. It is therefore important to determine whether chronic blockade of calcineurin may contribute to symptoms of anxiety and depression in these patients.

METHODS: Pharmacological (CSA) and viral-mediated gene transfer (adeno-associated viral expression of short hairpin RNA [shRNA]) approaches were used to inhibit calcineurin activity systemically or selectively in the amygdala of the mouse brain to determine the role of calcineurin in behaviors related to anxiety and depression.

RESULTS: Systemic inhibition of calcineurin activity with CsA or local downregulation of calcineurin levels in the amygdala using adeno-associated viral-delivered shRNAs targeting calcineurin B increased measures of anxiety-like behavior in the elevated plus maze, the light/dark box, and the open field test. A decrease in locomotor activity was also observed in mice treated systemically with CsA. In the forced swim model of depression-like behavior, both systemic CsA treatment and shRNA-mediated calcineurin blockade in the amygdala significantly increased immobility.

CONCLUSIONS: Taken together, these data demonstrate that decreasing calcineurin activity in the amygdala increases anxiety-like behaviors and to some extent depression-like behaviors. These studies suggest that chronic administration of CsA to organ transplant patients could have significant effects on anxiety and mood and this should be recognized as a potential clinical consequence of treatment to prevent transplant rejection.



Mineur, Y.S., Einstein, E.B., Bentham, M.P., Wigestrand, M.B., Blakeman, S., Newbold, S.A. and Picciotto, M.R. Expression of the 5HT1a serotonin receptor in the hippocampus is required for social stress resilience and the antidepressant-like effects induced by the nicotinic partial agonist cytisine. (2015) Neuropsychopharmacology, 40(4):938-46. PubMed PMID: 25505336; PubMed Central PMCID: PMC4330507.

Nicotinic acetylcholine receptor (nAChR) blockers potentiate the effects of selective serotonin reuptake inhibitors (SSRIs) in some treatment-resistant patients; however, it is not known whether these effects are independent, or whether the two neurotransmitter systems act synergistically. We first determined that the SSRI fluoxetine and the nicotinic partial agonist cytisine have synergistic effects in a mouse model of antidepressant efficacy, whereas serotonin depletion blocked the effects of cytisine. Using a pharmacological approach, we found that the 5-HT1A agonist 8-OH-DPAT also potentiated the antidepressant-like effects of cytisine, suggesting that this subtype might mediate the interaction between the serotonergic and cholinergic systems. The 5-HT1A receptors are located both presynaptically and postsynaptically. We therefore knocked down 5-HT1A receptors in either the dorsal raphe (presynaptic autoreceptors) or the hippocampus (a brain area with high expression of 5-HT1A heteroreceptors sensitive to cholinergic effects on affective behaviors). Knockdown of 5-HT1A receptors in hippocampus, but not dorsal raphe, significantly decreased the antidepressant-like effect of cytisine. This study suggests that serotonin signaling through postsynaptic 5-HT1A receptors in the hippocampus is critical for the antidepressant-like effects of a cholinergic drug and begins to elucidate the molecular mechanisms underlying interactions between the serotonergic and cholinergic systems related to mood disorders

Project 2: Sex Differences in Dopamine Release in Tobacco Smokers

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.

Kelly Cosgrove, PhD

Principal Investigator:
Kelly P. Cosgrove, Ph.D.
Associate Professor of Psychiatry and of Diagnostic Radiology
Yale University School of Medicine

Recent Findings

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.http://www.ncbi.nlm.nih.gov/pubmed/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.



Gaiser EC, Matuskey D, Perkins E, D'Amico C, Abdelghany O, McKee SA, Cosgrove KP. A Case Series on the Heightened Autonomic Response due to Guanfacine and Amphetamine Interaction. J Clin Psychopharmacol. 2015 Apr;35(2):197-9. PubMed PMID: 25634160; PubMed Central PMCID: PMC4344400.

