Nicotine Molecule

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Nicotine

Nicotine is an alkaloid found in the nightshade family of plants (Solanaceae), predominantly in tobacco and coca, and in lower quantities in tomato, potato, eggplant (aubergine), and green pepper. Nicotine has been found to constitute approximately 0.6-3% of dry weight of tobacco,[1] with biosynthesis taking place in the roots, and accumulating in the leaves. It functions as an antiherbivore chemical, being a potent neurotoxin with particular specificity to insects; therefore nicotine was widely used as an insecticide in the past, and currently nicotine derivatives such as imidacloprid continue to be widely used.

In low concentrations (an average cigarette yields about 1 mg of absorbed nicotine), the substance acts as a stimulant in mammals and is one of the main factors responsible for the dependence-forming properties of tobacco smoking. According to the American Heart Association, "Nicotine addiction has historically been one of the hardest addictions to break." The pharmacological and behavioral characteristics that determine tobacco addiction are similar to those that determine addiction to drugs such as heroin and cocaine.[2] 

History and name

Nicotine is named after the tobacco plant Nicotiana tabacum, which in turn is named after Jean Nicot, French ambassador in Portugal, who sent tobacco and seeds from Brazil to Paris in 1560 and promoted their medicinal use. Nicotine was first isolated from the tobacco plant in 1828 by German chemists Posselt & Reimann. Its chemical empirical formula was described by Melsens in 1843, and it was first synthesized by A. Pictet and Crepieux in 1893. 

Chemistry

Nicotine is a hygroscopic, oily liquid that is miscible with water in its base form. As a nitrogenous base, nicotine forms salts with acids that are usually solid and water soluble. Nicotine easily penetrates the skin. As shown by the physical data, free base nicotine will burn at a temperature below its boiling point, and its vapors will combust at 95 °F in air despite a low vapor pressure. Because of this, most of the nicotine is burned when a cigarette is smoked; however, enough is inhaled to provide the desired effects 

Pharmacology 

As nicotine enters the body, it is distributed quickly through the bloodstream and can cross the blood-brain barrier. On average it takes about seven seconds for the substance to reach the brain when inhaled. The half life of nicotine in the body is around two hours[3]. The amount of nicotine inhaled with tobacco smoke is a fraction of the amount contained in the tobacco leaves. The amount of nicotine absorbed by the body from smoking depends on many factors, including the type of tobacco, whether the smoke is inhaled, and whether a filter is used. For chewing tobacco, dipping tobacco and snuff, which are held in the mouth between the lip and gum, or taken in the nose, the amount released into the body tends to be much greater than smoked tobacco. Nicotine is metabolized in the liver by cytochrome P450 enzymes (mostly CYP2A6, and also by CYP2B6). A major metabolite is cotinine. 

In CNS 

By binding to CNS type nicotinic receptors, the nicotine molecule increases dopamine levels in the reward circuits of the brain. In this way, it activates the reward system and generates feelings of pleasure, similar to that caused by cocaine and other stimulants. Studies have shown that smoking tobacco inhibits monoamine oxidase (MAO)[5], an enzyme responsible for breaking down monoaminergic neurotransmitters such as dopamine, in the brain. It is currently believed that nicotine by itself does not inhibit the production of monoamine oxidase (MAO), but that other ingredients in inhaled tobacco smoke are believed to be responsible for this activity. Furthermore, it activates the sympathetic nervous system[citation needed], acting via splanchnic nerves to the adrenal medulla, stimulates the release of epinephrine. Acetylcholine released by preganglionic sympathetic fibers of these nerves acts on nicotinic acetylcholine receptors, causing the release of epinephrine (and norepinephrine) into the bloodstream. 

Psychoactive effects Nicotine's mood-altering effects are different by report. First causing a release of glucose from the liver and epinephrine (adrenaline) from the adrenal medulla, it causes stimulation. Users report feelings of relaxation, calmness, and alertness. It is even reported to produce a mildly euphoric state. By reducing the appetite and raising the metabolism, some smokers may lose weight as a consequence. It also allows the mouth to be stimulated without food, and the taste of tobacco smoke may curb the appetite.[citation needed]

When a cigarette is smoked, nicotine-rich blood passes from the lungs to the brain within seven seconds and immediately stimulates the release of many chemical messengers including acetylcholine, norepinephrine, epinephrine, vasopressin, arginine, dopamine, and beta-endorphin. This results in enhanced pleasure, decreased anxiety, and a state of alert relaxation. Nicotine enhances concentration and learning due to the increase of acetylcholine. It also enhances alertness due to the increases of acetylcholine and norepinephrine. Arousal is increased by the increase of norepinephrine. Pain is reduced by the increases of acetylcholine and beta-endorphin. Anxiety is reduced by the increase of beta-endorphin. The effects of nicotine last from five minutes to two hours. Most cigarettes (in the smoke inhaled) contain 0.1 to 2.8 milligrams of nicotine.[citation needed]

Research[6] suggests that, when smokers wish to achieve a stimulating effect, they take short quick puffs, which produce a low level of blood nicotine. This stimulates nerve transmission. When they wish to relax, they take deep puffs, which produce a high level of blood nicotine, which depresses the passage of nerve impulses, producing a mild sedative effect. At low doses, Nicotine potently enhances the actions of norepinephrine and dopamine in the brain, causing a drug effect typical of those of psychostimulants. At higher doses, nicotine enhances the effect of serotonin and opiate activity, producing a calming, pain-killing effect. Nicotine is unique in comparison to most drugs, as its profile changes from stimulant to sedative/pain killer in increasing dosages and use. 

