Nicotine

Nicotine

Overview
Nicotine is an alkaloid
Alkaloid
Alkaloids are a group of naturally occurring chemical compounds that contain mostly basic nitrogen atoms. This group also includes some related compounds with neutral and even weakly acidic properties. Also some synthetic compounds of similar structure are attributed to alkaloids...

 found in the nightshade family of plants (Solanaceae
Solanaceae
Solanaceae are a family of flowering plants that include a number of important agricultural crops as well as many toxic plants. The name of the family comes from the Latin Solanum "the nightshade plant", but the further etymology of that word is unclear...

) that constitutes approximately 0.6–3.0% of the dry weight of tobacco
Tobacco
Tobacco is an agricultural product processed from the leaves of plants in the genus Nicotiana. It can be consumed, used as a pesticide and, in the form of nicotine tartrate, used in some medicines...

, with biosynthesis
Biosynthesis
Biosynthesis is an enzyme-catalyzed process in cells of living organisms by which substrates are converted to more complex products. The biosynthesis process often consists of several enzymatic steps in which the product of one step is used as substrate in the following step...

 taking place in the roots and accumulation occurring in the leaves. It functions as an antiherbivore chemical
Plant defense against herbivory
Plant defense against herbivory or host-plant resistance describes a range of adaptations evolved by plants which improve their survival and reproduction by reducing the impact of herbivores. Plants use several strategies to defend against damage caused by herbivores...

 with particular specificity to insects; therefore nicotine was widely used as an insecticide
Insecticide
An insecticide is a pesticide used against insects. They include ovicides and larvicides used against the eggs and larvae of insects respectively. Insecticides are used in agriculture, medicine, industry and the household. The use of insecticides is believed to be one of the major factors behind...

 in the past, and currently nicotine analogs such as imidacloprid
Imidacloprid
Imidacloprid is a nicotine-based, systemic insecticide, which acts as a neurotoxin and belongs to a class of chemicals called the neonicotinoids. Although it is now off patent, the primary manufacturer of this chemical is Bayer CropScience,...

 continue to be widely used.

In low concentrations (an average cigarette
Cigarette
A cigarette is a small roll of finely cut tobacco leaves wrapped in a cylinder of thin paper for smoking. The cigarette is ignited at one end and allowed to smoulder; its smoke is inhaled from the other end, which is held in or to the mouth and in some cases a cigarette holder may be used as well...

 yields about 1 mg of absorbed nicotine), the substance acts as a stimulant
Stimulant
Stimulants are psychoactive drugs which induce temporary improvements in either mental or physical function or both. Examples of these kinds of effects may include enhanced alertness, wakefulness, and locomotion, among others...

 in mammal
Mammal
Mammals are members of a class of air-breathing vertebrate animals characterised by the possession of endothermy, hair, three middle ear bones, and mammary glands functional in mothers with young...

s and is the main factor responsible for the dependence-forming properties of tobacco smoking
Tobacco smoking
Tobacco smoking is the practice where tobacco is burned and the resulting smoke is inhaled. The practice may have begun as early as 5000–3000 BCE. Tobacco was introduced to Eurasia in the late 16th century where it followed common trade routes...

.
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Encyclopedia
Nicotine is an alkaloid
Alkaloid
Alkaloids are a group of naturally occurring chemical compounds that contain mostly basic nitrogen atoms. This group also includes some related compounds with neutral and even weakly acidic properties. Also some synthetic compounds of similar structure are attributed to alkaloids...

 found in the nightshade family of plants (Solanaceae
Solanaceae
Solanaceae are a family of flowering plants that include a number of important agricultural crops as well as many toxic plants. The name of the family comes from the Latin Solanum "the nightshade plant", but the further etymology of that word is unclear...

) that constitutes approximately 0.6–3.0% of the dry weight of tobacco
Tobacco
Tobacco is an agricultural product processed from the leaves of plants in the genus Nicotiana. It can be consumed, used as a pesticide and, in the form of nicotine tartrate, used in some medicines...

, with biosynthesis
Biosynthesis
Biosynthesis is an enzyme-catalyzed process in cells of living organisms by which substrates are converted to more complex products. The biosynthesis process often consists of several enzymatic steps in which the product of one step is used as substrate in the following step...

 taking place in the roots and accumulation occurring in the leaves. It functions as an antiherbivore chemical
Plant defense against herbivory
Plant defense against herbivory or host-plant resistance describes a range of adaptations evolved by plants which improve their survival and reproduction by reducing the impact of herbivores. Plants use several strategies to defend against damage caused by herbivores...

 with particular specificity to insects; therefore nicotine was widely used as an insecticide
Insecticide
An insecticide is a pesticide used against insects. They include ovicides and larvicides used against the eggs and larvae of insects respectively. Insecticides are used in agriculture, medicine, industry and the household. The use of insecticides is believed to be one of the major factors behind...

 in the past, and currently nicotine analogs such as imidacloprid
Imidacloprid
Imidacloprid is a nicotine-based, systemic insecticide, which acts as a neurotoxin and belongs to a class of chemicals called the neonicotinoids. Although it is now off patent, the primary manufacturer of this chemical is Bayer CropScience,...

 continue to be widely used.

In low concentrations (an average cigarette
Cigarette
A cigarette is a small roll of finely cut tobacco leaves wrapped in a cylinder of thin paper for smoking. The cigarette is ignited at one end and allowed to smoulder; its smoke is inhaled from the other end, which is held in or to the mouth and in some cases a cigarette holder may be used as well...

 yields about 1 mg of absorbed nicotine), the substance acts as a stimulant
Stimulant
Stimulants are psychoactive drugs which induce temporary improvements in either mental or physical function or both. Examples of these kinds of effects may include enhanced alertness, wakefulness, and locomotion, among others...

 in mammal
Mammal
Mammals are members of a class of air-breathing vertebrate animals characterised by the possession of endothermy, hair, three middle ear bones, and mammary glands functional in mothers with young...

s and is the main factor responsible for the dependence-forming properties of tobacco smoking
Tobacco smoking
Tobacco smoking is the practice where tobacco is burned and the resulting smoke is inhaled. The practice may have begun as early as 5000–3000 BCE. Tobacco was introduced to Eurasia in the late 16th century where it followed common trade routes...

. According to the American Heart Association
American Heart Association
The American Heart Association is a non-profit organization in the United States that fosters appropriate cardiac care in an effort to reduce disability and deaths caused by cardiovascular disease and stroke. It is headquartered in Dallas, Texas...

, nicotine addiction
Substance use disorder
Substance use disorders include substance abuse and substance dependence. In DSM-IV, the conditions are formally diagnosed as one or the other, but it has been proposed that DSM-5 combine the two into a single condition called "Substance-use disorder"....

 has historically been one of the hardest addictions to break, while the pharmacological and behavioral characteristics that determine tobacco addiction are similar to those determining addiction to heroin and cocaine
Cocaine
Cocaine is a crystalline tropane alkaloid that is obtained from the leaves of the coca plant. The name comes from "coca" in addition to the alkaloid suffix -ine, forming cocaine. It is a stimulant of the central nervous system, an appetite suppressant, and a topical anesthetic...

. Nicotine content in cigarettes has slowly increased over the years, and one study found that there was an average increase of 1.6% per year between the years of 1998 and 2005. This was found for all major market categories of cigarettes.

Research in 2011 has found that nicotine inhibits chromatin-modifying enzymes (class I and II histone deacetylases) which increases the ability of cocaine
Cocaine
Cocaine is a crystalline tropane alkaloid that is obtained from the leaves of the coca plant. The name comes from "coca" in addition to the alkaloid suffix -ine, forming cocaine. It is a stimulant of the central nervous system, an appetite suppressant, and a topical anesthetic...

 to cause an addiction
Addiction
Historically, addiction has been defined as physical and psychological dependence on psychoactive substances which cross the blood-brain barrier once ingested, temporarily altering the chemical milieu of the brain.Addiction can also be viewed as a continued involvement with a substance or activity...

