Nicotine and the Humphrey Bogart Gene

You can lead a fish to water, but can you make it smoke?

Zebrafish embryo showing axon tracts in green, viewed from lateral (top) and dorsal (bottom) orientations------>

Common denizens of home aquariums, the humble zebrafish may dart about the tank like any other small tropical specimen, but zebrafish have become one of the hot genetic research tools of the moment. The lab rat may have met its match in the lab zebrafish, a popular non-mammalian organism that is currently playing a leading role in government-sponsored research on the genetic aspects of nicotine addiction.

Scientists are fond of these new fishy animal models because zebrafish are cheap, develop rapidly, and are more biologically similar to humans than anyone might naively assume. Their transparent embryos allow researchers to inject flourescent proteins into living animals, and in some cases to track the regulation of gene expression as it is happening.

Research funded by the National Institute on Drug Abuse (NIDA) and  published in the Proceedings of the National Academy of Sciences used zebrafish in a hunt for genes

affecting nicotine exposure. Like rats, the fish show characteristic behaviorial responses to low doses, high doses, and the nicotine sensitization process. According to NIDA, the scientists “induced mutations in particular DNA segments of the zebrafish and looked at changes in the nicotine response profile of mutant carriers compared to their siblings.” The changes in nicotine response observed between the groups were mediated by two genes, which the scientists dubbed bdav/cct8 (bette davis) and hbog/gabbr1.2 (humphrey bogart), named after “celebrities that suffered from tobacco-related cancers.” These two genes, when expressed, caused zebrafish to respond more positively to nicotine.

“We all know how hard it is to quit smoking,” Dr. Ekker told Mayo’s online research magazine, Discovery’s Edge. “What most people don’t know is that genetic differences significantly contribute to the degree of nicotine dependence. We want to understand the genetics behind different responses to nicotine and come up with more effective and individualized treatments for people addicted to nicotine.”

The Mayo Clinic in Minnesota has taken a leading role in developing the fish for research, having established the Zebrafish Core Facility in 2007 under the direction of Dr. Stephen Ekker. Mayo’s zebrafish are now being used in various research laboratories for research in the fields of developmental biology and functional genomics. The fish are now a crucial part of biological research on cancer and heart disease, as well as addiction.

Graphics Credit: http://www.ucl.ac.uk/

Petzold AM, Balciunas D, Sivasubbu S, Clark KJ, Bedell VM, Westcot SE, Myers SR, Moulder GL, Thomas MJ, & Ekker SC (2009). Nicotine response genetics in the zebrafish. Proceedings of the National Academy of Sciences of the United States of America, 106 (44), 18662-7 PMID: 19858493

Low-Nicotine Cigarettes: Deadlier Than Regular Brands?

More tars, more cancer.

Now that the U.S. Congress has passed legislation enabling the Food and Drug Administration (FDA) to monitor the tobacco industry for the first time in history (see my earlier post), one of the primary issues the agency must deal with are health claims on behalf of allegedly less-toxic brands of “low-nicotine” cigarettes.

It has long been understood, and demonstrated clinically, that people addicted to nicotine will smoke “light” cigarettes harder, and in greater numbers, in order to compensate and obtain the same amount of nicotine they are used to--thereby staving off withdrawal. [See graphic at right for the secret of why light cigarette smokers must puff harder.]

As prominent tobacco researcher N.L. Benowitz wrote in a National Cancer Institute (NCI) monograph:

“In brief review—when faced with lower yield cigarettes, smokers can smoke more cigarettes per day, can take more and deeper puffs, can puff with a faster draw rate, and/or can block ventilation holes. Using these last four techniques, a smoker can increase his or her smoke intake from a particular cigarette several fold above the machine-predicted yields.”

