Tag Archives: nicotine receptors

Two Nicotine Addiction Puzzles Explained

The stranglehold of nicotine addiction leads to more than four million smoking-related deaths each year. Scientists at the California Institute of Technology have now explained two roots of that addiction. The discoveries may offer new hope not just for smokers, but eventually also for sufferers of Parkinson’s disease, a debilitating movement disorder that affects some 40 million people worldwide.

Researchers have known for decades that chronic exposure to nicotine increases the number of nicotine receptors–molecules that are activated by binding to the drug–on nerve cells. The binding of nicotine to these receptors, and in particular to one specific subunit known as alpha4, enhances the release of a pleasure-causing neurotransmitter called dopamine.

But “this increase is confusing,” says Henry A. Lester, the Bren Professor of Biology at Caltech, “because for opioid addiction, and for many other classes of addictions and of drugs in general, the body attempts homeostasis and adjusts the number of receptors downward if there is a constant stimulus.” Understanding this paradox–how it is possible that smokers become tolerant to the pleasurable effects of nicotine despite the fact that their brains produce new nicotine receptors in response to the chemical–is crucial for defeating nicotine’s addictive power.

Lester, his postdoctoral researcher Raad Nashmi, and their colleagues at Caltech, the University of Colorado at Boulder, and the University of Pennsylvania School of Medicine, have now solved the mystery, by developing a special mouse strain with fluorescent nicotine receptors. These fluorescent tags allowed the scientists to monitor the effects of the nicotine throughout the brain, down to the level of individual neurons.

“We find that alpha4 containing receptors, those with some of the highest sensitivity to nicotine, are upregulated”–or increased in number–“by chronic nicotine in a cell-specific fashion,” Lester explains. “In particular, the alpha4-containing receptors are indeed upregulated in the dopamine-producing portions of the brain, but not in the dopamine neurons themselves.” Instead, the increase in receptor number occurs only in neurons that inhibit dopamine neurons–a group called the GABAergic neurons.

Dopamine FormulaThis surprising result led the researchers to conduct experiments with delicate electrical probes. In chronic nicotine-treated mice (and presumably in chronic smokers), the dopamine neurons are chronically inhibited from firing in the absence of nicotine. And nicotine itself still excites the dopamine neurons, leading to pleasure, but much less than expected.

“This research explains tolerance during nicotine addiction,” Lester says. “Once in a while, an important piece of a puzzle does fall into place.”

“This is outstanding work that will open the door to further studies of nicotinic receptor upregulation in the cognitive and rewarding effects of nicotine,” comments Daniel S. McGehee of the University of Chicago, who studies the neurobiology of nicotine addiction. McGehee was not involved in the present research.

But there’s more. In the special Caltech mice, the largest number of new nicotine receptors appeared in the mouse forebrain. This is the part of the brain involved in cognition. Electrical measurements showed that these new receptors also helped to boost synaptic transmission. The result may explain why many smokers claim that cigarettes actually help them think better–and why 44 percent of the cigarettes smoked in the United States are consumed by people with mental health problems.

“People may attempt to medicate themselves with nicotine, and my research is also aimed at trying to understand the mechanism behind that,” Lester says.

“We now think that we need to concentrate on drugs that manipulate upregulation.” Lester adds. His lab is currently developing simpler cell-based systems using the fluorescently labeled nicotine receptors. Using special microscopes, the effect of particular drugs on those receptors can be monitored.

One long-term benefit of the research could be the development of better therapies for Parkinson’s disease, the chronic neurological condition that gradually destr

Chantix Helps Smokers Quit

MARTINSBURG, W.Va. – The first time Brian Kelly quit smoking, in the 1990s, he had nicotine cravings like crazy even though he was using a nicotine patch and nicotine gum.

This year when Kelly decided again to try to kick the habit he returned to the patch and gum, until he read on the Internet about Chantix, a prescription anti-smoking pill approved a year ago by the U.S. Food and Drug Administration.

“It’s like a wonder drug as far as I’m concerned,” said Kelly, 63, of Martinsburg.

Kelly said he quit smoking in three weeks – a date he set through a quit-smoking class at Waynesboro Hospital in Pennsylvania – and didn’t face the withdrawal symptoms that occurred the first time he quit.

Chantix, made by Pfizer, blocks the nicotine receptors in the brain so people don’t get a buzz from smoking, nor do they suffer withdrawal symptoms when they stop smoking, said Dr. Paul Quesenberry, a family doctor with Cumberland Valley Family Physicians in Chambersburg, Pa.

“It’s been a really amazing addition to our regimen for getting people to stop smoking,” Quesenberry said.

Still, it’s not an immediate fix.

How long it takes to stop smoking with Chantix varies from patient to patient, but usually it takes weeks to months because people have to learn to break the habit as well, Quesenberry said.