.

History and name


Nicotine is named after the tobacco plant Nicotiana tabacum
Nicotiana tabacum
Nicotiana tabacum, or cultivated tobacco, is a perennial herbaceous plant. It is found only in cultivation, where it is the most commonly grown of all plants in the Nicotiana genus, and its leaves are commercially grown in many countries to be processed into tobacco. It grows to heights between 1...

, which in turn is named after Jean Nicot de Villemain
Jean Nicot
Jean Nicot was a French diplomat and scholar.Born in Nîmes, in the south of France, he was French ambassador in Lisbon, Portugal from 1559 to 1561....

, French
France
The French Republic , The French Republic , The French Republic , (commonly known as France , is a unitary semi-presidential republic in Western Europe with several overseas territories and islands located on other continents and in the Indian, Pacific, and Atlantic oceans. Metropolitan France...

 ambassador in Portugal
Portugal
Portugal , officially the Portuguese Republic is a country situated in southwestern Europe on the Iberian Peninsula. Portugal is the westernmost country of Europe, and is bordered by the Atlantic Ocean to the West and South and by Spain to the North and East. The Atlantic archipelagos of the...

, who sent tobacco and seeds from Brazil
Brazil
Brazil , officially the Federative Republic of Brazil , is the largest country in South America. It is the world's fifth largest country, both by geographical area and by population with over 192 million people...

 to Paris
Paris
Paris is the capital and largest city in France, situated on the river Seine, in northern France, at the heart of the Île-de-France region...

 in 1560 and promoted their medicinal use. Nicotine was first isolated from the tobacco plant in 1828 by physician Wilhelm Heinrich Posselt and chemist Karl Ludwig Reimann of Germany
Germany
Germany , officially the Federal Republic of Germany , is a federal parliamentary republic in Europe. The country consists of 16 states while the capital and largest city is Berlin. Germany covers an area of 357,021 km2 and has a largely temperate seasonal climate...

, who considered it a poison. Its chemical empirical formula
Empirical formula
In chemistry, the empirical formula of a chemical compound is the simplest positive integer ratio of atoms of each element present in a compound. An empirical formula makes no reference to isomerism, structure, or absolute number of atoms. The empirical formula is used as standard for most ionic...

 was described by Melsens in 1843, its structure was
discovered by Adolf Pinner
Adolf Pinner
Adolf Pinner was a German chemist.He educated at the Jewish Theological Seminary at Breslau and at the University of Berlin . In 1871 he became privat-docent at the University of Berlin...

 and Richard Wolffenstein
Richard Wolffenstein (chemist)
Richard Wolffenstein was a German chemist.He discovered acetone peroxide in 1895 by reacting acetone with hydrogen peroxide....

 in 1893, and it was first synthesized by A. Pictet and Crepieux in 1904.

Chemistry


Nicotine is a hygroscopic
Hygroscopy
Hygroscopy is the ability of a substance to attract and hold water molecules from the surrounding environment. This is achieved through either absorption or adsorption with the absorbing or adsorbing material becoming physically 'changed,' somewhat, by an increase in volume, stickiness, or other...

, oily liquid that is miscible with water in its base
Base (chemistry)
For the term in genetics, see base A base in chemistry is a substance that can accept hydrogen ions or more generally, donate electron pairs. A soluble base is referred to as an alkali if it contains and releases hydroxide ions quantitatively...

 form. As a nitrogenous base
Nitrogenous base
A nitrogenous base is a nitrogen-containing molecule having the chemical properties of a base. It is an organic compound that owes its property as a base to the lone pair of electrons of a nitrogen atom. In biological sciences, nitrogenous bases are typically classified as the derivatives of two...

, nicotine forms salt
Salt
In chemistry, salts are ionic compounds that result from the neutralization reaction of an acid and a base. They are composed of cations and anions so that the product is electrically neutral...

s with acid
Acid
An acid is a substance which reacts with a base. Commonly, acids can be identified as tasting sour, reacting with metals such as calcium, and bases like sodium carbonate. Aqueous acids have a pH of less than 7, where an acid of lower pH is typically stronger, and turn blue litmus paper red...

s that are usually solid and water soluble. Nicotine easily penetrates the skin
Skin
-Dermis:The dermis is the layer of skin beneath the epidermis that consists of connective tissue and cushions the body from stress and strain. The dermis is tightly connected to the epidermis by a basement membrane. It also harbors many Mechanoreceptors that provide the sense of touch and heat...

. As shown by the physical data, free base
Freebase (chemistry)
Freebase or free base refers to the pure basic form of an amine, as opposed to its salt form. The amine is usually an alkaloid natural product. Free base is commonly used in organic chemistry and pharmaceuticals to describe the unprotonated amine form of a compound.Most alkaloids are unstable in...

 nicotine will burn at a temperature below its boiling point, and its vapors will combust at 308 K (34.9 °C; 94.7 °F) in air despite a low vapor pressure
Vapor pressure
Vapor pressure or equilibrium vapor pressure is the pressure of a vapor in thermodynamic equilibrium with its condensed phases in a closed system. All liquids have a tendency to evaporate, and some solids can sublimate into a gaseous form...

. Because of this, most of the nicotine is burned when a cigarette is smoked; however, enough is inhaled to cause pharmacological effects.

Optical activity


Nicotine is optically active, having two enantiomer
Enantiomer
In chemistry, an enantiomer is one of two stereoisomers that are mirror images of each other that are non-superposable , much as one's left and right hands are the same except for opposite orientation. It can be clearly understood if you try to place your hands one over the other without...

ic forms. The naturally occurring form of nicotine is levorotatory, with [α]D = –166.4°. The dextrorotatory form, (+)-nicotine, has only one-half the physiological activity of (–)-nicotine. The salts of (+)-nicotine are usually dextrorotatory.

Pharmacokinetics



As nicotine enters the body, it is distributed quickly through the blood
Blood
Blood is a specialized bodily fluid in animals that delivers necessary substances such as nutrients and oxygen to the cells and transports metabolic waste products away from those same cells....

stream and crosses the blood-brain barrier
Blood-brain barrier
The blood–brain barrier is a separation of circulating blood and the brain extracellular fluid in the central nervous system . It occurs along all capillaries and consists of tight junctions around the capillaries that do not exist in normal circulation. Endothelial cells restrict the diffusion...

 reaching the brain
Human brain
The human brain has the same general structure as the brains of other mammals, but is over three times larger than the brain of a typical mammal with an equivalent body size. Estimates for the number of neurons in the human brain range from 80 to 120 billion...

 within 10-20 seconds after inhalation. The elimination half-life of nicotine in the body is around two hours.

The amount of nicotine absorbed by the body from smoking depends on many factors, including the types of tobacco, whether the smoke is inhaled, and whether a filter is used. For chewing tobacco
Chewing tobacco
Chewing tobacco Chewing tobacco Chewing tobacco (also known colloquially as hoobastank, backy, tobac, doogooos,Hogleg, chewpoos, chits, chewsky, chawsky, dip, flab, chowers, guy, or a wad, as well as referred to as dipsky, snuff, a pinch, a yopper, a Packing a bomb, a tobbackey or packing a...

, dipping tobacco
Dipping tobacco
Dipping tobacco, traditionally referred to as moist snuff, is a type of finely ground or shredded, moistened smokeless tobacco product. It is commonly and idiomatically known by various terms – most often as dip and sometimes rub or chew...

, snus
Snus
Snus , or Swedish snuff, is a moist powder tobacco product originated from a variant of dry snuff in the early 19th century in Sweden, consumed by placing it under the lip for extended periods of time. The precursor of snus, the dry form of snuff inhaled through the nose, was introduced in Europe...

