Nicotine 1

Nicotine

Nicotine

Systematic (IUPAC) name

3-[(2S)-1-methylpyrrolidin-2-yl]pyridine

Identifiers

CAS number 54-11-5 [1]

ATC code N07 BA01 [2] QP53 AX13 [3]

PubChem CID 942 [4]

DrugBank DB00184 [5]

ChemSpider 80863 [6] 

UNII 6M3C89ZY6R [7] 

Chemical data

Formula C10H14N2

Mol. mass 162.26 g/mol

SMILES eMolecules [8] & PubChem [9]

Physical data

Density 1.01 g/cm³

Melt. point -79 °C (-110 °F)

Boiling point 247 °C (477 °F)

Pharmacokinetic data

Bioavailability 20 to 45% (oral)

Metabolism hepatic

Half-life 2 hours

Therapeutic considerations

Pregnancy cat. D(US)

Nicotine 2

Legal status Unscheduled (AU) ? (UK) ? (US)

Dependenceliability

Medium to high

Routes smoked (as smoking tobacco, mapacho, etc.), insufflated (as tobacco snuff or nicotine nasal spray), chewed (asnicotine gum, tobacco gum or chewing tobacco), transdermal (as nicotine patch, nicogel or topical tobaccopaste), intrabuccal (as dipping tobacco, snuffs, dissolvable tobacco or creamy snuff), vaporized (as electroniccigarette, etc.), directly inhaled (as nicotine inhaler), oral (as nicotini)

(what is this?)   (verify) [10]

Nicotine is an alkaloid found in the nightshade family of plants (Solanaceae) that constitutes approximately0.6–3.0% of the dry weight of tobacco,[11] [12] with biosynthesis taking place in the roots and accumulationoccurring in the leaves. It functions as an antiherbivore chemical with particular specificity to insects; thereforenicotine was widely used as an insecticide in the past,[13] [14] and currently nicotine analogs such as imidaclopridcontinue to be widely used. Nicotine is also found in several other members of the Solanaceae family, with smallamounts being present in species such as the Eggplant and Tomato.In low concentrations (an average cigarette yields about 1 mg of absorbed nicotine), the substance acts as a stimulantin mammals and is the main factor responsible for the dependence-forming properties of tobacco smoking.According to the American Heart Association, nicotine addiction has historically been one of the hardest addictionsto break, while the pharmacological and behavioral characteristics that determine tobacco addiction are similar tothose that determine addiction to drugs such as heroin and cocaine.[15] Nicotine content in cigarettes has slowlyincreased over the years, and one study found that there was an average increase of 1.6% per year between the yearsof 1998 and 2005. This was found for all major market categories of cigarettes.[16]

History and nameNicotine is named after the tobacco plant Nicotiana tabacum, which in turn is named after Jean Nicot de Villemain,French ambassador in Portugal, who sent tobacco and seeds from Brazil to Paris in 1560 and promoted theirmedicinal use. Nicotine was first isolated from the tobacco plant in 1828 by German chemists Posselt & Reimann,who considered it a poison.[17] Its chemical empirical formula was described by Melsens in 1843,[18] its structurewas discovered by Adolf Pinner and Richard Wolffenstein in 1893, and it was first synthesized by A. Pictet andCrepieux in 1904.[19]

ChemistryNicotine is a hygroscopic, oily liquid that is miscible with water in its base form. As a nitrogenous base, nicotineforms salts with acids that are usually solid and water soluble. Nicotine easily penetrates the skin. As shown by thephysical data, free base nicotine will burn at a temperature below its boiling point, and its vapors will combust at308 K (35 °C; 95 °F) in air despite a low vapor pressure. Because of this, most of the nicotine is burned when acigarette is smoked; however, enough is inhaled to cause pharmacological effects.

Nicotine 3

Optical activityNicotine is optically active, having two enantiomeric 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. It is therefore weaker in the sense that a higher dose is required to attain the same effects.[20] The saltsof (+)-nicotine are usually dextrorotatory.

