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The Action of Nicotine and Nicotine Cessation Drugs Inside Cells

Institution: California Institute of Technology
Investigator(s): Aaron Nichols, Ph.D.
Award Cycle: 2018 (Cycle 27) Grant #: 27FT-0022 Award: $182,184
Subject Area: Neuroscience of Nicotine Addiction and Treatment
Award Type: Postdoctoral Fellowship Awards

Initial Award Abstract

This project studies how nicotine and smoking cessation drugs work inside cells.  Nicotine causes many changes in a cell by binding to proteins on the outside of the cell, but nicotine can also directly enter a cell to affect the way it works.  When nicotine enters the cell and makes an internal change, it is called an “inside-out” effect.  These “inside-out” effects can contribute to addiction and may also determine how well a prescription drug works when someone tries to quit smoking.  Drugs to help smokers quit have not been studied to see if they work like nicotine and have “inside-out” effects.  We have a method that allows us to watch real-time as nicotine and smoking cessation drugs enter cells.  This project will advance understanding about how nicotine and smoking cessation drugs work inside cells and will also help us know how to better help smokers quit.

The tool our lab developed is something called a “biosensor.”  The biosensor is made of two parts: 1) a protein which acts like a clamp to bind a drug and 2) a protein that glows.  When there is no drug present, the protein clamp is open and the glowing protein is turned off.  Once a drug is present, however, the protein clamp closes and the glowing protein turns on.  We can change what the clamp portion of the protein binds by mutating parts of the protein and seeing if the clamp closes to give a signal.  So far in our lab we have made a few biosensors, one of which binds to nicotine.  When we put this biosensor inside a cell and expose the cell to different concentrations of nicotine, we can watch as nicotine enters and leaves a cell in real time.  We also have a biosensor that binds to varenicline, a drug used for helping people quit smoking.  Varenicline also enters and leaves cells like nicotine.

We now propose to develop new biosensors for the smoking cessation drugs cytisine and dianicline to examine whether these drugs exhibit an “inside out” effect similar to that of nicotine and varenicline.  This will help us understand if these drugs all work the same way.  Since some of these drugs are more effective than others in helping people quit, we think that some of the difference in effectiveness could be tied to whether or not a drug can have an “inside-out” effect.  We will then use our biosensors to study nicotine, varenicline, cytisine, and dianicline in the brains of mice.  Testing the biosensors on the brains of mice will help us see what our panel of drugs is doing in a biological system, rather than in just a single cell.  If the smoking cessation drugs that are best at helping people quit all use an “inside-out” pathway, we then know that we need to incorporate “inside-out” function as a requirement for future drug development.