Project 3: Effect of an Alpha-2a Adrenergic Agonist on Stress-Induced Smoking and Smoking Reinforcement: An Examination of Mechanisms and Clinical Outcomes by Gender

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).

Sherry McKee, PhD

Principal Investigator:
Sherry A. McKee, Ph.D.
Professor of Psychiatry
Yale University School of Medicine

Recent Findings

Verplaetse TL, Weinberger AH, Smith PH, Cosgrove KP, Mineur YS, Picciotto MR, Mazure CM, McKee SA. Targeting the noradrenergic system for gender-sensitive medication development for tobacco dependence. Nicotine Tob Res. 2015; 17(4): 486-95. PubMed PMID: 25762760; PubMed Central PMCID: PMC4432402

INTRODUCTION: Tobacco use remains the leading cause of morbidity and mortality for both women and men in the United States, and women often experience poorer smoking cessation outcomes than men. Preliminary evidence suggests there are sex differences in medication effectiveness for smoking cessation. However, current medications do not take into account gender-sensitive treatment development and efficacy, underscoring the importance of this underdeveloped area of research.

METHODS: We reviewed preclinical and clinical evidence for gender differences in the inability to quit smoking by examining (a) the effect of increased negative affect and stress reactivity on smoking outcomes in women and (b) smoking for nicotine reinforcement in men. We also reviewed the current literature targeting the noradrenergic system as a novel gender-sensitive treatment strategy for tobacco dependence.

RESULTS: We hypothesize that noradrenergic agents that normalize noradrenergic activity may differentially attenuate stress reactivity in women and nicotine-related reinforcement in men, indicating that targeting the noradrenergic system for smoking cessation may be effective for both genders, with benefits operating through sex-specific mechanisms.

CONCLUSIONS: Converging lines of preclinical and clinical evidence suggest that gender-sensitive approaches to medication development for smoking cessation are a critical next step for addressing low quit rates and exacerbated health risks among women. Evidence reviewed indicates that smoking activates different brain systems modulated by noradrenergic activity in women versus men, and noradrenergic compounds may preferentially target these gender-sensitive systems.



McKee SA, Potenza MN, Kober H, Sofuoglu M, Arnsten AF, Picciotto MR, Weinberger AH, Ashare R, Sinha R. A translational investigation targeting stress-reactivity and prefrontal cognitive control with guanfacine for smoking cessation. J Psychopharmacol. 2015 Mar;29(3):300-11. PubMed PMID: 25516371; PubMed Central PMCID: PMC4376109.

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.

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 McKee, PhD

Sherry A. McKee, Ph.D. (Principal Investigator)
Professor of Psychiatry
Yale University School of Medicine

Carolyn Mazure, PhD

Carolyn M. Mazure, Ph.D. (Scientific Director)
Professor of Psychiatry and of Psychology
Director, Women’s Health Research at Yale
Yale University School of Medicine

Recent Findings

McKee SA, Weinberger AH. Innovations in translational sex and gender-sensitive tobacco research. Nicotine Tob Res. 2015 Apr;17(4):379-81. Epub 2015 Mar 11. PubMed PMID: 25762746; PubMed Central PMCID: PMC4481708.

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.

  1. Commentary: Innovations in Translational Sex and Gender-Sensitive Tobacco Research. Sherry A. McKee, Andrea H. Weinberger
  2. Sex Differences in Hormonal Responses to Stress and Smoking Relapse: A Prospective Examination. Mustafa al’Absi, Motohiro Nakajima, Sharon Allen, Andrine Lemieux, Dorothy Hatsukami
  3. 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
  4. 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
  5. 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
  6. 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
  7. Gender and Stimulus Control of Smoking Behavior. Stuart G. Ferguson, Mai Frandsen, Michael S. Dunbar, Saul Shiffman
  8. 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
  9. Sex Differences in Acute Relief of Abstinence-Induced Withdrawal and Negative Affect due to Nicotine Content in Cigarettes. Kenneth A. Perkins, Joshua L. Karelitz
  10. Sex Differences in Time Perception During Smoking Abstinence. Rebecca L. Ashare, Joseph W. Kable
  11. 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
  12. 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
  13. Nicotine Concentrations With Electronic Cigarette Use: Effects of Sex and Flavor. Cheryl Oncken, Mark D. Litt, Lynn D. McLaughlin, Nausherwan A. Burki
  14. 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
  15. 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
  16. Protecting Children From Smoke Exposure in Disadvantaged Homes. Neneh Rowa-Dewar, Colin Lumsdaine, Amanda Amos

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.