 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
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...

 by cytochrome P450 enzymes (mostly CYP2A6
CYP2A6
Cytochrome P450 2A6 is a member of the cytochrome P450 mixed-function oxidase system, which is involved in the metabolism of xenobiotics in the body. CYP2A6 is the primary enzyme responsible for the oxidation of nicotine and cotinine. It is also involved in the metabolism of several...

, and also by CYP2B6
CYP2B6
Cytochrome P450 2B6 is an enzyme that in humans is encoded by the CYP2B6 gene. CYP2B6 is a member of the Cytochrome P450 group of enzymes. Along with CYP2A6, it is involved with metabolizing nicotine, along with many other substances.- Function :...

). A major metabolite is cotinine
Cotinine
Cotinine is an alkaloid found in tobacco and is also a metabolite of nicotine. The word "cotinine" is an anagram of "nicotine". Cotinine is used as a biomarker for exposure to tobacco smoke and has also been sold as an antidepressant under the brand name Scotine.Similarly to nicotine, cotinine...

.

Other primary metabolites include nicotine N-oxide, nornicotine, nicotine isomethonium ion, 2-hydroxynicotine and nicotine glucuronide. Under some conditions, other substances may be formed such as myosmine
Myosmine
Myosmine is an alkaloid found in tobacco and other plants. Chemically, it is closely related to nicotine....

.

Glucuronidation
Glucuronidation
Glucuronidation is the addition of glucuronic acid to a substrate. Glucuronidation is often involved in xenobiotic metabolism of substances such as drugs, pollutants, bilirubin, androgens, estrogens, mineralocorticoids, glucocorticoids, fatty acid derivatives, retinoids, and bile acids...

 and oxidative metabolism of nicotine to cotinine are both inhibited by menthol
Menthol
Menthol is an organic compound made synthetically or obtained from peppermint or other mint oils. It is a waxy, crystalline substance, clear or white in color, which is solid at room temperature and melts slightly above. The main form of menthol occurring in nature is -menthol, which is assigned...

, an additive to mentholated cigarettes, thus increasing the half-life of nicotine in vivo.

Medical detection


Nicotine can be quantified in blood, plasma, or urine to confirm a diagnosis of poisoning or to facilitate a medicolegal death investigation. Urinary or salivary cotinine concentrations are frequently measured for the purposes of pre-employment and health insurance medical screening programs. Careful interpretation of results is important, since passive exposure to cigarette smoke can result in significant accumulation of nicotine, followed by the appearance of its metabolites in various body fluids. Nicotine use is not regulated in competitive sports programs, yet the drug has been shown to have a significant beneficial effect on athletic performance.

Pharmacodynamics


Nicotine acts on the nicotinic acetylcholine receptor
Nicotinic acetylcholine receptor
Nicotinic acetylcholine receptors, or nAChRs, are cholinergic receptors that form ligand-gated ion channels in the plasma membranes of certain neurons and on the postsynaptic side of the neuromuscular junction...

s, specifically the ganglion type nicotinic receptor
Ganglion type nicotinic receptor
The ganglion type nicotinic receptor is a type of nicotinic acetylcholine receptor, consisting of the subunit combination 23.It is located in the autonomic ganglia, where activation yields EPSP, mainly by increased Na+ and K+ permeability....

 and one CNS nicotinic receptor
Alpha-4 beta-2 nicotinic receptor
The alpha-4 beta-2 nicotinic receptor, also known as the α4β2 receptor, is a type of nicotinic acetylcholine receptor, consisting of α4 and β2 subunits...

. The former is present in the adrenal medulla
Adrenal medulla
The adrenal medulla is part of the adrenal gland. It is located at the center of the gland, being surrounded by the adrenal cortex. It is the innermost part of the adrenal gland, consisting of cells that secrete epinephrine , norepinephrine , and a small amount of dopamine in response to...

 and elsewhere, while the latter is present in the central nervous system
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...

 (CNS). In small concentrations, nicotine increases the activity of these receptors. Nicotine also has effects on a variety of other neurotransmitters through less direct mechanisms.

In the central nervous system



By binding to nicotinic acetylcholine receptor
Nicotinic acetylcholine receptor
Nicotinic acetylcholine receptors, or nAChRs, are cholinergic receptors that form ligand-gated ion channels in the plasma membranes of certain neurons and on the postsynaptic side of the neuromuscular junction...

s, nicotine increases the levels of several neurotransmitter
Neurotransmitter
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...

s - acting as a sort of "volume control". It is thought that increased levels of dopamine
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...

 in the reward circuits of the brain
Human brain
The human brain has the same general structure as the brains of other mammals, but is over three times larger than the brain of a typical mammal with an equivalent body size. Estimates for the number of neurons in the human brain range from 80 to 120 billion...

 are responsible for the euphoria
Euphoria (emotion)
Euphoria is medically recognized as a mental and emotional condition in which a person experiences intense feelings of well-being, elation, happiness, ecstasy, excitement and joy...

 and relaxation
Relaxation (psychology)
In psychology, relaxation is the emotional state of low tension, in which there is an absence of arousal that could come from sources such as anger, anxiety, or fear. Relaxation is a form of mild ecstasy coming from the frontal lobe of the brain in which the backward cortex sends signals, or...

 and eventual addiction caused by nicotine consumption. Nicotine has a higher affinity for acetylcholine
Acetylcholine
The chemical compound acetylcholine is a neurotransmitter in both the peripheral nervous system and central nervous system in many organisms including humans...

 receptors in the brain than those in skeletal muscle
Skeletal muscle
Skeletal muscle is a form of striated muscle tissue existing under control of the somatic nervous system- i.e. it is voluntarily controlled. It is one of three major muscle types, the others being cardiac and smooth muscle...

, though at toxic doses it can induce contractions and respiratory paralysis. Nicotine's selectivity is thought to be due to a particular amino acid difference on these receptor subtypes.

Tobacco smoke contains the monoamine oxidase inhibitor
Monoamine oxidase inhibitor
Monoamine oxidase inhibitors are a class of antidepressant drugs prescribed for the treatment of depression. They are particularly effective in treating atypical depression....

s harman
Harmala alkaloid
Several alkaloids that function as monoamine oxidase inhibitors are found in the seeds of Peganum harmala , including harmine, harmaline, and harmalol, which are members of a group of substances with a similar chemical structure collectively known as harmala alkaloids...

, norharman, anabasine
Anabasine
Anabasine is a pyridine alkaloid found in the Tree Tobacco plant, a close relative of the common tobacco plant . Chemically, it is similar to nicotine...

, anatabine
Anatabine
Anatabine is one of the minor alkaloids found in plants in the Solanaceae family, which includes the tobacco plant, that has been shown to affect monoamine oxidase activity...

, and nornicotine. These compounds significantly decrease MAO
Mao
, is a Japanese remake of the Korean suspense drama series titled Ma Wang which aired on KBS 2TV in 2007. The drama stars Satoshi Ohno of Arashi and Toma Ikuta, both under the talent agency Johnny & Associates.-Synopsis:...

 activity in smokers. MAO enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...

s break down monoaminergic neurotransmitters such as dopamine
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...

, norepinephrine
Norepinephrine
Norepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...

, and serotonin
Serotonin
Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...

. It is thought that the powerful interaction between the MAOI's and the nicotine is responsible for most of the addictive properties of tobacco smoking. The addition of five minor tobacco alkaloids increases nicotine-induced hyperactivity, sensitization and intravenous self-administration in rats.

Chronic nicotine exposure via tobacco smoking up-regulates alpha4beta2
Alpha-4 beta-2 nicotinic receptor
The alpha-4 beta-2 nicotinic receptor, also known as the α4β2 receptor, is a type of nicotinic acetylcholine receptor, consisting of α4 and β2 subunits...

