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Nicotine Receptor in Nicotine Dependence

Institution: California Institute of Technology
Investigator(s): Henry Lester, Ph.D.
Award Cycle: 2011 (Cycle 20) Grant #: 20XT-0006 Award: $404,642
Subject Area: Nicotine Dependence
Award Type: Exploratory/Developmental Award

Initial Award Abstract
In the first step in the biology of nicotine addiction, molecules of nicotine bind to receptor molecules on the surface nerve cells in the brain. Scientists understand that the nicotine receptors excite their nerve cells electrically. However, chronic exposure to nicotine (for instance during repeated tobacco smoking) starts a poorly understood chain of chemical events that apparently comprise the cellular and circuit basis of addiction. If we understood these events, perhaps we could avoid or cure nicotine addiction.

There are several types of nicotine receptors. Recent experiments show that nicotine also binds to some receptor types within nerve cells. We hypothesize that this intracellular nicotine-receptor interaction can influence events in the nerve cell’s nucleus, changing the complement of genes activated.

We wish to use genetic engineering and molecular biology to address this gene activation hypothesis. Previous work has generated mouse strains with fluorescent nicotine receptors; each strain illuminates only one receptor type. These strains now constitute valuable tools to test the hypothesis that chronic exposure to nicotine changes the activity of specific genes, in specific nerve cell types, that have only specific subtypes of nicotine receptors. In each of three brain areas thought to control nicotine addiction, we will isolate genetic material from just a few dozen nerve cells that are identified by fluorescent receptors. We will analyze the extracts from the isolated nerve cells, using contemporary tools of molecular biology that allow one to describe gene activation with unprecedented precision. We think that detailed testing of the gene activation hypothesis will provide new insights into the events that lead to nicotine addiction

Nicotine upregulates a4B2 nicotinic receptors and ER exit sites via stoichiometry-dependent chaperoning
Periodical: Journal of General Physiology Index Medicus:
Authors: Srinivasan R, Pantoja R, Moss FJ, Mackey EDW, Son C, Miwa J, and Lester HA ART
Yr: 2011 Vol: Nbr: 137 Abs: Pg: 59-79

Characterizing functional a6B2 nicotinic acetylcholine receptors in vitro: mutant B2 subunits improve membrane expression, and fluorescent proteins reveal responsive cells
Periodical: Biochemical Pharmacology Index Medicus:
Authors: Xiao C, Srinivasan R, Drenan RM, Mackey ED, Mcintosh JM, and Lester HA ART
Yr: 2011 Vol: Nbr: 82 Abs: Pg: 852-61

Insights into the Neurobiology of the Nicotinic Cholinergic System and Nicotine Addiction from Mice Expressing Nicotinic Receptors Harboring Gain-of-Function Mutations.
Periodical: Pharmacological Reviews Index Medicus:
Authors: Drenan RM, and Lester HA ART
Yr: 2012 Vol: Nbr: Abs: Pg: PMID 22885704

Psychiatric Drugs Bind to Classical Targets Within Early Exocytotic_x000D_ Pathways: Therapeutic Effects
Periodical: Biological Psychiatry Index Medicus:
Authors: Lester HA, Miwa JM, and Srinivasan R ART
Yr: 2012 Vol: Nbr: Abs: Pg: PMID 22771239

a6* Nicotinic Acetylcholine Receptor Expression and Function in a_x000D_ Visual Salience Circuit
Periodical: Journal of Neuroscience Index Medicus:
Authors: Mackey ED, Engle SE, Kim MR, O'Neill HC, Wageman CR, Patzlaff NE, Wang Y, Grady SR, Mcinto ART
Yr: 2012 Vol: Nbr: 32 Abs: Pg: 10226-37

Live-Cell Imaging of Single Receptor Composition Using Zero-Mode Waveguide Nanostructures
Periodical: Nano Letters Index Medicus:
Authors: Richards CI, Luong K, Srinivasan R, Turner SW, Dougherty DA, Korlach J, and Lester HA ART
Yr: 2012 Vol: Nbr: 12 Abs: Pg: 11474-80

Pharmacological chaperoning of nicotinic acetylcholine receptors reduces the ER stress response
Periodical: Molecular Pharmacology Index Medicus:
Authors: Srinivasan R, Richards CI, Xiao C, Rhee D, Pantoja R, Dougherty DA, Miwa JM, and Lester HA ART
Yr: 2012 Vol: Nbr: 81 Abs: Pg: 759-69