Novel research model clarifies nicotine's effects on the brain

Paul Basilio, MDLinx | February 14, 2017

New research from a group at the University of Kentucky has shed some light on the role nicotine plays in the assembly of nicotinic receptors in the brain.

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The group's results may offer valuable insights for the therapeutic targets of future smoking cessation products.

While nicotine has been known to change the grouping of some subtypes of nicotinic receptors, the mechanism for nicotine addiction has remained unclear. This research centers on the group’s fluorescence-based “single molecule” technique. It is being presented at the Biophysical Society’s 61st Annual Meeting in New Orleans, currently taking place through February 15.

The group explored whether nicotine exposure increases the total number of nicotinic receptors on cell surfaces and if it changes the way the receptor is grouped.

“To do this, we used custom-built microscopes to expose our samples to laser excitation while we detect the fluorescence signal given off from the labeled proteins,” said Faruk Moonschi, a graduate student in the department of chemistry at the University.

A ligand—which can be a small molecule or peptide—typically binds with the corresponding receptor protein on its cell surface.

“[In contrast], some researchers hypothesized that nicotine actually gets inside the cells of smokers’ brains and changes the assembly of nicotinic receptors by altering the ratio of nicotinic receptor subunits,” Moonschi said. “This potentially alters the trafficking of some subtypes of nicotinic receptors to the cell surface.”

Moonschi and his colleagues devised a single molecule technique that allows them to separate freshly assembled nicotinic receptor (from the endoplasmic reticulum of cells) from those already assembled and transferred to the cell surface.

“By doing this, we were able to show that nicotine changes the subunit ratio of nicotinic receptors in the endoplasmic reticulum,” Moonschi explained. “Further, we showed that one assembly is preferentially transported from the endoplasmic reticulum to the plasma membrane.”

These findings stand to be an important contribution to clarifying the mechanism of nicotine addiction.

“Understanding how nicotine alters the assembly of receptors in the context of addiction should provide insight into therapeutic targets for smoking cessation compounds,” Moonschi noted.

Next, the group plans to extend their research to in vivo studies. They will use genetically modified mice to determine whether similar changes in stoichiometry are seen in live animals due to nicotine exposure. In addition, they will study how smoking cessation compounds affect the stoichiometry of nicotinic receptors.

Moonschi, who will present the group’s work, became interested in the mechanics of nicotine addiction after his father’s many attempts to quit smoking.

“Like many people in my country, Bangladesh, my father is a heavy smoker,” he said. “Despite the fact that my mother and siblings have encouraged him to quit, he has never been able to stop smoking. I’ve always been interested in what led to his addiction, so I joined a research group working within the area of addiction to study the underlying mechanisms of nicotine dependency.”

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