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Subcellular pharmacokinetics of nicotinic compounds

Institution: California Institute of Technology
Investigator(s): Henry Lester, Ph.D.
Award Cycle: 2014 (Cycle 23) Grant #: 23XT-0007 Award: $314,942
Subject Area: Disparities /Prevention/ Cessation/ Nicotine Dependence
Award Type: Exploratory/Developmental Award

Initial Award Abstract

What happens when a person takes a puff on a cigarette? What changes in the brain when a person smokes repeatedly, for days or weeks? We study the basic neuroscience of nicotine addiction. Recent studies affirm that nicotine interacts with nicotine receptors on nerve cells in the brain; but studies also show that some effects of such chronic exposure take place due to nicotine-receptor interactions deep inside nerve cells. To understand nicotine addiction, and eventually to prevent addiction dependence, it is important to learn where these interactions take place, The concept of "inside-out" mechanisms in nicotine dependence will be studied with special detector proteins, which glow they bind nicotine. The project develops such detectors, then uses them to study nicotine within nerve cells.

We expect the measurements developed in this project to take their place in various experiments on nicotinic drugs. First, the experiments can be directly used to ask whether additives, such as menthol, actually do change the nicotine in the compartment of interest.

Second, we expect these measurements to take their place in the development of smoking and “vaping” cessation drugs such as antibodies and improved drugs of the varenicline class. These experiments will tell us whether improving on varenicline requires entry into the neurons; and if so, how much.