* nAChR in cerebellum
Cerebellum
The cerebellum is a region of the brain that plays an important role in motor control. It may also be involved in some cognitive functions such as attention and language, and in regulating fear and pleasure responses, but its movement-related functions are the most solidly established...

 and brainstem regions but not habenulopeduncular
Habenula
In neuroanatomy, habenula originally denoted the stalk of the pineal gland , but gradually came to refer to a neighboring group of nerve cells with which the pineal gland was believed to be associated, the habenular nucleus...

 structures. Alpha4beta2 and alpha6beta2 receptors, present in the ventral tegmental area, play a crucial role in mediating the reinforcement effects of nicotine.

In the sympathetic nervous system


Nicotine also activates the sympathetic nervous system
Sympathetic nervous system
The sympathetic nervous system is one of the three parts of the autonomic nervous system, along with the enteric and parasympathetic systems. Its general action is to mobilize the body's nervous system fight-or-flight response...

, acting via splanchnic nerves
Splanchnic nerves
The splanchnic nerves are paired nerves that contribute to the innervation of the viscera, carrying fibers of the autonomic nervous system as well as sensory fibers from the organs...

 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. Nicotine also has an affinity for melanin
Melanin
Melanin is a pigment that is ubiquitous in nature, being found in most organisms . In animals melanin pigments are derivatives of the amino acid tyrosine. The most common form of biological melanin is eumelanin, a brown-black polymer of dihydroxyindole carboxylic acids, and their reduced forms...

-containing tissues due to its precursor function in melanin synthesis or due to the irreversible binding of melanin and nicotine. This has been suggested to underlie the increased nicotine dependence and lower smoking cessation
Smoking cessation
Smoking cessation is the process of discontinuing the practice of inhaling a smoked substance. This article focuses exclusively on cessation of tobacco smoking; however, the methods described may apply to cessation of smoking other substances that can be difficult to stop using due to the...

 rates in darker pigmented individuals.

In adrenal medulla


By binding to ganglion type nicotinic receptor
Ganglion type nicotinic receptor
The ganglion type nicotinic receptor is a type of nicotinic acetylcholine receptor, consisting of the subunit combination 23.It is located in the autonomic ganglia, where activation yields EPSP, mainly by increased Na+ and K+ permeability....

s in the adrenal medulla nicotine increases flow of adrenaline (epinephrine), a stimulating hormone
Hormone
A hormone is a chemical released by a cell or a gland in one part of the body that sends out messages that affect cells in other parts of the organism. Only a small amount of hormone is required to alter cell metabolism. In essence, it is a chemical messenger that transports a signal from one...

 and neurotransmitter. By binding to the receptors, it causes cell depolarization and an influx of calcium
Calcium
Calcium is the chemical element with the symbol Ca and atomic number 20. It has an atomic mass of 40.078 amu. Calcium is a soft gray alkaline earth metal, and is the fifth-most-abundant element by mass in the Earth's crust...

 through voltage-gated calcium channels. Calcium triggers the exocytosis
Exocytosis
Exocytosis , also known as 'The peni-cytosis', is the durable process by which a cell directs the contents of secretory vesicles out of the cell membrane...

 of chromaffin granules
Chromaffin cell
Chromaffin cells are neuroendocrine cells found in the medulla of the adrenal gland and in other ganglia of the sympathetic nervous system. They are modified post-synaptic sympathetic neurons that receive sympathetic input...

 and thus the release of epinephrine
Epinephrine
Epinephrine is a hormone and a neurotransmitter. It increases heart rate, constricts blood vessels, dilates air passages and participates in the fight-or-flight response of the sympathetic nervous system. In chemical terms, adrenaline is one of a group of monoamines called the catecholamines...

 (and norepinephrine) into the bloodstream. The release of epinephrine
Epinephrine
Epinephrine is a hormone and a neurotransmitter. It increases heart rate, constricts blood vessels, dilates air passages and participates in the fight-or-flight response of the sympathetic nervous system. In chemical terms, adrenaline is one of a group of monoamines called the catecholamines...

 (adrenaline) causes an increase in heart rate
Heart rate
Heart rate is the number of heartbeats per unit of time, typically expressed as beats per minute . Heart rate can vary as the body's need to absorb oxygen and excrete carbon dioxide changes, such as during exercise or sleep....

, blood pressure
Blood pressure
Blood pressure is the pressure exerted by circulating blood upon the walls of blood vessels, and is one of the principal vital signs. When used without further specification, "blood pressure" usually refers to the arterial pressure of the systemic circulation. During each heartbeat, BP varies...

 and respiration
Breathing
Breathing is the process that moves air in and out of the lungs. Aerobic organisms require oxygen to release energy via respiration, in the form of the metabolism of energy-rich molecules such as glucose. Breathing is only one process that delivers oxygen to where it is needed in the body and...

, as well as higher blood glucose levels.

Nicotine is the natural product of tobacco, having a half-life of 1 to 2 hours. Cotinine
Cotinine
Cotinine is an alkaloid found in tobacco and is also a metabolite of nicotine. The word "cotinine" is an anagram of "nicotine". Cotinine is used as a biomarker for exposure to tobacco smoke and has also been sold as an antidepressant under the brand name Scotine.Similarly to nicotine, cotinine...

 is an active metabolite of nicotine that remains in the blood for 18 to 20 hours, making it easier to analyze due to its longer half-life.

Psychoactive effects


Nicotine's mood
Mood (psychology)
A mood is a relatively long lasting emotional state. Moods differ from emotions in that they are less specific, less intense, and less likely to be triggered by a particular stimulus or event....

-altering effects are different by report: in particular it is both a stimulant and a relaxant. First causing a release of glucose
Glucose
Glucose is a simple sugar and an important carbohydrate in biology. Cells use it as the primary source of energy and a metabolic intermediate...

 from the liver and epinephrine
Epinephrine
Epinephrine is a hormone and a neurotransmitter. It increases heart rate, constricts blood vessels, dilates air passages and participates in the fight-or-flight response of the sympathetic nervous system. In chemical terms, adrenaline is one of a group of monoamines called the catecholamines...

 (adrenaline) from the adrenal medulla
Adrenal medulla
The adrenal medulla is part of the adrenal gland. It is located at the center of the gland, being surrounded by the adrenal cortex. It is the innermost part of the adrenal gland, consisting of cells that secrete epinephrine , norepinephrine , and a small amount of dopamine in response to...

, it causes stimulation
Stimulation
Stimulation is the action of various agents on nerves, muscles, or a sensory end organ, by which activity is evoked; especially, the nervous impulse produced by various agents on nerves, or a sensory end organ, by which the part connected with the nerve is thrown into a state of activity.The word...

. Users report feelings of relaxation
Relaxation (psychology)
In psychology, relaxation is the emotional state of low tension, in which there is an absence of arousal that could come from sources such as anger, anxiety, or fear. Relaxation is a form of mild ecstasy coming from the frontal lobe of the brain in which the backward cortex sends signals, or...

, sharpness, calmness
Calmness
Calmness is the mental state of being free from agitation, excitement, or disturbance. Calmness can most easily occur for the average person during a state of relaxation, but it can also be found during much more alert and aware states. Some people find that focusing the mind on something external,...

, and alertness
Alertness
Alertness is the state of paying close and continuous attention, being watchful and prompt to meet danger or emergency, or being quick to perceive and act. It is related to psychology as well as to physiology...

. Like any stimulant, it may very rarely cause the often catastrophically uncomfortable neuropsychiatric effect of akathisia
Akathisia
Akathisia, or acathisia, is a syndrome characterized by unpleasant sensations of inner restlessness that manifests itself with an inability to sit still or remain motionless...

. By reducing the appetite
Appetite
The appetite is the desire to eat food, felt as hunger. Appetite exists in all higher life-forms, and serves to regulate adequate energy intake to maintain metabolic needs. It is regulated by a close interplay between the digestive tract, adipose tissue and the brain. Decreased desire to eat is...

 and raising the metabolism
Metabolism
Metabolism is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories...