In the description of a patent for a low-tar and low-nicotine technique in 1995, Duke University Researchers wrote:

“Unfortunately, it has been discovered that only a small proportion of the total smoking population (e.g., less than 25%) has substituted low tar cigarettes (e.g., cigarettes that deliver less than 10 milligrams of tar) for conventional and more hazardous cigarettes. Also of note, only about 2.0-3.0% of total cigarette sales are accounted for by very low tar cigarettes (e.g., cigarettes that deliver less than 3 milligrams of tar). Moreover, even among the cigarette smokers who have substituted low tar cigarettes for conventional cigarettes, it has been discovered that these individuals will tend to smoke low tar cigarettes more intensively in order to extract more tar and nicotine than the nominal values listed on the pack. This, of course, defeats part of the objective of the low tar cigarettes.”|

Moreover, there has never been any significant body of evidence to suggest that switching to lights or ultra-lights in a way actually contributes to the success of smoking cessation efforts. According to the National Cancer Institute, there are no health benefits for smokers of light cigarettes, period.

In a letter published in the August 21 issue of Science, Marshall E. Deutsch argues that cigarettes with reduced nicotine may in fact “increase tobacco related death and disease” and are therefore potentially more dangerous than regular smokes.

Deutsch’s argument is that by smoking more cigarettes with lower concentration of nicotine, smokers “will be subjected to more of the ‘tars’ (the cancer-causing ingredients of the smoke) in their attempts to get their usual dosage of nicotine, (the ingredient responsible for heart disease and stroke). In the end, smokers of low-nicotine cigarettes will remain at the same risk for heart disease and stroke but increase their chances of developing cancer.”

It’s never too late to quit, and the earlier the better: The National Cancer Institute tells us that smokers who quite before age 50 cut their risk of dying by 50 % over the next 15 years, compared to those who keep smoking.

Graphics Credit: www.tobaccoinaustralia.org.au

addiction drugs smoking nicotine

E-Cigarettes: Another Look

FDA remains conflicted over safety concerns.

The Food and Drug Administration (FDA) issued a controversial Safety Alert over electronic cigarettes, known as “e-cigarettes,” then held a press conference to explain itself. The agency’s muddled response to the issue has prompted increased advertising and online sales for Asian e-cigarette manufacturers, as well as a countering burst of criticism about the newest nicotine delivery system under the sun.

The FDA conducted a small-scale lab analysis of two different brands of e-cigarettes, and found “carcinogens and toxic chemicals such as diethylene glycol, an ingredient used in antifreeze.” The FDA’s Division of Pharmaceutical Analysis also found evidence of small amounts of cancer-causing nitrosamines. “These products do not contain any health warnings comparable to FDA-approved nicotine replacement products or conventional cigarettes,” the agency bulletin said. Therefore, the agency “has no way of knowing, except for the limited testing it has performed, the levels of nicotine or the amounts or kinds of other chemicals that the various brands of these products deliver to the user.”

The agency did not seek to ban e-cigarettes, as Canada did in March. However, in a written statement to CNN in March, the FDA admitted it had been detaining or refusing importations of electronic cigarettes for more than a year.

Debate has raged recently over the safety of e-cigarettes, which are battery-operated cigarette substitutes that technically dodge no-smoking bans, since no actual smoke is emitted. When a smoker inhales on the e-cigarette, the battery warms liquid nicotine stored in a plastic filter, producing a smokeless but inhalable form of synthetic nicotine. Upon exhalation, there is a small puff of vapor that quickly evaporates (See my earlier post, "E-Cigarettes and Health").

Michael Levy, director of compliance for the FDA’s division of drug evaluation and research, said he believes the products are illegal. However, “There is pending litigation on the issue of FDA’s jurisdiction over e-cigarettes,” he said.

Proponents of the e-cigarette claim that the devices are self-evidently safer than smoking cigarettes, and can help people stop using tobacco products. Critics respond that the safety of synthetic nicotine drug-delivery devices has not been established. Moreover, the range of fruit and candy flavors offered by e-cigarette manufacturers suggests to Jonathan Inickoff of the American Academy of Pediatrics Tobacco Consortium that the devices seem “tailor-made to appeal to kids,” while addicting them to nicotine and turning them into future cigarette smokers.

