Kenneth Kellar: Decoding the Brain’s Addiction to Nicotine
.jpg "Kenneth Kellar, PhD, in his lab")
It is fair to say that Kenneth Kellar, PhD, contributed to the moment the United States began in earnest to turn against cigarette smoking -- the 1994 Congressional hearing when seven tobacco company executives declared under oath that nicotine is not addictive.
Not many people believed the CEOs, least of all Kellar. In the early 1980’s Kellar and one of his graduate students, Rochelle Schwartz, had shown that chronic administration of nicotine actually increases the number of nicotinic receptors in rat brains. Then, in the early 1990’s, Kellar and his colleagues Martha Dávila-García, PhD, of Georgetown and David Perry, PhD of George Washington University, produced autoradiographic images of nicotinic receptors in the brains of long-time smokers. The images showed that the postmortem brains of smokers had substantially more of these receptors than did brains of non-smokers. The connection between the chronic exposure to nicotine via smoking and the increased receptors was clear.
Kellar, a professor of pharmacology at Georgetown University Medical Center, was told those pictures helped convince the FDA to seek regulation of nicotine in cigarettes, which led Congressman Henry Waxman, chair of the House Subcommittee on Health and the Environment, to haul the CEOs up to their feet to swear the infamous oath.
“We don’t understand addiction for any drug, but nicotine is almost surely the most harmful of all drug addictions,” says Kellar. “The CDC estimates that lifelong smokers in the United States lose 12-14 years of life.”
Although much progress has been made in understanding the effects of nicotine in the brain, scientists still don’t understand the cellular changes that result in addiction. Now, however, Kellar and his laboratory colleague, Yingxian Xiao, PhD, are proposing a theory that he admits is controversial, but which he says makes sense if one considers how the brain responds in other contexts.
Kellar believes that nicotine works to keep nicotinic receptors in a desensitized state, and that the cycle of addiction happens when the only way to keep those receptors from being reactivated is to take in more nicotine by smoking another cigarette. “If a person doesn’t smoke for 2 or 3 hours, the receptors become active again, and because smokers have more of these receptors in their brains, this activity increases feelings of anxiety and craving,” he says. “A smoker has learned that the easiest way to relieve this discomfort is to smoke another cigarette, which turns off these receptors by desensitizing them. And that starts up the cycle all over again.
“It is probably similar to what happens when we are hungry. Signals in our brains tell us when we need to eat, and when we do, they quiet down until we are hungry again,” Kellar says.
The theory is somewhat contentious, he says, because it proposes that nicotine’s addictive effects are due primarily to turning off (desensitizing) these nicotinic receptors in the brain, whereas most studies have focused on nicotine’s effect to turn on the receptors.
Kellar is working with GUMC’s Drug Discovery Program Director Milton Brown, MD, PhD, on agents that can desensitize certain subtypes of nicotinic receptors as a potential way to help smokers stop using cigarettes. One compound is already being tested in animals at Duke University Medical Center, in collaboration with Kellar’s group.
As he advances his notions of addiction, Kellar is also looking into how nicotine may actually be helpful for some ailing brains. “Under some conditions, nicotine can increase focus and concentration and enhance performance in certain cognitive tests,” he says. He is part of a multi-center research group that has just completed an early-phase clinical trial testing the use of nicotine patches in 74 patients with a disorder known as minimal cognitive impairment, and the group hopes to secure funding for a much larger study to determine if nicotine can slow the progression of minimal cognitive impairment to Alzheimer’s disease.
“Nicotinic receptors mediate important effects in the brain, and they need to be understood for both their positive and negative aspects,” Kellar says. “There are still many important questions left to explore.”
By Renee Twombly, GUMC Communications