, some smokers may lose weight
Weight loss
Weight loss, in the context of medicine, health or physical fitness, is a reduction of the total body mass, due to a mean loss of fluid, body fat or adipose tissue and/or lean mass, namely bone mineral deposits, muscle, tendon and other connective tissue...

 as a consequence.

When a cigarette
Cigarette
A cigarette is a small roll of finely cut tobacco leaves wrapped in a cylinder of thin paper for smoking. The cigarette is ignited at one end and allowed to smoulder; its smoke is inhaled from the other end, which is held in or to the mouth and in some cases a cigarette holder may be used as well...

 is smoked, nicotine-rich blood passes from the lung
Human lung
The human lungs are the organs of respiration in humans. Humans have two lungs, with the left being divided into two lobes and the right into three lobes. Together, the lungs contain approximately of airways and 300 to 500 million alveoli, having a total surface area of about in...

s to the brain
Human brain
The human brain has the same general structure as the brains of other mammals, but is over three times larger than the brain of a typical mammal with an equivalent body size. Estimates for the number of neurons in the human brain range from 80 to 120 billion...

 within seven seconds and immediately stimulates the release of many chemical messengers including acetylcholine
Acetylcholine
The chemical compound acetylcholine is a neurotransmitter in both the peripheral nervous system and central nervous system in many organisms including humans...

, norepinephrine
Norepinephrine
Norepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...

, epinephrine
Epinephrine
Epinephrine is a hormone and a neurotransmitter. It increases heart rate, constricts blood vessels, dilates air passages and participates in the fight-or-flight response of the sympathetic nervous system. In chemical terms, adrenaline is one of a group of monoamines called the catecholamines...

, vasopressin
Vasopressin
Arginine vasopressin , also known as vasopressin, argipressin or antidiuretic hormone , is a neurohypophysial hormone found in most mammals, including humans. Vasopressin is a peptide hormone that controls the reabsorption of molecules in the tubules of the kidneys by affecting the tissue's...

, arginine
Arginine
Arginine is an α-amino acid. The L-form is one of the 20 most common natural amino acids. At the level of molecular genetics, in the structure of the messenger ribonucleic acid mRNA, CGU, CGC, CGA, CGG, AGA, and AGG, are the triplets of nucleotide bases or codons that codify for arginine during...

, dopamine
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...

, autocrine agents, and beta-endorphin
Beta-endorphin
β-endorphin is an endogenous opioid peptide neurotransmitter found in the neurons of both the central and peripheral nervous system.The amino acid sequence is:...

. This release of neurotransmitters and hormones is responsible for most of nicotine's effects. Nicotine appears to enhance concentration
Attention
Attention is the cognitive process of paying attention to one aspect of the environment while ignoring others. Attention is one of the most intensely studied topics within psychology and cognitive neuroscience....

 and memory due to the increase of acetylcholine
Acetylcholine
The chemical compound acetylcholine is a neurotransmitter in both the peripheral nervous system and central nervous system in many organisms including humans...

. It also appears to enhance alertness
Alertness
Alertness is the state of paying close and continuous attention, being watchful and prompt to meet danger or emergency, or being quick to perceive and act. It is related to psychology as well as to physiology...

 due to the increases of acetylcholine
Acetylcholine
The chemical compound acetylcholine is a neurotransmitter in both the peripheral nervous system and central nervous system in many organisms including humans...

 and norepinephrine
Norepinephrine
Norepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...

. Arousal
Arousal
Arousal is a physiological and psychological state of being awake or reactive to stimuli. It involves the activation of the reticular activating system in the brain stem, the autonomic nervous system and the endocrine system, leading to increased heart rate and blood pressure and a condition of...

 is increased by the increase of norepinephrine
Norepinephrine
Norepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...

. Pain
Pain
Pain is an unpleasant sensation often caused by intense or damaging stimuli such as stubbing a toe, burning a finger, putting iodine on a cut, and bumping the "funny bone."...

 is reduced by the increases of acetylcholine
Acetylcholine
The chemical compound acetylcholine is a neurotransmitter in both the peripheral nervous system and central nervous system in many organisms including humans...

 and beta-endorphin. Anxiety
Anxiety
Anxiety is a psychological and physiological state characterized by somatic, emotional, cognitive, and behavioral components. The root meaning of the word anxiety is 'to vex or trouble'; in either presence or absence of psychological stress, anxiety can create feelings of fear, worry, uneasiness,...

 is reduced by the increase of beta-endorphin
Beta-endorphin
β-endorphin is an endogenous opioid peptide neurotransmitter found in the neurons of both the central and peripheral nervous system.The amino acid sequence is:...

. Nicotine also extends the duration of positive effects of dopamine and increases sensitivity in brain reward systems. Most cigarettes (in the smoke inhaled) contain 1 to 3 milligrams of nicotine.

Research 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
Action potential
In physiology, an action potential is a short-lasting event in which the electrical membrane potential of a cell rapidly rises and falls, following a consistent trajectory. Action potentials occur in several types of animal cells, called excitable cells, which include neurons, muscle cells, and...

. 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
Norepinephrine
Norepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...

 and dopamine
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...

 in the brain, causing a drug effect typical of those of psychostimulants. At higher doses, nicotine enhances the effect of serotonin
Serotonin
Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...

 and opiate
Opiate
In medicine, the term opiate describes any of the narcotic opioid alkaloids found as natural products in the opium poppy plant.-Overview:Opiates are so named because they are constituents or derivatives of constituents found in opium, which is processed from the latex sap of the opium poppy,...

 activity, producing a calming, pain-killing
Analgesic
An analgesic is any member of the group of drugs used to relieve pain . The word analgesic derives from Greek an- and algos ....

 effect. Nicotine is unique in comparison to most drug
Drug
A drug, broadly speaking, is any substance that, when absorbed into the body of a living organism, alters normal bodily function. There is no single, precise definition, as there are different meanings in drug control law, government regulations, medicine, and colloquial usage.In pharmacology, a...

s, as its profile changes from stimulant
Stimulant
Stimulants are psychoactive drugs which induce temporary improvements in either mental or physical function or both. Examples of these kinds of effects may include enhanced alertness, wakefulness, and locomotion, among others...

 to sedative
Sedative
A sedative or tranquilizer is a substance that induces sedation by reducing irritability or excitement....

/pain killer in increasing dosage
Dose (biochemistry)
A dose is a quantity of something that may impact an organism biologically; the greater the quantity, the larger the dose. In nutrition, the term is usually applied to how much of a specific nutrient is in a person's diet or in a particular food, meal, or dietary supplement...

s and use.

Technically, nicotine is not significantly addictive, as nicotine administered alone does not produce significant reinforcing properties. However, after coadministration with an MAOI, such as those found in tobacco, nicotine produces significant behavioral sensitization, a measure of addiction potential. This is similar in effect to amphetamine
Amphetamine
Amphetamine or amfetamine is a psychostimulant drug of the phenethylamine class which produces increased wakefulness and focus in association with decreased fatigue and appetite.Brand names of medications that contain, or metabolize into, amphetamine include Adderall, Dexedrine, Dextrostat,...

.

Nicotine gum
Nicotine gum
Nicotine gum is a type of chewing gum that delivers nicotine to the body. It is used as an aid in nicotine replacement therapy , a process for smoking cessation and quitting smokeless tobacco. The nicotine is delivered to the bloodstream via absorption by the tissues of the mouth.It is currently...

, usually in 2-mg or 4-mg doses, and nicotine patches are available, as well as smokeless tobacco
Smokeless tobacco
Smokeless Tobacco may refer to:* Dipping tobacco, a type of tobacco that is placed between the lower or upper lip and gums.* Chewing tobacco, a type of tobacco that is chewed.* Snuff, a type of tobacco that is insufflated or "snuffed" through the nose....

