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.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Scientist Development Award - Research & Training (K01)
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Study Section
Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section (NPAS)
Program Officer
Chavez, Mark
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Yale University
Schools of Medicine
New Haven
United States
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Hillmer, A T; Esterlis, I; Gallezot, J D et al. (2016) Imaging of cerebral α4β2* 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
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 [11C]ABP688 and [18F]FPEB. J Cereb Blood Flow Metab :
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:
DeLorenzo, Christine; DellaGioia, Nicole; Bloch, Michael et al. (2015) In vivo ketamine-induced changes in [¹¹C]ABP688 binding to metabotropic glutamate receptor subtype 5. Biol Psychiatry 77:266-75
Cosgrove, Kelly P; Esterlis, Irina; Sandiego, Christine et al. (2015) Imaging Tobacco Smoking with PET and SPECT. Curr Top Behav Neurosci 24:1-17
Esterlis, Irina; Ranganathan, Mohini; Bois, Frederic et al. (2014) In vivo evidence for β2 nicotinic acetylcholine receptor subunit upregulation in smokers as compared with nonsmokers with schizophrenia. Biol Psychiatry 76:495-502
Gallezot, Jean-Dominique; Esterlis, Irina; Bois, Frederic et al. (2014) Evaluation of the sensitivity of the novel α4β2* nicotinic acetylcholine receptor PET radioligand 18F-(-)-NCFHEB to increases in synaptic acetylcholine levels in rhesus monkeys. Synapse 68:556-64
Hannestad, Jonas O; Cosgrove, Kelly P; DellaGioia, Nicole F et al. (2013) Changes in the cholinergic system between bipolar depression and euthymia as measured with [123I]5IA single photon emission computed tomography. Biol Psychiatry 74:768-76
Esterlis, Irina; Hannestad, Jonas O; Perkins, Evgenia et al. (2013) Effect of a nicotine vaccine on nicotine binding to β2*-nicotinic acetylcholine receptors in vivo in human tobacco smokers. Am J Psychiatry 170:399-407
Esterlis, Irina; Hannestad, Jonas O; Bois, Frederic et al. (2013) Imaging changes in synaptic acetylcholine availability in living human subjects. J Nucl Med 54:78-82

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