Pharmacology

Pharmacokinetics

Side effects of nicotine.[21]

As nicotine enters the body, it is distributedquickly through the bloodstream and can crossthe blood-brain barrier. On average it takes aboutseven seconds for the substance to reach thebrain when inhaled. The half life of nicotine inthe body is around two hours.[22]

The amount of nicotine absorbed by the bodyfrom smoking depends on many factors,including the type of tobacco, whether the smokeis inhaled, and whether a filter is used. Forchewing tobacco, dipping tobacco, snus andsnuff, which are held in the mouth between thelip and gum, or taken in the nose, the amountreleased into the body tends to be much greaterthan smoked tobacco. Nicotine is metabolized inthe liver by cytochrome P450 enzymes (mostlyCYP2A6, and also by CYP2B6). A majormetabolite is cotinine.

Other primary metabolites include nicotine N'-oxide, nornicotine, nicotine isomethonium ion, 2-hydroxynicotine andnicotine glucuronide.[23]

Glucuronidation and oxidative metabolism of nicotine to cotinine are both inhibited by menthol, an additive tomentholated cigarettes, thus increasing the half-life of nicotine in vivo.[24]

Detection of useNicotine can be quantified in blood, plasma, or urine to confirm a diagnosis of poisoning or to facilitate amedicolegal death investigation. Urinary or salivary cotinine concentrations are frequently measured for thepurposes of pre-employment and health insurance medical screening programs. Careful interpretation of results isimportant, since passive exposure to cigarette smoke can result in significant accumulation of nicotine, followed bythe appearance of its metabolites in various body fluids.[25] [26] Interestingly, nicotine use is not regulated incompetitive sports programs, yet the drug has been shown to have a significant beneficial effect on athleticperformance.[27]

Nicotine 4

PharmacodynamicsNicotine acts on the nicotinic acetylcholine receptors, specifically the ganglion type nicotinic receptor and one CNSnicotinic receptor. The former is present in the adrenal medulla and elsewhere, while the latter is present in thecentral nervous system (CNS). In small concentrations, nicotine increases the activity of these receptors. Nicotinealso has effects on a variety of other neurotransmitters through less direct mechanisms.

In CNS

Effect of nicotine on dopaminergic neurons

By binding to nicotinic acetylcholine receptors, nicotine increases thelevels of several neurotransmitters - acting as a sort of "volumecontrol". It is thought that increased levels of dopamine in the rewardcircuits of the brain are responsible for the euphoria and relaxation andeventual addiction caused by nicotine consumption. Nicotine has ahigher affinity for acetylcholine receptors in the brain than those inskeletal muscle, though at toxic doses it can induce contractions andrespiratory paralysis.[28] Nicotine's selectivity is thought to be due to aparticular amino acid difference on these receptor subtypes.[29]

Tobacco smoke contains the monoamine oxidase inhibitors harman,norharman,[30] anabasine, anatabine, and nornicotine. Thesecompounds significantly decrease MAO activity in smokers.[30] [31]

MAO enzymes break down monoaminergic neurotransmitters such asdopamine, norepinephrine, and serotonin.

Chronic nicotine exposure via tobacco smoking up-regulates alpha4beta2* nAChR in cerebellum and brainstemregions[32] [33] but not habenulopeduncular structures.[34] Alpha4beta2 and alpha6beta2 receptors, present in theventral tegmental area, play a crucial role in mediating the reinforcement effects of nicotine.[35]

In SNS

Nicotine also activates the sympathetic nervous system,[36] acting via splanchnic nerves to the adrenal medulla,stimulates the release of epinephrine. Acetylcholine released by preganglionic sympathetic fibers of these nerves actson nicotinic acetylcholine receptors, causing the release of epinephrine (and norepinephrine) into the bloodstream.Nicotine also has an affinity for melanin-containing tissues due to its precursor function in melanin synthesis or itsirreversible binding of melanin and nicotine. This has been suggested to underlie the increased nicotine dependenceand lower smoking cessation rates in darker pigmented individuals.[37]

Effect of nicotine on chromaffin cells

In adrenal medulla

By binding to ganglion type nicotinic receptors in the adrenal medullanicotine increases flow of adrenaline (epinephrine), a stimulatinghormone and neurotransmitter. By binding to the receptors, it causescell depolarization and an influx of calcium through voltage-gatedcalcium channels. Calcium triggers the exocytosis of chromaffingranules and thus the release of epinephrine (and norepinephrine) intothe bloodstream. The release of epinephrine (adrenaline) causes anincrease in heart rate, blood pressure and respiration, as well as higherblood glucose levels.[38]