, nicotine lozenges and electronic cigarettes, which do not have all the other ingredients in tobacco.

Dependence and withdrawal



Modern research
Research
Research can be defined as the scientific search for knowledge, or as any systematic investigation, to establish novel facts, solve new or existing problems, prove new ideas, or develop new theories, usually using a scientific method...

 shows that nicotine acts on the brain to produce a number of effects. Specifically, research examining its addictive nature has been found to show that nicotine activates the Mesolimbic pathway
Mesolimbic pathway
The mesolimbic pathway is one of the dopaminergic pathways in the brain. The pathway begins in the ventral tegmental area of the midbrain and connects to the limbic system via the nucleus accumbens, the amygdala, and the hippocampus as well as to the medial prefrontal cortex...

 ("reward system") —the circuitry within the brain that regulates feelings of pleasure and euphoria.

Dopamine
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...

 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
Cocaine
Cocaine is a crystalline tropane alkaloid that is obtained from the leaves of the coca plant. The name comes from "coca" in addition to the alkaloid suffix -ine, forming cocaine. It is a stimulant of the central nervous system, an appetite suppressant, and a topical anesthetic...

 and heroin. Like other physically addictive drugs, nicotine withdrawal
Nicotine withdrawal
Nicotine withdrawal is a term used to describe the effects felt by a person who is nicotine dependent and suddenly stops or significantly reduces his/her nicotine intake. Since smoking cigarettes is the most popular form of nicotine use, the effects of nicotine withdrawal have been most commonly...

 causes down-regulation of the production of dopamine and other stimulatory neurotransmitters as the brain attempts to compensate for artificial stimulation. As dopamine regulates 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. An example is the increase in norepinephrine
Norepinephrine
Norepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...

, one of the successors to dopamine, which inhibit reuptake of the glutamate receptors, in charge of memory and cognition. The net effect is an increase in reward pathway sensitivity, opposite of other drugs of abuse such as cocaine and heroin, which reduce reward pathway sensitivity. This neuronal brain alteration persists for months after administration ceases.

A study found that nicotine exposure in adolescent mice retards the growth of the dopamine system, thus increasing the risk of substance abuse during adolescence.

Immunology prevention


Because of the severe addictions and the harmful effects of smoking, vaccination protocols have been developed. The principle is under the premise that if an antibody is attached to a nicotine molecule, it will be prevented from diffusing through the capillaries, thus making it less likely that it ever affects the brain by binding to nicotinic acetylcholine receptors.

These include attaching the nicotine molecule to a hapten
Hapten
A hapten is a small molecule that can elicit an immune response only when attached to a large carrier such as a protein; the carrier may be one that also does not elicit an immune response by itself...

 such as Keyhole limpet hemocyanin
Keyhole limpet hemocyanin
Keyhole limpet hemocyanin is a large, multisubunit, oxygen-carrying, metalloprotein found in the hemolymph of the giant keyhole limpet, Megathura crenulata, that lives off the coast of California from Monterey Bay to Isla Asuncion off Baja California.-Protein properties:Keyhole limpet hemocyanin...

 or a safe modified bacterial toxin to elicit an active immune response. Often it is added with bovine serum albumin
Bovine serum albumin
Bovine serum albumin is a serum albumin protein derived from cows. It is often used as a protein concentration standard....

.

Additionally, because of concerns with the unique immune systems of individuals being liable to produce antibodies against endogenous hormones and over the counter drugs, monoclonal antibodies
Monoclonal antibodies
Monoclonal antibodies are monospecific antibodies that are the same because they are made by identical immune cells that are all clones of a unique parent cell....

 have been developed for short term passive immune protection. They have half-lives varying from hours to weeks. Their half-lives depend on their ability to resist degradation from pinocytosis
Pinocytosis
In cellular biology, pinocytosis is a form of endocytosis in which small particles are brought into the cell—forming an invagination, and then suspended within small vesicles that subsequently fuse with lysosomes to hydrolyze, or to break down, the particles...

 by epithelial cells.

Toxicology


NFPA 704
NFPA 704
NFPA 704 is a standard maintained by the U.S.-based National Fire Protection Association. It defines the colloquial "fire diamond" used by emergency personnel to quickly and easily identify the risks posed by nearby hazardous materials...

}
|-
|}
The of nicotine is 50 mg/kg for rat
Rat
Rats are various medium-sized, long-tailed rodents of the superfamily Muroidea. "True rats" are members of the genus Rattus, the most important of which to humans are the black rat, Rattus rattus, and the brown rat, Rattus norvegicus...

s and 3 mg/kg for mice
Mouse
A mouse is a small mammal belonging to the order of rodents. The best known mouse species is the common house mouse . It is also a popular pet. In some places, certain kinds of field mice are also common. This rodent is eaten by large birds such as hawks and eagles...

. 40–60 mg (0.5-1.0 mg/kg) can be a lethal dosage for adult humans. Nicotine therefore has a high toxicity
Toxicity
Toxicity is the degree to which a substance can damage a living or non-living organisms. Toxicity can refer to the effect on a whole organism, such as an animal, bacterium, or plant, as well as the effect on a substructure of the organism, such as a cell or an organ , such as the liver...

 in comparison to many other alkaloids such as cocaine
Cocaine
Cocaine is a crystalline tropane alkaloid that is obtained from the leaves of the coca plant. The name comes from "coca" in addition to the alkaloid suffix -ine, forming cocaine. It is a stimulant of the central nervous system, an appetite suppressant, and a topical anesthetic...

, which has an LD50 of 95.1 mg/kg when administered to mice. It is unlikely that a person would overdose on nicotine through smoking alone, although overdose can occur through combined use of nicotine patches or nicotine gum and cigarettes at the same time. Spilling a high concentration of nicotine onto the skin can cause intoxication or even death, since nicotine readily passes into the bloodstream following dermal contact.

The carcinogen
Carcinogen
A carcinogen is any substance, radionuclide, or radiation that is an agent directly involved in causing cancer. This may be due to the ability to damage the genome or to the disruption of cellular metabolic processes...

ic properties of nicotine in standalone form, separate from tobacco smoke, have not been evaluated by the IARC
International Agency for Research on Cancer
The International Agency for Research on Cancer is an intergovernmental agency forming part of the World Health Organisation of the United Nations....

, and it has not been assigned to an official carcinogen group. The currently available literature indicates that nicotine, on its own, does not actively induce the development of cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...

 in healthy tissue and has no mutagen
Mutagen
In genetics, a mutagen is a physical or chemical agent that changes the genetic material, usually DNA, of an organism and thus increases the frequency of mutations above the natural background level. As many mutations cause cancer, mutagens are therefore also likely to be carcinogens...

ic properties. However, nicotine and the increased cholinergic
Nicotinic acetylcholine receptor
Nicotinic acetylcholine receptors, or nAChRs, are cholinergic receptors that form ligand-gated ion channels in the plasma membranes of certain neurons and on the postsynaptic side of the neuromuscular junction...

 activity it causes have been shown to impede apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...

, which is one of the methods by which the body destroys unwanted cells (programmed cell death
Programmed cell death
Programmed cell-death is death of a cell in any form, mediated by an intracellular program. PCD is carried out in a regulated process which generally confers advantage during an organism's life-cycle...

). Since apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...

 helps to remove mutated or damaged cells that may eventually become cancerous, the inhibitory actions of nicotine creates a more favourable environment for cancer to develop. In one study, nicotine administered to mice with tumors caused increases in tumor size (twofold increase), metastasis
Metastasis
Metastasis, or metastatic disease , is the spread of a disease from one organ or part to another non-adjacent organ or part. It was previously thought that only malignant tumor cells and infections have the capacity to metastasize; however, this is being reconsidered due to new research...

