How Nicotine Tricks The Brain -- The Pleasure - And Pull - Come From Its Ability To Mimic A Chemical We Can`T Live Without

Chemistry. Nicotine is one of the world's most unusual psychoactive drugs. By a coincidence of nature, our bodies cannot distinguish it from a key neural transmitter. And that's the starting point for the drug's addictive effects.

Sometime in the course of evolution, a combination of 26 atoms was given the power to unlock a few of life's deepest chemical secrets.

Secrets of pleasure. Secrets of death.

Ten of the atoms were carbons, 14 were hydrogens, two nitrogens. Arranged in a particular pattern, they triggered powerful physical and psychological reactions in species as diverse as cockroaches and humans.

The combination of atoms is called nicotine.

It is one of the most unusual psychoactive drugs known.

Put it on the tip of an arrow, as the ancient hunters did, and you can bring down an animal. Swallow a cigarette and the nicotine, which makes up 2 to 3 percent of the cigarette, is likely to start you vomiting. Drop a few cigarettes into a glass of water overnight and you'll have liquid pesticide by morning.

Humans ingest billions of doses of nicotine every year, through cigarettes, cigars, pipes, tobacco juice and snuff. Nicotine and tobacco-related disease, medical experts say, claim some 3 million lives a year worldwide - 425,000 of them American lives.

The tobacco industry is locked in debate with the government about whether nicotine is an addictive drug - an admission that could open the industry to stringent regulation. Against that backdrop, the findings of research in nicotine takes on increased importance.

For scientists, the answer to the question of the addictiveness of nicotine is already in.

"It works like a drug, it looks like a drug, it is a drug - pure and simple," said Jack Henningfield, a top government pharmacologist. "From a scientific perspective, nicotine is a drug and cigarettes are a drug-delivery system."

Primarily, it's a poison

Nicotine products have been abused for centuries, as part of tribal rituals and mysticism, as an accompaniment to after-dinner conversation and more recently as a prop for a rugged cowboy, an advertising symbol for independence.

Along the way, smoking has adapted to social and regulatory pressures: Tobacco juice gradually went out of fashion toward the end of the 19th century because spitting came to be frowned upon.

"Convenience has always influenced whatever tobacco product has been used," said Lynn Kozlowski, a psychology professor at Penn State University, in State College, Pa., who has studied the history of tobacco use.

A pipe, he said, quoting another scientist, was a tobacco product for a sedentary society. A cigar was a tobacco product for an ambulatory society. Cigarettes were a perfect product for an impatient society.

"You can squeeze a cigarette into a 10-minute time frame," Kozlowski said. "A real cigar could be lit for close to an hour."

The curious thing is that nicotine is primarily a poison.

Most of the human diseases associated with smoking, however, are not directly caused by nicotine. They are side-effects of the drug, and are mostly caused by the tar that smokers inhale along with the drug.

"Nature gave us the tobacco plant, which when burned is highly toxic," Henningfield said. "A cigarette is a little blast furnace. Any product that burns tobacco is almost impossible to have at an acceptably safe level."

What it does - and how it does it

The drug is immediately toxic only in large doses: The average cigarette contains about 10 milligrams of the drug. Only a tenth of that gets inside the smoker. It takes about 40 to 60 milligrams for nicotine poisoning to occur.

(Two young Chinese men recently proved how toxic nicotine is. They took a bet on who could smoke more cigarettes at one sitting, with the loser paying for all the cigarettes. One of them quit at 40, the other went up to 100. He then collapsed and was taken to the hospital, where he was pronounced dead.)

In the early 17th century, nicotine was tried as a medicine, and modern science is wondering whether it may have beneficial effects for people suffering from Alzheimer's and Parkinson's disease, diseases caused by a destruction of certain brain cells.

"When the brains of smokers are examined post mortem, what you find are an increased number of receptors," said Edythe London, chief of the brain-imaging section at the National Institute of Drug Abuse. The more receptors, the more protection against these diseases.

Of course, she added, an ideal medicine would not carry nicotine's dangers. The long-term use of nicotine, for example, has been implicated in heart disease.

Nicotine triggers its pleasurable effects on the brain by binding to certain receptors in the body. Receptors are the locks of the nervous system. A chemical like nicotine acts like a key.

In nonsmokers, the receptor locks are opened by a natural key, a chemical called acetylcholine. This chemical transmits messages for many body functions. It triggers sexual arousal, problem solving and thinking; it tells blood vessels to constrict or dilate; it relaxes some muscles and squeezes others; it carries messages from the spinal cord to various parts of the body.

The nicotine key, by an accident of nature, has the same ridges and shape as the acetylcholine key and it fools the receptor lock into springing open.

At high doses, however, nicotine overloads the receptors. Many crucial processes, including breathing, can halt.

"At low rates, nicotine causes arousal, stimulation, increased heart rate and blood pressure," said Neal Benowitz, the top pharmacologist at the University of California in San Francisco. "At high concentrations, you block the autonomic nervous system."

"Nicotine paralyzes your diaphragm and you can't breathe," he said. "It blocks the activation of the muscles."

This is exactly what happened when ancient hunters shot an animal with a nicotine-poisoned arrow.

Calming effect may be illusory

While nicotine is basically a stimulant - smokers tend to reach for their first cigarette as they roll out of bed - it can also appear to be a relaxant. The effect, say scientists, may be illusory.

"If smokers go an hour or so without smoking, their nicotine levels start falling," said Henningfield, who works at the National Institute of Drug Abuse. "When the person smokes, the nicotine level goes back up and the patient goes `ahhhh.'

"The effect on the person is relaxation, stress relief," he said. "One of the misconceptions is that nicotine relieves stress. It could be the reverse."

Nicotine addiction is a complex process. Most first-time smokers, or people who inhale secondhand smoke, find the effect of nicotine distasteful. But smokers' brains get used to a certain level of the drug. When nicotine levels fall, the smoker craves a cigarette to bring it back up.

Keeping the smoker off nicotine leaves the brain off balance and affects the smoker's physical and mental well-being.

The lure of the roller coaster

Can addiction be "cured?" Actually, quite easily. The problem is, preventing the nervous system from responding to nicotine would also block the normal functioning of the nervous system. It would be like curing a cold with a cyanide capsule.

Drugs like nicotine "operate through neuronal systems that are necessary for your survival," said Steven Goldberg, another scientist at the National Institute of Drug Abuse's Addiction Research Center in Baltimore.

"So far, the major medication for nicotine has been nicotine," he said.

Nicotine patches supply a steady stream of the drug into smokers trying to quit, which ends the craving for the drug. They are a lot safer than cigarettes, because the user is not getting tobacco tar into his or her body.

The challenge facing scientists is that a steady stream of nicotine isn't as pleasurable as the spikes of inhaling the drug. The rises and falls of the nicotine roller coaster are what have kept smokers hooked for centuries.

"If a roller coaster went slowly up and down," Goldberg asked, "would people go on it?"