Nicotine is the natural product of tobacco, having a half-life of 1 to 2 hours. In the other hand, cotinine is the metabolite of nicotine which remains in the blood for 18 to 20 hours, making it a more stable compound, which

Nicotine 5

results more desirable and easier to analyze due to its longer half-life.[39]

Psychoactive effectsNicotine's mood-altering effects are different by report: in particular it is both a stimulant and a relaxant.[40] Firstcausing a release of glucose from the liver and epinephrine (adrenaline) from the adrenal medulla, it causesstimulation. Users report feelings of relaxation, sharpness, calmness, and alertness.[41] Like any stimulant, it mayvery rarely cause the often catastrophically uncomfortable neuropsychiatric effect of akathisia. By reducing theappetite and raising the metabolism, some smokers may lose weight as a consequence.[42] [43]

Smokers often report that cigarettes help relieve feelings of stress. However, the stress levels of adult smokers areslightly higher than those of nonsmokers, adolescent smokers report increasing levels of stress as they developregular patterns of smoking, and smoking cessation leads to reduced stress . Far from acting as an aid for moodcontrol, nicotine dependency seems to exacerbate stress. This is confirmed in the daily mood patterns described bysmokers, with normal moods during smoking and worsening moods between cigarettes. Thus, the apparent relaxanteffect of smoking only reflects the reversal of the tension and irritability that develop during nicotine depletion.Dependent smokers need nicotine to remain feeling normal.[44]

When a cigarette is smoked, nicotine-rich blood passes from the lungs to the brain within seven seconds andimmediately stimulates the release of many chemical messengers including acetylcholine, norepinephrine,epinephrine, vasopressin, arginine, dopamine, autocrine agents, and beta-endorphin.[45] This release ofneurotransmitters and hormones is responsible for most of nicotine's effects. Nicotine appears to enhanceconcentration[46] and memory due to the increase of acetylcholine. It also appears to enhance alertness due to theincreases of acetylcholine and norepinephrine. Arousal is increased by the increase of norepinephrine. Pain isreduced by the increases of acetylcholine and beta-endorphin. Anxiety is reduced by the increase of beta-endorphin.Nicotine also extends the duration of positive effects of dopamine[47] and increases sensitivity in brain rewardsystems.[48] Most cigarettes (in the smoke inhaled) contain 1 to 3 milligrams of nicotine.[49]

Research suggests that, when smokers wish to achieve a stimulating effect, they take short quick puffs, whichproduce a low level of blood nicotine.[50] This stimulates nerve transmission. When they wish to relax, they takedeep puffs, which produce a high level of blood nicotine, which depresses the passage of nerve impulses, producinga mild sedative effect. At low doses, nicotine potently enhances the actions of norepinephrine and dopamine in thebrain, causing a drug effect typical of those of psychostimulants. At higher doses, nicotine enhances the effect ofserotonin and opiate activity, producing a calming, pain-killing effect. Nicotine is unique in comparison to mostdrugs, as its profile changes from stimulant to sedative/pain killer in increasing dosages and use.Technically, nicotine is not significantly addictive, as nicotine administered alone does not produce significantreinforcing properties.[51] However, only 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 toamphetamine.[52]

Nicotine gum, usually in 2-mg or 4-mg doses, and nicotine patches are available, as well as smokeless tobacco andelectronic cigarettes which do not have all the other ingredients in smoked tobacco.

Nicotine 6

A 21 mg patch applied to the left arm. TheCochrane Collaboration finds that NRT increasesa quitter's chance of success by 50 to 70%.[53]

But in 1990, researchers found that 93% of usersreturned to smoking within six months.[54]

Dependence and withdrawal

Modern research shows that nicotine acts on the brain to produce anumber of effects. Specifically, its addictive nature has been found toshow that nicotine activates reward pathways—the circuitry within thebrain that regulates feelings of pleasure and euphoria.[55]