According to Pfizer’s Web site, smokers should start taking Chantix one week before their quit-smoking date so the drug can build up in the body. They can keep smoking during that first week.

Dr. Dwight Wooster, a pulmonologist with Newman, Wooster, Kass, Bradford, McCormack & Hurwitz at Robinwood Medical Center, said he recommends his patients try to reduce how much they smoke before they start Chantix. Of the 22 patients for whom he has prescribed Chantix, about 17 already have quit smoking.

Most people take Chantix for up to 12 weeks, according to Pfizer.

The most common side effects include gastrointestinal problems such as nausea and constipation, and difficulty sleeping, doctors said.

Quesenberry said most people he’s prescribed Chantix to haven’t had problems with side effects.

Most people who experience side effects will tolerate them because the benefit of quitting smoking is so huge, he said.

Dr. Sanjay Saxena, a family doctor with Hagerstown Family Medicine, said he’s had patients ask about Chantix, whether they’ve tried other smoking cessation tools or not, because they’ve heard how successful the drug has been for others.

Health benefits

Kelly began smoking at age 7 when he was living in Brooklyn, N.Y., because it was a tough neighborhood and smoking was cool.

When he quit the first time, Kelly had been smoking as many as 4 1/2 packs a day.

He began smoking again around 2001 after several deaths in his family and got up to a pack and a half a day.

Since he quit with Chantix, Kelly feels terrific, he said.

His breathing has improved, and he no longer has a smoker’s cough.

The carbon monoxide that gets into the bloodstream from smoking can lead to heart disease and strokes, Quesenberry said.

Smoking also can lead to chronic lung diseases such as emphysema and cancers, including lung, mouth, esophagus, and cervical and bladder cancers, he said.

Lesa Spedden, 32, of Chambersburg, Pa., took Chantix to quit smoking so she would have more energy and to be an example for her children.

“I don’t want to be a hypocrite and say, ‘Now, you can’t do this.’ Meanwhile, I’m there huffing and puffing in front of them,” Spedden said.

Spedden said she truly enjoyed smoking and wanted something to help her not enjoy the habit. Chantix helped curb that desire. After taking the drug a few days, smoking cigarettes developed an unpleasant, bitter taste, she said.

Smoking didn’t appeal to her anymore.

The most immediate benefit is getting rid of the expense of smoking, Quesenberry said.

Chantix can be pricey and sometimes health insurance doesn’t cover it, but the flip side is the expense of cigarettes, Quesenberry said.

A one-month supply – a 1-milligram Chantix pill per day – would cost $60 to $65 without insurance coverage, said David Russo, pharmacist and owner of Russo’s Rx in Hagerstown.

Other options

Other options for smokers wanting to quit include the nicotine patch, nicotine gum, nicotine inhaler and the anti-smoking drug Zyban.

Saxena said Chantix has been more successful than other treatments, but there’s still a place for those other treatments. He’s had at least one patient who experienced bad nausea with Chantix.

For that person, he might recommend the nicotine inhaler, which gives smokers nicotine as well as something to do with their hands rather than handle a cigarette or turn to more food as a substitution.

Quesenberry said he typically hasn’t recommended the nicotine patch because it causes skin irritation, and smokers usually don’t like it because it doesn’t deliver that quick nicotine buzz as a cigarette does. Instead, the patch provides a slow release of nicotine.

While the taste of nicotine gum isn’t pleasant, it does a better job of providing a nicotine buzz, like a cigarette, he said.

Quesenberry said he would prescribe Zyban for smokers with significant co-existing anxiety or depression because the pill is actually an anti-anxiety medicine, marketed for the latter purpose as Wellbutrin. The drug, generically known as bupropion, was approved by the FDA in May 1997 as an anti-smoking medication and marketed under the name Zyban.

If someone specifically asked for Zyban because they knew someone who quit with it, Quesenberry would prescribe the person that drug, he said.

Wanting to quit is a big factor in succeeding quitting, local doctors said.

Quesenberry said he won’t prescribe Zyban or Chantix for smokers who don’t want to quit but say they want an anti-smoking drug because a family member wants them to quit, because they have to want to quit themselves.

A bit of psychology is involved, he said.

“Once it’s in the heart and they want to do it, it doesn’t take much. It’s getting people to where they’re ready to stop that’s the big deal sometimes,” Quesenberry said.

“If you’re not motivated, no medication is going to work,” Wooster said.

For more information about Chantix, check out this Web site:

U.S. Food and Drug Administration’s patient information sheet for Chantix: www.fda.gov/cder/drug/InfoSheets/patient/vareniclinePIS.htm.

Source: JULIE E. GREENE, The Herald-Mail Company