Nicotine gum and patches are available, usually in 2-mg or 4-mg doses of gum, that do not have all the other ingredients in smoked tobacco. They appear to be not as addictive or as pleasurable, and, it is claimed, have fewer side-effects[citation needed]. Whether all the other psychoactive effects also occur has not been well-studied

Dependence 

Modern research shows that nicotine acts on the brain to produce a number of effects. Specifically, its addictive nature has been found to show that nicotine activates reward pathways—the circuitry within the brain that regulates feelings of pleasure and euphoria. [7] Dopamine is one of the key neurotransmitters actively involved in the brain. Research shows that by increasing the levels of dopamine within the reward circuits in the brain, nicotine acts as a chemical with intense addictive qualities. In many studies it has been shown to be more addictive than cocaine and heroin, though chronic treatment has an opposite effect on reward thresholds. Like other physically addictive drugs, nicotine causes down-regulation of the production of dopamine and other stimulatory neurotransmitters as the brain attempts to compensate for artificial stimulation. In addition, the sensitivity of nicotinic acetylcholine receptors decreases. To compensate for this compensatory mechanism, the brain in turn upregulates the number of receptors, convoluting its regulatory effects with compensatory mechanisms meant to counteract other compensatory mechanisms. The net effect is an increase in reward pathway sensitivity, opposite of other drugs of abuse (namely cocaine and heroin, which reduce reward pathway sensitivity)[citation needed]. This neuronal brain alteration persists for months after administration ceases. Due to an increase in reward pathway sensitivity, nicotine withdrawal is relatively mild compared to ethanol or heroin withdrawal.[citation needed] Nicotine also has the potential to cause dependence in many animals other than humans. Mice have been administered nicotine and exhibit withdrawal reactions when its administration is stopped. Gorillas have been forced to smoke cigarettes by humans, and have similar difficulty quitting.[8] A study found that nicotine exposure in adolescent mice retards the growth of the dopamine system, thus increasing the risk of substance abuse during adulthood.[9] There is significant anecdotal evidence from pharmacist vendors, via their customers, about addiction to nicotine gum or nicotine patches. 

Toxicology 

The LD50 of nicotine is 50 mg/kg for rats and 3 mg/kg for mice. 40–60 mg (0.5-1.0 mg/kg) can be a lethal dosage for adult humans.[10] [11] This makes it an extremely deadly poison. It is more toxic than many other alkaloids such as cocaine, which has an LD50 of 95.1 mg/kg when administered to mice. 

Toxicology 

The LD50 of nicotine is 50 mg/kg for rats and 3 mg/kg for mice. 40–60 mg (0.5-1.0 mg/kg) can be a lethal dosage for adult humans.[10] [11] This makes it an extremely deadly poison. It is more toxic than many other alkaloids such as cocaine, which has an LD50 of 95.1 mg/kg when administered to mice.

The carcinogenic properties of nicotine in standalone form, separate from tobacco smoke, have not been evaluated by the IARC, and it has not been assigned to an official carcinogen group. The currently available literature indicates that nicotine, on its own, does not promote the development of cancer in healthy tissue and has no mutagenic properties. Its teratogenic properties have not yet been adequately researched, and while the likelihood of birth defects caused by nicotine is believed to be very small or nonexistent, nicotine replacement product manufacturers recommend consultation with a physician before using a nicotine patch or nicotine gum while pregnant or nursing. However, nicotine and the increased cholinergic activity it causes have been shown to impede apoptosis[citation needed], which is one of the methods by which the body destroys unwanted cells (programmed cell death). Since apoptosis helps to remove mutated or damaged cells that may eventually become cancerous, the inhibitory actions of nicotine create a more favourable environment for cancer to develop. Thus nicotine plays an indirect role in carcinogenesis. It is also important to note that its addictive properties are often the primary motivating factor for tobacco smoking, contributing to the proliferation of cancer. At least one study has concluded that exposure to nicotine alone, not simply as a component of cigarette smoke, could be responsible for some of the neuropathological changes observed in infants dying from Sudden Infant Death Syndrome (SIDS).[12] It has been noted that the majority of people diagnosed with schizophrenia smoke tobacco. Estimates for the number of schizophrenics that smoke range from 75% to 90%. It was recently argued that the increased level of smoking in schizophrenia may be due to a desire to self-medicate with nicotine. [13] [14] More recent research has found the reverse, that it is a risk factor without long-term benefit, used only for its short term effects.[15] However, research on nicotine as administered through a patch or gum is ongoing.