With half a million Americans dying prematurely each year from smoking, according to figures from the Centers for Disease Control (CDC), some doctors and tobacco researchers have pointed out that nitrosamines are also found in everything from nicotine patches to bacon. According to one researcher, “FDA should be encouraging, not maligning the manufacture and sale of electronic cigarettes, and working with manufacturers to assure the highest possible quality control.”

For a robust discussion of the e-cigarette question, see www.e-cigarette-forum.com


Photo Credit: www.politech.wordpress.com

addiction drugs smoking nicotine

New World Nicotine: A Brief History

“Drinking the Smoke”

The prototypically North American contribution to the world drug trade has always been tobacco. Tobacco pipes have been found among the earliest known Aztec and Mayan ruins. Early North Americans apparently picked up the habit from their South American counterparts. Native American pipes subjected to gas chromatography show nicotine residue going back as far as 1715 B.C. “Drinking” the smoke of tobacco leaves was an established New World practice long before European contact. An early technique was to place tobacco on hot coals and inhale the smoke with a hollow bone inserted in the nose.

The addicting nature of tobacco alarmed the early missionary priests from Europe, who quickly became addicted themselves. Indeed, so enslaved to tobacco were the early priests that laws were passed to prevent smoking and the taking of snuff during Mass.

New World tobacco quickly came to the attention of Dutch and Spanish merchants, who passed the drug along to European royalty in the 17th Century. In England, American tobacco was worth its weight in silver, and American colonists fiercely resisted British efforts to interfere with its cultivation and use. Sir Francis Bacon noted that “The use of tobacco is growing greatly and conquers men with a certain secret pleasure, so that those who have once become accustomed thereto can later hardly be restrained therefrom.” (As a former smoker, I am hard pressed to imagine a better way of putting it.)

Early sea routes and trading posts were determined in part by a desired proximity to overseas tobacco plantations. The expedition routes of the great 17th and 18th Century European explorers were marked by the strewing of tobacco seeds along the way. Historians estimate that the Dutch port of Amsterdam had processed more than 12 million pounds of tobacco by the end of the 17th Century, with brisk exports to Scandinavia, Russia, Prussia, and Turkey. (Historian Simon Schama has speculated that a few enterprising merchants in the Dutch tobacco industry might have “sauced” their product with cannabis sativa from India and the Orient.)

Troubled by the rising tide of nicotine dependence among the common folk, Bavaria, Saxony, Zurich, and other European states outlawed tobacco at various times during the 17th Century. The Sultan Murad IV decreed the death penalty for smoking tobacco in Constantinople, and the first of the Romanoff czars decreed that the punishment for smoking was the slitting of the offender’s nostrils. Still, there is no evidence to suggest that any culture that has ever taken up the smoking of tobacco has ever wholly relinquished the practice voluntarily.

A century later, the demand for American tobacco was growing steadily, and the market was worldwide. Prices soared, with no discernible effect on demand. “This demand for tobacco formed the economic basis for the establishment of the first colonies in Virginia and Maryland,” according to drug researcher Ronald Siegel. Furthermore, writes Siegel, in his book “Intoxication”:

"The colonists continued to resist controls on tobacco. The tobacco industry became as American as Yankee Doodle and the Spirit of Independence…. British armies, trampling across the South, went out of their way to destroy large inventories of cured tobacco leaf, including those stored on Thomas Jefferson’s plantation. But tobacco survived to pay for the war and sustain morale."

In many ways, tobacco was the perfect American drug, distinctly suited to the robust American lifestyle of the 18th and 19th Centuries. Tobacco did not lead to debilitating visions or rapturous hallucinations—no nodding out, no sitting around wrestling with the angels. Unlike alcohol, it did not render them stuporous or generally unfit for labor. Tobacco acted, most of the time, as a mild stimulant. People could work and smoke at the same time. It picked people up; it lent itself well to the hard work of the day and the relaxation of the evening. It did not act like a psychoactive drug at all.

