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Understanding Nicotine and Smoking Cessation Drugs: Release

Institution: California Institute of Technology
Investigator(s): Henry Lester, Ph.D.
Award Cycle: 2018 (Cycle 27) Grant #: 27IP-0057 Award: $660,000
Subject Area: Neuroscience of Nicotine Addiction and Treatment
Award Type: High Impact Pilot Award

Initial Award Abstract

The project addresses “The Conundrum”: how the nicotine from a single combustible cigarette can affect a nicotine-dependent person for as long as 1 hour.  Nicotine’s effect endures even though within a few minutes, nicotine concentration in the fluid that surrounds the brain drops to levels that activate only a few per cent of nicotine receptors on brain cells (neurons).

We hypothesize that nicotine accumulates in specific organelles, called synaptic vesicles, of neurons. When neurons are stimulated, they then release nicotine together with the chemicals they normally release, such as acetylcholine or other neurotransmitters. This provides a transient source of nicotine during periods that far outlast the times nicotine can be detected in the fluid that surrounds the brain.
We also address the efficacy of varenicline, the most successful smoking cessation drug. We hypothesize that varenicline also accumulates in acidic organelles, especially the synaptic vesicles, of neurons.

Varenicline is then released, with acetylcholine or other neurotransmitters, during neural stimulation. This partially blocks nicotine receptors, increasing the efficacy of varenicline during smoking cessation.

The project investigates such release, using a series of cutting edge biosensors we introduce into brain cells of animals. These biosensors allow us to follow the presence of nicotine and / or varenicline within brain cells as they respond to stimulation. We expect the signals to be highly sensitive, displaying a temporal resolution of ~ 500 milliseconds and a spatial resolution of micrometers, allowing us to test our hypotheses about a new drug release mechanism associated with nicotine addiction and smoking cessation drugs.