In 1964, the United States Surgeon General issued a report that suggested a relationship between smoking cigarettes and poor health outcomes. Despite an overwhelming amount of evidence that smoking can lead to disease, millions of people still use tobacco. Nicotine, the drug in tobacco, drives the persistent urges to smoke that make abstaining so difficult for those looking to quit.
Forty-two years after that initial report from the Surgeon General, the Food and Drug Administration (FDA) approved the drug varenicline (Chantix®) to help curb those cravings for nicotine. Varenicline has helped some people quit, but the actions of varenicline, especially during long-term nicotine exposure, have been debated.
When nicotine enters the body, it binds to neurotransmitter receptors in the brain called nicotinic acetylcholine receptors (nAChRs) that in turn bind to the neurotransmitter acetylcholine (ACh). There are different types of nAChRs, and some have bigger roles than others in producing pleasure. Varenicline partially activates pleasure-causing nAChRs, with the notion being if varenicline competes for the nAChRs that nicotine targets, there would be fewer nAChRs available for nicotine to bind to and a reduction in nicotine’s effects.
However, these actions only explain varenicline’s short-term effects and do not account for how varenicline works in cells with long-term nicotine exposure. The combination of the two drugs is relevant in people who start taking varenicline after years of smoking, so understanding the mechanisms of this relationship has been paramount for researchers.
William Green, PhD, Professor in the Department of Neurobiology at UChicago and Anitha Govind, PhD, an Assistant Research Professor in his lab, sought to discover the unknown mechanisms that make varenicline more or less effective following long-term nicotine exposure.
“Unlike the neurotransmitter ACh, both varenicline and nicotine enter neurons in the brain and interact with nAChRs before they arrive on the surface of neurons,” Green said. “We were interested in testing how varenicline altered the long-lasting effects of nicotine on nAChRs and determining whether this process involved nAChRs inside of cells.”
In the brain, there is an upregulation (an increase in number and sensitivity) of nAChRs as they adapt to chronic nicotine. When smoking ceases, withdrawal sets in as the nAChRs crave nicotine to return to the nicotine-induced equilibrium. Like nicotine, varenicline also appears to upregulate nAChRs, so how exactly varenicline reduces cravings during long-term nicotine exposure has puzzled scientists.
“We found that varenicline dampens the effects of upregulation,” Govind said. “Surprisingly, varenicline reduced the nAChR signaling that had increased with nicotine-induced upregulation.”
The research team also discovered that varenicline gets trapped within acidic compartments called vesicles that contain nAChRs. Nicotine, however, does not get trapped and rapidly exits the vesicles. The trapped varenicline then gets slowly released from the vesicles, which helps dampen the nAChR signaling that contributes to withdrawal.
Green’s lab found that both the acidity within the vesicles and the binding affinity (the strength in which nicotine binds to nAChRs) are critical components that change the degree to which the trapping and slow release of varenicline occurs. These components diminish nAChR signaling which hinders cell communication that produces feelings of pleasure and withdrawal.
“We discovered that high-affinity nAChRs within the acidic vesicles are required for its selective trapping,” Green said. “However, we still do not know how the vesicle acidity together with nAChR affinity for varenicline leads to its trapping.”
Varenicline appears to deter the signaling of neurons in the brain that drive the urges to smoke, but the effects are greater when varenicline is accompanied by nicotine upregulation.
“Long-term exposure to nicotine increases the number of acidic vesicles that contain nAChRs,” Govind said. “The more acidic vesicles there are, the more varenicline gets trapped, and this trapping appears to dampen nAChR signaling.”
Understanding the trapping and slow-release mechanisms appear to be crucial in understanding what makes varenicline and other anti-smoking agents effective. However, it remains to be determined if the degree of trapping and slow release directly correlates with stronger varenicline effects, as there are many factors that shape the effectiveness of the drug.
Pharmaceutical companies can take this information and focus the development of future anti-smoking agents toward these trapping and slow release mechanisms. Their lab’s findings also have implications for other drugs of abuse, like amphetamines or opioids. “Almost all drugs of abuse have chemical properties similar to varenicline and nicotine that allow them to enter neurons and accumulate in acidic vesicles,” Govind said.
In the wake of their findings, Green looks forward to next steps.
“All of this work was performed ‘in vitro’ using cultured cells and neurons. We are exploring imaging techniques, such as positron emission tomography (PET) scanning to validate some of our ideas about the cellular distribution of varenicline, with the end goal of eventually testing our results in humans,” he said.
This study was funded by the National Institutes of Health (RO1 DA035430) and was partially supported through a Pilot Project from the University of Chicago Cancer Center.