As with plant drugs in other times and cultures, women generally weren’t allowed to use it. Smoking tobacco was a man’s habit, a robust form of relaxation deemed inappropriate for the weaker sex. (Women in history did take snuff, and cocaine, and laudanum, and alcohol, but mostly they learned to be discreet about it, or to pass it off as doctor-prescribed medication for a host of vague ailments, which, in most cases, it was.)

Excerpted from The Chemical Carousel: What Science Tells Us About Beating Addiction © Dirk Hanson 2008, 2009.
By Dirk Hanson

Vaccinating Against Vices

Developing a pill or a vaccine for a specific drug addiction has long been one of the tantalizing potential rewards of addiction research. Now a company in Florida has garnered national attention, a spate of clinical trails, and a positive response from the National Institute on Drug Abuse (NIDA) with a compound called NicVAX, aimed at nicotine addiction. In addition, Celtic Pharma in Bermuda is working on a similar product for cocaine addiction.

The idea of vaccinating for addictions is not new. If you want the body to recognize a heroin molecule as a foe rather than a friend, one strategy is to attach heroin molecules to a foreign body--commonly a protein which the body ordinarily rejects--in order to switch on the body’s immune responses against the invader. The idea of a vaccine for cocaine, for example, is that the body’s immune system will crank out antibodies to the cocaine vaccination, preventing the user from getting high. A strong advantage to this approach, say NIDA researchers, is that the vaccinated compound does not enter the brain and therefore is free of neurological side effects.

Preliminary research at the University of Minnesota showed that a dose of vaccine plus booster shots markedly reduce the amount of nicotine that reaches the brain. Animal studies have shown the same effect. NicVAX, from Nabi Biopharmaceuticals, consists of nicotine molecules attached to a protein found in a species of infectious bacteria. When smokers light up, antibodies attack the protein-laden nicotine molecules, which, further encumbered by these antibodies, can no longer fit through the blood-brain barrier and allow the user to enjoy his smoke.

That, at least, is the idea. It is a difficult and expensive proposition, the closest thing to a miracle drug for addiction, but it does not specifically attack drug craving in addicted users. The idea of vaccination is that, once a drug user cannot get high on his or her drug of choice, the user will lose interest in the drug.

This assertion is somewhat speculative, in that users of the classic negative reinforcer, Antabuse, have found ways to circumvent its effects--primarily by not taking it. There remain a wealth of questions related to the effects of long-lasting antibodies. And it is sometimes possible to “swamp” the vaccine by ingesting four or five times as much cocaine or nicotine as usual.

Drugs that substantially reduce the addict’s craving may yet prove to be a more fruitful avenue of investigation. While several anti-craving medications have been approved for use by the Food and Drug Administraton (FDA), no vaccines have made it onto the approved least yet.

For more on pharmaceutical approaches to fighting drug addiction, see my website at http://www.dirkhanson.org

Brain Injury Stops Smokers Cold

In a research development that the director of the National Institute on Drug Abuse (NIDA) calls nothing short of “ming-boggling,” stroke victims lost all desire for cigarettes after suffering damage to a tiny structure in the forebrain. The stroke victims who smoked were seemingly freed from nicotine addiction by damage to the insula, a part of the brain that has not previously been a primary target of addiction research.

Along with the nucleus accumbens, the amygdala, and other structures in the limbic system, certain regions of the cerebral cortex are also implicated in active addiction. Now, said NIDA’s Dr. Nora Volkow, “Everybody’s going to be looking at the insula.”

Researchers at the University of Iowa and the University of Southern California collaborated on the brain injury study, published in the January 26 issue of Science. Neuroscientist Antoine Bechara of USC had learned of a stroke patient known only as N.