 (nine-fold increase), and tumor recurrence (threefold increase). Through mechanisms like these, nicotine can cause cancer, even if it does not actively induce development of cancer in healthy tissue by being mutagenic.

Though the teratogenic properties of nicotine may or may not yet have been adequately researched, women who use nicotine gum
Nicotine gum
Nicotine gum is a type of chewing gum that delivers nicotine to the body. It is used as an aid in nicotine replacement therapy , a process for smoking cessation and quitting smokeless tobacco. The nicotine is delivered to the bloodstream via absorption by the tissues of the mouth.It is currently...

  and patches during the early stages of pregnancy face an increased risk of having babies with birth defects, according to a study of around 77,000 pregnant women in Denmark. The study found that women who use nicotine-replacement therapy in the first 12 weeks of pregnancy have a 60 percent greater risk of having babies with birth defects, compared to women who are non-smokers.

Effective April 1, 1990, the Office of Environmental Health Hazard Assessment (OEHHA) of the California Environmental Protection Agency
California Environmental Protection Agency
The California Environmental Protection Agency is a state cabinet-level agency within the government of California. Cal/EPA is composed of six departments, boards and offices responsible for environmental research, regulating and administering the state's environmental protection programs, and...

  added nicotine to the list of chemicals known to the state to cause developmental toxicity, for the purposes of Proposition 65.

Link to circulatory disease


Nicotine has very powerful effects on arteries throughout the body. Nicotine is a stimulant, it raises blood pressure
Blood pressure
Blood pressure is the pressure exerted by circulating blood upon the walls of blood vessels, and is one of the principal vital signs. When used without further specification, "blood pressure" usually refers to the arterial pressure of the systemic circulation. During each heartbeat, BP varies...

, and is a vasoconstrictor, making it harder for the heart to pump through the constricted arteries. It causes the body to release its stores of fat and cholesterol
Cholesterol
Cholesterol is a complex isoprenoid. Specifically, it is a waxy steroid of fat that is produced in the liver or intestines. It is used to produce hormones and cell membranes and is transported in the blood plasma of all mammals. It is an essential structural component of mammalian cell membranes...

 into the blood.

It has been speculated that nicotine increases the risk of blood clots by increasing plasminogen activator inhibitor-1, though this has not been proven. Plasma fibrinogen levels are elevated in smokers and are further elevated during acute COPD exacerbation. Also Factor XIII, which stabilizes fibrin clots, is increased in smokers. But neither of these two effects has been shown to be caused by nicotine .

Therapeutic uses


The primary therapeutic use of nicotine is in treating nicotine dependence in order to eliminate smoking
Smoking
Smoking is a practice in which a substance, most commonly tobacco or cannabis, is burned and the smoke is tasted or inhaled. This is primarily practised as a route of administration for recreational drug use, as combustion releases the active substances in drugs such as nicotine and makes them...

 with the damage it does to health. Controlled levels of nicotine are given to patients through gums, dermal patches, lozenges, electronic/substitute cigarettes or nasal sprays in an effort to wean them off their dependence.

However, in a few situations, smoking has been observed to apparently be of therapeutic value.
These are often referred to as "Smoker’s Paradoxes". Although in most cases the actual mechanism is understood only poorly or not at all, it is generally believed that the principal beneficial action is due to the nicotine administered, and that administration of nicotine without smoking may be as beneficial as smoking, without the higher risk to health due to tar
Tar (tobacco residue)
Tar is the common name for the resinous partially combusted and healed particulate matter produced by the burning of tobacco and other plant material in the act of smoking. Tar is purportedly the most destructive component in habitual tobacco smoking, accumulating in the smoker's lungs over time...

 and other ingredients found in tobacco
Tobacco
Tobacco is an agricultural product processed from the leaves of plants in the genus Nicotiana. It can be consumed, used as a pesticide and, in the form of nicotine tartrate, used in some medicines...

.

For instance, recent studies suggest that smokers require less frequent repeated revascularization
Revascularization
Revascularization is "a surgical procedure for the provision of a new, additional, or augmented blood supply to a body part or organ." The term derives from the prefix re-, in this case meaning "restoration" and vasculature, which refers to the circulatory structures of an organ.Revascularization...

 after percutaneous coronary intervention
Percutaneous coronary intervention
Percutaneous coronary intervention , commonly known as coronary angioplasty or simply angioplasty, is one therapeutic procedure used to treat the stenotic coronary arteries of the heart found in coronary heart disease. These stenotic segments are due to the build up of cholesterol-laden plaques...

 (PCI). Risk of ulcerative colitis
Ulcerative colitis
Ulcerative colitis is a form of inflammatory bowel disease . Ulcerative colitis is a form of colitis, a disease of the colon , that includes characteristic ulcers, or open sores. The main symptom of active disease is usually constant diarrhea mixed with blood, of gradual onset...

 has been frequently shown to be reduced by smokers on a dose-dependent basis; the effect is eliminated if the individual stops smoking.
Smoking also appears to interfere with development of Kaposi's sarcoma
Kaposi's sarcoma
Kaposi's sarcoma is a tumor caused by Human herpesvirus 8 , also known as Kaposi's sarcoma-associated herpesvirus . It was originally described by Moritz Kaposi , a Hungarian dermatologist practicing at the University of Vienna in 1872. It became more widely known as one of the AIDS defining...

 in patients with HIV,http://jnci.oxfordjournals.org/content/94/22/1712.full.

Nicotine reduces the chance of breast cancer
Breast cancer
Breast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...

 among women carrying the very high risk BRCA
BRCA1
BRCA1 is a human caretaker gene that produces a protein called breast cancer type 1 susceptibility protein, responsible for repairing DNA. The first evidence for the existence of the gene was provided by the King laboratory at UC Berkeley in 1990...

 gene,
preeclampsia,
and atopic disorder
Atopy
Atopy or atopic syndrome is a predisposition toward developing certain allergic hypersensitivity reactions.Atopy may have a hereditary component, although contact with the allergen must occur before the hypersensitivity reaction can develop ....

s such as allergic asthma.
A plausible mechanism of action in these cases may be nicotine acting as an anti-inflammatory agent
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...

, and interfering with the inflammation-related disease process, as nicotine has vasoconstrictive effects.

Tobacco smoke has been shown to contain compounds capable of inhibiting MAO
Mao
, is a Japanese remake of the Korean suspense drama series titled Ma Wang which aired on KBS 2TV in 2007. The drama stars Satoshi Ohno of Arashi and Toma Ikuta, both under the talent agency Johnny & Associates.-Synopsis:...

. Monoamine oxidase
Monoamine oxidase
L-Monoamine oxidases are a family of enzymes that catalyze the oxidation of monoamines. They are found bound to the outer membrane of mitochondria in most cell types in the body. The enzyme was originally discovered by Mary Bernheim in the liver and was named tyramine oxidase...

 is responsible for the degradation of dopamine in the human brain. When dopamine is broken down by MAO-B, neurotoxic by-products are formed, possibly contributing to Parkinson's and Alzheimers disease.
Many such papers regarding Alzheimer's disease
and Parkinson's Disease
have been published. Recent studies find no beneficial link between smoking and Alzheimer's disease and in some cases, suggest it may actually result in an earlier onset of the disease.
However, nicotine has been shown to delay the onset of Parkinson's disease in studies involving monkeys and humans. However a study has shown a protective effect of nicotine itself on neurons due to nicotine activation of α7-nAChR and the PI3K/Akt pathway which inhibits AIF
AIF
AIF may refer to:*AIF , refer List of role-playing games by name*Accredited Investment Fiduciary*Adult Interactive fiction, a game genre*American India Foundation*Anti-Iraqi Forces*Apoptosis inducing factor...

 release and mitochondrial translocation, cytochrome c
Cytochrome c
The Cytochrome complex, or cyt c is a small heme protein found loosely associated with the inner membrane of the mitochondrion. It belongs to the cytochrome c family of proteins. Cytochrome c is a highly soluble protein, unlike other cytochromes, with a solubility of about 100 g/L and is an...

 release and caspase 3
Caspase 3
Caspase 3 is a caspase protein that interacts with caspase 8 and caspase 9. It is encoded by the CASP3 gene. CASP3 orthologs have been identified in numerous mammals for which complete genome data are available...

 activation.

