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Two Nicotine Addiction Puzzles Explained

Aug 02, 2007




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. 



This 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 destroys some dopamine cells. Although the cause of Parkinson's disease is unknown in most patients, one curious observation is that few smokers are ever affected. In fact, they seem to be protected against the condition. The reason, researchers suspect, is nicotine--and the new brain studies reveal that the reason may be those cell-specific differences in the regulation of nicotine receptors.



Previously, animal models of Parkinson's have shown that the excessive activity of dopamine neurons, firing in hysterical bursts, can lead to the death of those neurons. The affected neurons are located in a brain region called the substantia nigra, which is a center of voluntary movement control. 


"These dopamine cells are actually persuaded by chronic nicotine to fire less, which may help them to live longer," says Lester, who hopes the research will lead to the development of drugs that act "very specifically" on these nicotine receptors and prevent cell death, "so people with the early stages of Parkinson's disease get the protection that they need."



The paper, "Chronic Nicotine Cell Specifically Upregulates Functional alpha4* Nicotinic Receptors: Basis for Both Tolerance in Midbrain and Enhanced Long-Term Potentiation in Perforant Path," was published in the August 1 issue of the Journal of Neuroscience.

Source: Caltech


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Understanding Nicotine Addiction

By Dennis Thompson Jr. | Medically reviewed by Pat F. Bass III, MD, MPH




Cigarettes and other tobacco products contain one of the most addictive drugs around: nicotine. Nicotine withdrawal is a difficult proposition.



“I can quit whenever I want to,” is a familiar refrain among many cigarette smokers. But if that were really true, the statistics would paint a different picture. According to the Centers for Disease Control and Prevention, about 70 percent of smokers want to quit completely, and about 40 percent try to stop each year — but of those who try to quit, only about four to seven percent are successful. Any smoker who’s tried to quit can tell you it isn’t just a question of willpower. For many, it’s all about the nicotine.


Nicotine is the powerful alkaloid found in tobacco that causes cigarette smokers to become addicted, and it's even more powerful than morphine. Nicotine acts on neurotransmitters in the brain, causing a wide range of biochemical reactions that result in pleasure for the smoker. But, like other drugs, nicotine's effect weakens as the body adapts to it. Smokers must smoke more to get the same good feeling, and will have to deal with nicotine withdrawal if they try to stop smoking or using tobacco products.



Nicotine Delivery and Effect


Cigarettes are the most efficient delivery system for nicotine. A lit cigarette vaporizes the nicotine in the tobacco, which enters the body in vapor form and on tar droplets as part of cigarette smoke. The lungs and the mucosal lining of the nose and mouth absorb the nicotine into the smoker's system.


Once inside the smoker's bloodstream, the nicotine stimulates the body's adrenal glands to produce more adrenaline. The adrenaline creates a "rush" that increases the smoker's blood pressure, heart rate, and respiration.



Nicotine also manipulates a number of neurotransmitters in the body, producing varied effects that last longer than the initial adrenaline kick. Nicotine affects: 

  • Dopamine, resulting in pleasure and appetite suppression
  • Norepinephrine, resulting in arousal and appetite suppression
  • Acetylcholine, resulting in arousal and enhancement of cognition
  • Vasopressin, resulting in memory improvement
  • Serotonin, resulting in mood control and appetite suppression
  • Beta-endorphin, resulting in reduced anxiety and tension 


Because cigarette smokers inhale tobacco smoke into their lungs, nicotine is processed rapidly and can reach the brain in as little as 10 seconds. Cigar and pipe smokers typically do not take smoke into their lungs, so the nicotine is instead absorbed more slowly through the mucous membranes in the mouth and nose, muting the drug's effect. 


Nicotine Addiction 


A smoker inhales 1 to 2 milligrams of nicotine with every cigarette, taking 10 puffs over an average 5-minute period. That means a person who smokes one to two packs a day receives 200 to 400 "hits" of nicotine to the brain a day. 


However, the kick experienced with every cigarette lasts only a few minutes, and the neurotransmitter effects are equally short-lived. The body breaks down, or metabolizes, nicotine rapidly, and the estimated half-life of nicotine in the bloodstream is about two hours. The smoker must light up another cigarette within a few hours to maintain the nicotine high. If the smoker doesn’t, nicotine withdrawal will begin. 