A heavy smoker from the age of 14, N. quit cold after a stroke at age 28, telling doctors: “My body forgot the urge to smoke.” A striking percentage of smokers with similar damage to the insula had apparently quit smoking after the injury just as effortlessly as had Patient N.

The role of the insula in brain activity is not well understood, but neurologists believe that the structure may help integrate subcortical inputs into coherent emotions and conscious urges.

No one is suggesting brain surgery for nicotine addiction, but researchers hope to discover ways of interfering with the operation of the insula, perhaps by means of a targeted drug. However, it is not yet clear what other functions the insula may perform, and whether the damage that seemingly eliminates the cigarette urge might also eliminate more positive urges and emotions as well.

Sources:

--Naqvi. N.H., et. al. “Damage to the insula disrupts addiction to cigarette smoking.” Science 315 531-534. Jan 26, 2007.

--Brownlee, Christen. “Addiction Subtraction: Brain damage curbs cigarette urge.” Science News 171 51. Jan 27, 2007.

--Carey, Benedict. “In Clue to Addiction, Brain Injury Halts Smoking.” New York Times. January 26, 2007.

Snail Toxin and Nicotine

This post courtesy of Biology-blog.com

http://www.biology-blog.com/

A New Tool Against Brain Disease

University of Utah scientists isolated an unusual nerve toxin in an ocean-dwelling snail, and say its ability to glom onto the brain's nicotine receptors may be useful for designing new drugs to treat a variety of psychiatric and brain diseases.

"We discovered a new toxin from a venomous cone snail that may enable researchers to more effectively develop medications for a wide range of nervous system disorders including Parkinson's disease, Alzheimer's disease, depression, nicotine addiction and perhaps even schizophrenia," says J. Michael McIntosh.

McIntosh is the same University of Utah researcher who as an incoming freshman student in 1979 discovered another "conotoxin" that was developed into Prialt, a drug injected into fluid surrounding the spinal cord to treat severe pain due to cancer, AIDS, injury, failed back surgery and certain nervous system disorders. Prialt was approved in late 2004 in the United States and was introduced in Europe last month.

Prialt, sold by Ireland's Elan Pharmaceuticals, took roughly 25 years to reach market after its discovery in venom from the fish-eating cone snail Conus magus or magician's cone. McIntosh says he expects it will take 10 to 20 years to develop new medications based on what is learned from the new toxin named alpha conotoxin OmIA (oh-em-one-ay) isolated from a cone snail species named Conus omaria, which lives in the Pacific and Indian oceans and eats other snails. It ranges from 1 to 3 inches long....

Diseases that Might Benefit from the New Snail Toxin

McIntosh says the OmIA toxin will be useful in designing new medicines because it fits like a key into certain lock-like "nicotinic acetylcholine receptors" found on nerve cells in the brain and the rest of the nervous system.

"Those are the same types of receptors you activate if you smoke a cigarette," he says, explaining that nicotine in cigarette smoke "binds" to the receptor to trigger the release of a neurotransmitter, which is a chemical that carries a nerve impulse from one nerve cell to another, allowing nerve cells to communicate....

A medicine that could block certain nicotinic receptors could be used to help people stop smoking cigarettes, and the same method might work for alcoholism because nicotinic receptors may be involved in alcohol addiction, McIntosh says.

Other nicotinic receptors trigger the release of neurotransmitters involved in memory, so activating the right receptors might lessen Alzheimer's memory loss.

"One reason people smoke is they feel their thinking may be a little better, with increased attention and focus," McIntosh says, noting that pharmaceutical companies "would like to mimic that positive benefit without all the downsides of cigarette smoke".

Other nicotinic receptors influence "the release of serotonin and norepinephrine, two neurotransmitters strongly implicated in mood disorders" such as depression, so a drug to activate those receptors might treat depression, he adds.

Schizophrenics tend to smoke heavily because something in cigarette smoke "seems to help them filter out irrelevant stimuli. They can focus better," McIntosh says. So a drug aimed at certain nicotinic receptors might treat schizophrenia.