Carolyn Mazure, PhD

Carolyn M. Mazure, Ph.D. (Principal Investigator)
Professor of Psychiatry and of Psychology
Director, Women’s Health Research at Yale
Yale University School of Medicine

Sherry McKee, PhD

Sherry A. McKee, Ph.D.
Professor of Psychiatry
Yale University School of Medicine

Recent Findings

Weinberger AH, Smith PH, Allen SS, Cosgrove KP, Saladin ME, Gray KM, Mazure CM, Wetherington CL, McKee SA. Systematic and meta-analytic review of research examining the impact of menstrual cycle phase and ovarian hormones on smoking and cessation. Nicotine Tob Res 2015 Apr; 17(4); 407-21. PubMed PMID: 25762750; PubMed Central PMCID: PMC4429881.

INTRODUCTION: To determine the effect of ovarian hormones on smoking, we conducted a systematic review of menstrual cycle effects on smoking (i.e., ad lib smoking, smoking topography, and subjective effects) and cessation-related behaviors (i.e., cessation, withdrawal, tonic craving, and cue-induced craving).

METHODS: Thirty-six papers were identified on MEDLINE that included a menstrual-related search term (e.g., menstrual cycle, ovarian hormones), a smoking-related search term (e.g., smoking, nicotine), and met all inclusion criteria. Thirty-two studies examined menstrual phase, 1 study measured hormone levels, and 3 studies administered progesterone.

RESULTS: Sufficient data were available to conduct meta-analyses for only 2 of the 7 variables: withdrawal and tonic craving. Women reported greater withdrawal during the luteal phase than during the follicular phase, and there was a nonsignificant trend for greater tonic craving in the luteal phase. Progesterone administration was associated with decreased positive and increased negative subjective effects of nicotine. Studies of menstrual phase effects on the other outcome variables were either small in number or yielded mixed outcomes.

CONCLUSIONS: The impact of menstrual cycle phase on smoking behavior and cessation is complicated, and insufficient research is available upon which to conduct meta-analyses on most smoking outcomes. Future progress will require collecting ovarian hormone levels to more precisely quantify the impact of dynamic changes in hormone levels through the cycle on smoking behavior. Clarifying the relationship between hormones and smoking-particularly related to quitting, relapse, and medication response-could determine the best type and timing of interventions to improve quit rates for women.



Smith PH, Rose JS, Mazure CM, Giovino GA, McKee SA. What is the evidence for hardening in the cigarette smoking population? Trends in nicotine dependence in the US, 2002-2012. Drug Alcohol Depend. 2014 Sep 1;142:333-40. PubMed PMID: 25064023; PubMed Central PMCID: PMC4158455.

As the prevalence of cigarette smoking continues to decline in the U.S., there is concern that tobacco control efforts and concomitant reductions in smoking have resulted in a “hardened” population of remaining smokers, who may have more difficulty quitting. To evaluate this hypothesis, this paper examined time trends in nicotine dependence from 2002-2012, utilizing data from the National Survey on Drug Use and Health from 130,637 smokers. Despite the lack of hardening for the overall population of smokers, there was some evidence of hardening among specific sub-groups, namely women and low-income smokers. Aspects of nicotine dependence that increased over time in women and low-income smokers were smoking to alleviate negative affect, and having greater stability in their smoking over time. These dimensions of dependence warrant particular attention, as they are strongly related to difficulty with smoking cessation.