(provided by candidate): Alterations in nicotinic cholinergic signaling in the brain have been implicated in numerous diseases and disorders, such as Alzheimer's disease (AD), autism, anxiety and depression. In addition, studies using mice lacking specific nicotinic receptor subunits have implicated these receptors in both anxiety and depression. Therefore, nicotine and subtype-specific nicotinic drugs present a rich area for investigation of their therapeutic potential in these mental disorders. However, a dearth of ideal animal models and subtype- selective ligands that easily cross the blood-brain barrier have previously hampered inquiry into this area. Equipped with novel compounds and a variety of behavioral models, this grant aims to examine the behavioral effects of nicotine and the nicotinic partial agonists, varenicline and sazetidine-A, in models of anxiety and depression as well as elucidate the molecular and cellular underpinnings of these behaviors. Initially, the acute and chronic effects of these drugs will be investigated in models of anxiety and depression (e.g., the novelty-induced hypophagia test and the forced swim test). Additionally, the effects of acute and chronic administration of nicotine, varenicline and sazetidine-A on adult neurogenesis, which has been implicated as mechanism for antidepressant action, will be examined using a fluorescently-activated cell sorting (FACS) method to detect BrdU labeled cells in hippocampi from treated animals. Finally, radioligand binding and sequential immunoprecipitation assays will be utilized to determine what nicotinic receptor subtypes are altered by nicotinic ligand administration and, thus, may be responsible for these behavioral and neuronal effects. The goal of this research is to identify new potential therapeutic uses of these drugs for disorders such as anxiety and depression, investigate the molecular correlates underlying the behavioral effects, as well as examine and evaluate the most appropriate behavioral models for use in nicotinic drug discovery. This research may ultimately lead to new therapies for depression and anxiety disorders, as well lay the groundwork for application of nicotinic compounds in the treatment of mental disease and disorders.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1-F02A-J (20))
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Babecki, Beth
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University of Pennsylvania
Schools of Medicine
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Forcelli, Patrick A; Turner, Jill R; Lee, Bridgin G et al. (2016) Anxiolytic- and antidepressant-like effects of the methadone metabolite 2-ethyl-5-methyl-3,3-diphenyl-1-pyrroline (EMDP). Neuropharmacology 101:46-56
Turner, J R; Ray, R; Lee, B et al. (2014) Evidence from mouse and man for a role of neuregulin 3 in nicotine dependence. Mol Psychiatry 19:801-10
Turner, Jill R; Ecke, Laurel E; Briand, Lisa A et al. (2013) Cocaine-related behaviors in mice with deficient gliotransmission. Psychopharmacology (Berl) 226:167-76
Wilkinson, Derek S; Turner, Jill R; Blendy, Julie A et al. (2013) Genetic background influences the effects of withdrawal from chronic nicotine on learning and high-affinity nicotinic acetylcholine receptor binding in the dorsal and ventral hippocampus. Psychopharmacology (Berl) 225:201-8
Balu, Darrick T; Turner, Jill R; Brookshire, Bethany R et al. (2013) Brain monoamines and antidepressant-like responses in MRL/MpJ versus C57BL/6J mice. Neuropharmacology 67:503-10
Turner, Jill R; Gold, Allison; Schnoll, Robert et al. (2013) Translational research in nicotine dependence. Cold Spring Harb Perspect Med 3:a012153
Turner, Jill R; Wilkinson, Derek S; Poole, Rachel Lf et al. (2013) Divergent functional effects of sazetidine-a and varenicline during nicotine withdrawal. Neuropsychopharmacology 38:2035-47
Portugal, George S; Wilkinson, Derek S; Turner, Jill R et al. (2012) Developmental effects of acute, chronic, and withdrawal from chronic nicotine on fear conditioning. Neurobiol Learn Mem 97:482-94
Hilario, Monica R F; Turner, Jill R; Blendy, Julie A (2012) Reward sensitization: effects of repeated nicotine exposure and withdrawal in mice. Neuropsychopharmacology 37:2661-70
Hussmann, G Patrick; Turner, Jill R; Lomazzo, Ermelinda et al. (2012) Chronic sazetidine-A at behaviorally active doses does not increase nicotinic cholinergic receptors in rodent brain. J Pharmacol Exp Ther 343:441-50

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