New Neurotoxin is a Key for Designing New Medicines

McIntosh says the new toxin itself is unlikely to become a drug because it blocks rather than stimulates nicotinic receptors. But because it can act on some types of nicotinic receptors and not others like a key that opens some locks but not others it has great potential as a tool for precisely identifying the shape and structure of the receptor "locks," thus making it easier to design new medicines or "keys" to fit those receptors and trigger them to release desired neurotransmitters....


Posted by: Kelly Source: http://www.unews.utah.edu/

Smokers Drink More

It’s no secret that smoking and drinking go together like salt and pepper. No comes further evidence that smoking helps drinkers hold more liquor. Put simply, “Cigarette smoking appears to promote the consumption of alcohol,” says Wei-Jeun Chen of the Texas A&M Health Science Center.

Nicotine seems to slow the movement of alcohol through the intestines, leaving more alcohol molecules backed up and metabolised before reaching the bloodstream by means of intestinal absorption. In animal studies, in which rats were given stomache injections of alcohol and nicotine, clinicians found that “smoking” rats exhibited lower blood-alcohol levels than rats given the same amount of alcohol without the addiction of nicotine.

Dr. David Ball of the Institute of Psychiatry in London, told BBC news: This is a really interesting study. I’m surprised nobody has done it before.”

Chen, an associate professor of neuroscience and experimental therapeutics at Texas A&M College of Medicine, stressed that the results of such “cross tolerance” between alcohol and nicotine could be to “encourage drinkers to drink more to achieve the pleasurable or expected effect.”*

Susan Maier, a spokesperson for the National Institutes of Health (NIH), which sponsored the research, pointed to the potential for harm among young binge drinkers who choose to smoke, and who could “develop chronic alcohol-related diseases earlier in life because of it.”

Conceivably, other drugs might interact with alcohol in a similar fashion. Scientists are beginning to take a look at popular gastric upset products like Pepcid and Tagamet. “Individuals who abuse alcohol are likely to use other drugs,” Chen said. “The potential interactive effects of alcohol and other drugs needs to be considered. For example, the co-use of alcohol and cocaine will result in the formation of cocaethylene, which is highly toxic and has led to a higher mortality rate in animal studies.”

*Coffee and cigarettes go very naturally together as well. This is probably true for as many different reasons as there are coffee drinkers and cigarette smokers, but as we previously noted in the case of alcohol and tobacco, there is a metabolic synergism at work. The two drugs really do seem to have been made for each other. Rats on caffeine will self-administer nicotine faster and more steadily than decaffeinated control rats. This is because nicotine causes caffeine to clear the body at twice the normal rate, thereby allowing coffee or tea drinkers to imbibe larger amounts than usual, whether consciously aware of it or not. In turn, caffeine has an equivalent reinforcing effect on nicotine. The more you smoke, the more coffee you can drink, and vice versa. At the chemical level, smokers may be drinking caffeine in order to more finely balance the mood-altering effects of nicotine. A moment’s reflection brings us to the coffee house, an ancient establishment wherein tobacco and coffee are combined to maximum effect. Coffee and cigarettes, to be sure, are the least psychoactive of the psychoactive drugs—more proof that the sheer intensity of the drug high is not the primary determinant of addiction.

--excerpted from The Chemical Carousel: What Science Tells Us About Beating Addiction © Dirk Hanson 2008, 2009.

Sources:

--Scott E Parnell, James R West, Wei-Jung A Chen. “Nicotine Decreases Blood Alcohol Concentrations in Adult Rats: A Phenomenon Potentially Related to Gastric Function” Alcoholism: Clinical and Experimental Research 30 (8), 2006 1408–1413.

--”Smoking ‘reduces alcohol effect.’” BBC News, July 24, 2006. http://news.bbc.co.uk/go/pr/fr/-/2/hi/5209990.stm.