This K01 application proposes support essential for Dr. Esterlis'career development as she transitions to an independent investigator in neuroreceptor imaging of mood and comorbid substance use disorders. The proposed career award plan is designed to further her scientific development as an expert neuroimager, with increased expertise in mood disorders and mood-substance disorder comorbidity, including the conduct of two unique receptor imaging studies. Dr. Esterlis'career development plan focuses on rigorous training in methods of single photon emission computerized tomography (SPECT) and positron emission tomography (PET) brain imaging, including noise- correction techniques and quantitative skills, and application of these techniques to the neuroimaging of biological basis of mood disorders. Training will include an integration of individual meetings with mentors and collaborators in the Departments of Psychiatry and Radiology, intramural and extramural didactics, presentations at scientific meetings and manuscript and grant submissions. The scientific focus of the proposed project is the investigation of a novel mechanism that may be involved in the pathophysiology of bipolar disorder (BD) and comorbid tobacco dependence. Tobacco dependence is three times as prevalent in BD as compared to general population, however, the reasoning behind this comorbidity is not well understood nor are there well-established efficacious treatments for smoking cessation or associated depression symptoms in BD. Thus, there is an urgent need for investigation of new molecular mechanisms for pharmacotherapeutic targets. Emerging evidence implicates the nicotinic acetylcholine receptor (nAChR) system in the pathophysiology of BD and its mood and cognitive symptoms. Thus, we propose an innovative study of the relationship between tobacco smoking and mood and cognitive dysfunction in BD, which may be mediated by the 22 subunit of the nAChR system. Nonsmokers (n=20) and smokers (n=20) with BD and matched controls will participate in a [123I]5-IA-85380 SPECT scan to determine 22-nAChR availability. Mood and cognitive assessments will be administered to smokers before smoking cessation, after 24h smoking cessation, and again on SPECT scan day, and at corresponding times to nonsmokers. Differences in the magnitude and distribution of the 22-nAChR in BD versus controls will be measured, as well as in BD smokers versus nonsmokers. Relationships to mood and cognitive symptoms will be assessed. {{{Furthermore, proposed career training project will provide data on the distribution of the metabotropic glumatamatergic system (mGluR5) in the same BD subjects and will enable a unique investigation of a multi-receptor involvement in BD.

Public Health Relevance

This study will contribute to our understanding of the pathophysiology associated with bipolar disorder and may provide biological and cognitive information that will contribute to the investigation of new pharmacotherapies. Development of more efficacious treatments for depression and smoking cessation, in turn, will lead to a better quality of life for these individuals, as well as reduced healthcare costs associated with medical and psychiatric issues in mood disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01MH092681-04
Application #
8640974
Study Section
Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section (NPAS)
Program Officer
Chavez, Mark
Project Start
2011-07-01
Project End
2016-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Yale University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
City
New Haven
State
CT
Country
United States
Zip Code
06510
Boggs, Douglas L; Surti, Toral S; Esterlis, Irina et al. (2017) Minimal effects of prolonged smoking abstinence or resumption on cognitive performance challenge the ""self-medication"" hypothesis in schizophrenia. Schizophr Res :
Scheinost, Dustin; Holmes, Sophie E; DellaGioia, Nicole et al. (2017) Multimodal Investigation of Network Level Effects Using Intrinsic Functional Connectivity, Anatomical Covariance, and Structure-to-Function Correlations in Unmedicated Major Depressive Disorder. Neuropsychopharmacology :
Esterlis, I; DellaGioia, N; Pietrzak, R H et al. (2017) Ketamine-induced reduction in mGluR5 availability is associated with an antidepressant response: an [11C]ABP688 and PET imaging study in depression. Mol Psychiatry :
Abdallah, Chadi G; Hannestad, Jonas; Mason, Graeme F et al. (2017) Metabotropic Glutamate Receptor 5 and Glutamate Involvement in Major Depressive Disorder: A Multimodal Imaging Study. Biol Psychiatry Cogn Neurosci Neuroimaging 2:449-456
Holmes, Sophie E; Girgenti, Matthew J; Davis, Margaret T et al. (2017) Altered metabotropic glutamate receptor 5 markers in PTSD: In vivo and postmortem evidence. Proc Natl Acad Sci U S A 114:8390-8395
Hillmer, Ansel T; Li, Songye; Zheng, Ming-Qiang et al. (2017) PET imaging of ?7 nicotinic acetylcholine receptors: a comparative study of [18F]ASEM and [18F]DBT-10 in nonhuman primates, and further evaluation of [18F]ASEM in humans. Eur J Nucl Med Mol Imaging 44:1042-1050
Hillmer, A T; Esterlis, I; Gallezot, J D et al. (2016) Imaging of cerebral ?4?2* nicotinic acetylcholine receptors with (-)-[(18)F]Flubatine PET: Implementation of bolus plus constant infusion and sensitivity to acetylcholine in human brain. Neuroimage 141:71-80
Esterlis, Irina; Hillmer, Ansel T; Bois, Frederic et al. (2016) CHRNA4 and ANKK1 Polymorphisms Influence Smoking-Induced Nicotinic Acetylcholine Receptor Upregulation. Nicotine Tob Res 18:1845-52
DeLorenzo, Christine; Gallezot, Jean-Dominique; Gardus, John et al. (2016) In vivo variation in same-day estimates of metabotropic glutamate receptor subtype 5 binding using [(11)C]ABP688 and [(18)F]FPEB. J Cereb Blood Flow Metab :271678X16673646
McClure-Begley, Tristan D; Esterlis, Irina; Stone, Kathryn L et al. (2016) Evaluation of the Nicotinic Acetylcholine Receptor-Associated Proteome at Baseline and Following Nicotine Exposure in Human and Mouse Cortex. eNeuro 3:

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