The nicotine delivered by cigarette smoking is considered as addictive as heroin and is: 

  • 1,000 times more potent than alcohol
  • 10 to 100 times more potent that barbiturates
  • 5 to 10 times more potent than cocaine or morphine

Nicotine Withdrawal


Smokers dealing with nicotine withdrawal are known to experience: 

  • Irritability
  • Intense cravings
  • Anger and hostility
  • Anxiety, nervousness, and panic
  • Depression
  • Difficulty concentrating and thinking
  • Disturbed sleep
  • Increased appetite and weight gain


Smokers going through nicotine withdrawal also might experience a range of physical effects that include sweating, constipation, dry mouth, mouth ulcers, pain in their limbs, coughing, and soreness of their throat, gums, or tongue.


When Nicotine Withdrawal Symptoms Start


Nicotine withdrawal symptoms begin a few hours after the last cigarette is smoked, producing intense and overwhelming cravings. These symptoms peak within a few days after quitting smoking, and can subside within a few weeks. 


However, some smokers trying to quit could feel some of these symptoms for months after smoking that last cigarette. The nicotine high also becomes associated with certain activities and triggers in the smoker's mind, so that the urge to smoke could strike when the person is doing something as simple as drinking a cup of coffee or chatting with a friend on the phone. Nicotine is an insidious drug that requires focused effort to kick.


Last Updated: 9/9/2011


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Nicotine Addiction - An Explanation

Someone made me aware of the below and - altho it's quite long -- it's quite informative and sure makes sense to me. I found it well worth the read and hope you do, too. It's in quotes, but I can't give credit 'cause I don't know who wrote it. Anyway, here it is: 

"I've been doing research (actually, more like rooting around) into the neuropharmacological aspects of nicotine addiction and thought I'd share a bit here. When you experience something pleasurable, certain areas of your brain called reward centers activate by releasing dopamine. The presence of dopamine is what causes the pleasurable feeling, the enjoyment, the “ahhh”. 

Smoking causes an increase in the dopamine levels. The actual mechanism is debated, but MRI studies confirm the increase occurs. As you continue to smoke, the dopamine levels remain high and the brain starts shutting down some of the reward centers in an attempt to return to normal. This causes the smoker to require more, which raises the dopamine levels, which causes the brain to shut down even more reward centers. A balance is eventually reached, typically at the point of a pack per day (about 20 mg of nicotine). This also applies to users of chewing tobacco and snuff. 

So now a balance has been reached. The nicotine has raised dopamine levels and the brain has shut down reward centers to compensate. Heroin and cocaine users also reach this maintenance level where the fix no longer causes pleasure, but simply maintains “normal”. When the dopamine level begins to drop (30 – 60 minutes after the last smoke) the smoker begins to feel “the need” and has another fix which re-establishes the dopamine levels. 

When the smoker quits the levels of nicotine fall rapidly, as do the dopamine levels. After three to five days the nicotine is out of the system. The brain, however, does not recover as quickly. Without the constant smoking stimulus, dopamine levels are far below where they were. Since reward centers were long ago shut down to compensate for the increased dopamine levels caused by smoking, the (now) ex-smoker is operating at a “reward deficit”. As a result, the ex-smoker feels depressed, ill-tempered, and sad (cries a lot). Those who use sleep as an escape mechanism will tend to sleep much more. 

Another effect of this “reward deficit” is that ordinary, everyday rewards don’t seem to work anymore. In reality, they do cause an increase in dopamine levels, but with so many reward centers deactivated the increase is barely noticeable, if it can be noticed at all. This is why we quitters need to reward ourselves often. The size of the reward isn’t important, the quantity is. Essentially, we need to exercise our reward centers to rebuild them, just like muscles need to be exercised after a long period of disuse. 

The research I’ve dug into indicates it takes “several months” to “over a year” , (depending on who you read) for the brain to reactivate enough reward centers to approach the “normal” of never-smokers. Perhaps this is the root of the idea that you aren’t fully quit until you’ve experienced all the seasons.  

So early in your quits, reward yourselves often. Little stuff is great. Window shopping, watching ducks at the park, special coffee after work, whatever. Doesn’t have to be expensive, just enjoyable. Think free weights for the brain."

Read more: http://www.healthboards.com/boards/smoking-cessation/487857-nicotine-addiction-explanation.html#ixzz3SQmfNDul

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