Recent studies have indicated that nicotine can be used to help adults suffering from autosomal dominant nocturnal frontal lobe epilepsy
Autosomal dominant nocturnal frontal lobe epilepsy
Autosomal dominant nocturnal frontal lobe epilepsy is a rare epileptic disorder that causes frequent violent seizures during sleep. These seizures often involve complex motor movements, such as hand clenching, arm raising/lowering, and knee bending. Vocalizations such as shouting, moaning, or...

. The same areas that cause seizures in that form of epilepsy
Epilepsy
Epilepsy is a common chronic neurological disorder characterized by seizures. These seizures are transient signs and/or symptoms of abnormal, excessive or hypersynchronous neuronal activity in the brain.About 50 million people worldwide have epilepsy, and nearly two out of every three new cases...

 are responsible for processing nicotine in the brain.

Studies suggest a correlation between smoking and schizophrenia
Schizophrenia
Schizophrenia is a mental disorder characterized by a disintegration of thought processes and of emotional responsiveness. It most commonly manifests itself as auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking, and it is accompanied by significant social...

, with estimates near 75% for the proportion of schizophrenic patients who smoke. Although the nature of this association remains unclear, it was recently argued that the increased level of smoking in schizophrenia may be due to a desire to self-medicate
Self-medication
Self-medication is a term used to describe the use of drugs or other self-soothing forms of behavior to treat untreated and often undiagnosed mental distress, stress and anxiety, including mental illnesses and/or psychological trauma...

 with nicotine. More recent research has found that mildly dependent users got some benefit from nicotine, but not those who were highly dependent. All of these studies are based only on observation, and no interventional (randomized) studies have been done. Research on nicotine as administered through a patch or gum is ongoing.

Nicotine appears to improve ADHD symptoms. Some studies are focusing on benefits of nicotine therapy in adults with ADHD.

Nicotine (in the form of chewing gum or a transdermal patch) is being explored as an experimental treatment for OCD. Small studies show some success, even in otherwise treatment-refractory cases.

Research as a potential basis for an antipsychotic agent


When the metabolites of nicotine were isolated and their effect on first the animal brain and then the human brain in people with schizophrenia were studied, it was shown that the effects helped with cognitive and negative symptoms of schizophrenia. Therefore, the nicotinergic agents, as antipsychotics which do not contain nicotine but act on the same receptors in the brain are showing promise as adjunct antipsychotics in early stages of FDA studies on schizophrenia.
The prepulse inhibition
Prepulse inhibition
Prepulse Inhibition is a neurological phenomenon in which a weaker prestimulus inhibits the reaction of an organism to a subsequent strong startling stimulus . The stimuli are usually acoustic, but tactile stimuli Prepulse Inhibition (PPI) is a neurological phenomenon in which a weaker...

 (PPI) is a phenomenon in which a weak prepulse attenuates the response to a subsequent startling stimulus. Therefore, PPI is believed to have face, construct, and predictive validity for the PPI disruption in schizophrenia, and it is widely used as a model to study the neurobiology of this disorder and for screening antipsychotics.
Additionally, studies have that there are genes predisposing people with schizophrenia to nicotine use.

Therefore with these factors taken together the heavy usage of cigarettes and other nicotine related products among people with schizophrenia may be explained and novel antipsychotic agents developed that have these effects in a manner that is not harmful and controlled and is a promising arena of research for schizophrenia.

See also

  • Nicotiana
    Nicotiana
    Nicotiana is a genus of herbs and shrubs of the nightshade family indigenous to North and South America, Australia, south west Africa and the South Pacific. Various Nicotiana species, commonly referred to as tobacco plants, are cultivated and grown to produce tobacco. Of all Nicotiana species,...

    • Nicotiana rustica
      Nicotiana rustica
      Nicotiana rustica, known in South America as Mapacho and in Vietnam as Thuoc Lao , is a plant in the Solanaceae family. It is a very potent variety of tobacco. The high concentration of nicotine in its leaves makes it useful for creating organic pesticides.Rustica is also used for entheogenic...

      • Mapacho
    • Nicotiana tabacum
      Nicotiana tabacum
      Nicotiana tabacum, or cultivated tobacco, is a perennial herbaceous plant. It is found only in cultivation, where it is the most commonly grown of all plants in the Nicotiana genus, and its leaves are commercially grown in many countries to be processed into tobacco. It grows to heights between 1...

      • Tobacco
        Tobacco
        Tobacco is an agricultural product processed from the leaves of plants in the genus Nicotiana. It can be consumed, used as a pesticide and, in the form of nicotine tartrate, used in some medicines...

        • Tobacco products
          Tobacco products
          After tobacco has been processed, it is used to produce a number of different products.- Chewing tobacco :Chewing is one of the oldest ways of consuming tobacco leaves. Native Americans in both North and South America chewed the fresh leaves of the plant, frequently mixed with lime. Modern chewing...

  • Nicotinic acid (Niacin)
  • Drug addiction
  • Tobacco cessation
    • Chantix
    • Zyban
    • Nicogel
      Nicogel
      Nicogel is a "tobacco gel", applied to skin as a substitute for cigarette use. Nicogel is a tobacco product, and is not a smoking cessation product.-Usage:...

    • Nicotini
      Nicotini
      A nicotini is any alcoholic drink which includes nicotine as an ingredient. Its name is modeled after the word "martini" in the fashion of such drinks as the appletini. In places which ban smoking, use of the nicotini provides those addicted to nicotine with the opportunity to manage cravings...

    • NicVAX
      NicVAX
      NicVAX is a nicotine conjugate vaccine intended to reduce or eliminate physical addiction to nicotine. According to the U.S. National Institute on Drug Abuse, NicVAX can potentially be used to inoculate against addiction. This proprietary vaccine is being developed by Nabi Biopharmaceuticals of...

    • Nicotine gum
      Nicotine gum
      Nicotine gum is a type of chewing gum that delivers nicotine to the body. It is used as an aid in nicotine replacement therapy , a process for smoking cessation and quitting smokeless tobacco. The nicotine is delivered to the bloodstream via absorption by the tissues of the mouth.It is currently...

    • Nicotine patch
      Nicotine patch
      A nicotine patch is a transdermal patch that releases nicotine into the body through the skin. It is used as an aid in nicotine replacement therapy , a process for smoking cessation. The first published study of the pharmacokinetics of a transdermal nicotine patch in humans was authored by Jed E....

    • Nicotine inhaler
    • Nicotine nasal spray
      Nicotine nasal spray
      A nicotine nasal spray is a nasal spray that contains a small dose of nicotine, which enters the blood by being absorbed through the lining of the nose. This helps stop nicotine cravings and relieves symptoms that occur when a person is trying to quit smoking. A prescription is needed for nicotine...

    • Snus
      Snus
      Snus , or Swedish snuff, is a moist powder tobacco product originated from a variant of dry snuff in the early 19th century in Sweden, consumed by placing it under the lip for extended periods of time. The precursor of snus, the dry form of snuff inhaled through the nose, was introduced in Europe...

    • Electronic Cigarette

  • Psychoactive drug
    Psychoactive drug
    A psychoactive drug, psychopharmaceutical, or psychotropic is a chemical substance that crosses the blood–brain barrier and acts primarily upon the central nervous system where it affects brain function, resulting in changes in perception, mood, consciousness, cognition, and behavior...

  • Drug Discovery and Development: Nicotinic Acetylcholine Receptor Agonists
  • Nicotinic receptor

Further reading


External links