Dopamine is one of the key neurotransmitters actively involved in thebrain. Research shows that by increasing the levels of dopamine withinthe reward circuits in the brain, nicotine acts as a chemical with intenseaddictive qualities. In many studies it has been shown to be moreaddictive than cocaine and heroin. Like other physically addictivedrugs, nicotine withdrawal causes down-regulation of the production ofdopamine and other stimulatory neurotransmitters as the brain attemptsto compensate for artificial stimulation. As dopamine regulates the In addition, the sensitivity of nicotinicacetylcholine receptors decreases. To compensate for this compensatory mechanism, the brain in turn upregulates thenumber of receptors, convoluting its regulatory effects with compensatory mechanisms meant to counteract othercompensatory mechanisms. An example is the increase in norepinephrine, one of the successors to dopamine, whichinhibit reputake of the glutamate receptors,[56] in charge of memory and cognition. The net effect is an increase inreward pathway sensitivity, opposite of other drugs of abuse such as cocaine and heroin, which reduce rewardpathway sensitivity.[48] This neuronal brain alteration persists for months after administration ceases. Nicotine alsohas the potential to cause dependence in many animals other than humans, assuming they were to consume it.

A study found that nicotine exposure in adolescent mice retards the growth of the dopamine system, thus increasingthe risk of substance abuse during adolescence.[57]

Immunology preventionBecause 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 fromdiffusing through the capillaries, thus making it less likely that it ever affects the brain by binding to nicotinicacetylcholine receptors.These include attaching the nicotine molecule to a hapten such as Keyhole limpet hemocyanin or a safe modifiedbacterial toxin to elicit an active immune response. Often it is added with bovine serum albumin.Additionally, because of concerns with the unique immune systems of individuals being liable to produce antibodiesagainst endogenous hormones and over the counter drugs, monoclonal antibodies have been developed for short termpassive immune protection. They have half-lives varying from hours to weeks. Their half-lives depend on theirability to resist degradation from pinocytosis by epithelial cells.[58]

ToxicologyThe 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 foradult humans.[59] [60] Nicotine therefore has a high toxicity in comparison to many other alkaloids such as cocaine,which has an LD50 of 95.1 mg/kg when administered to mice. It is unlikely that a person would overdose on nicotinethrough smoking alone, although intoxication can occur through the excessive use of nicotine patches, gum, nasalsprays or oral inhalers intended as smoking cessation aids.[61] [62] Spilling a high concentration of nicotine onto theskin can cause intoxication or even death, since nicotine readily passes into the bloodstream following dermalcontact.[63]

Nicotine 7

The carcinogenic properties of nicotine in standalone form, separate from tobacco smoke, have not been evaluatedby the IARC, and it has not been assigned to an official carcinogen group. The currently available literature indicatesthat nicotine, on its own, does not promote the development of cancer in healthy tissue and has no mutagenicproperties. However, nicotine and the increased cholinergic activity it causes have been shown to impede apoptosis,which is one of the methods by which the body destroys unwanted cells (programmed cell death). Since apoptosishelps to remove mutated or damaged cells that may eventually become cancerous, the inhibitory actions of nicotinemay create a more favourable environment for cancer to develop, though this also remains to be proven.[64]

Though the teratogenic properties of nicotine may or may not yet have been adequately researched, women who usenicotine gum and patches during the early stages of pregnancy face an increased risk of having babies with birthdefects, according to a study of around 77,000 pregnant women in Denmark. The study found that women who usenicotine-replacement therapy in the first 12 weeks of pregnancy have a 60 percent greater risk of having babies withbirth defects, compared to women who are non-smokers, the Daily Mail reported. The findings were published in thejournal Obstetrics and Gynaecology.Effective April 1, 1990, the Office of Environmental Health Hazard Assessment (OEHHA) of the CaliforniaEnvironmental Protection Agency added nicotine to the list of chemicals known to the state to cause developmentaltoxicity, for the purposes of Proposition 65.[65]

Link to circulatory diseaseNicotine has very powerful effects on arteries throughout the body. Nicotine is a stimulant, it raises blood pressure,and is a vasoconstrictor, making it harder for the heart to pump through the constricted arteries. It causes the body torelease its stores of fat and cholesterol into the blood.[66]

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 duringacute COPD exacerbation. Also Factor XIII, which stabilizes fibrin clots, is increased in smokers. But neither ofthese two effects has been shown to be caused by nicotine [67] as of 2009.Peripheral circulation in arteries going to the extremities is also highly susceptible to the vasoconstrictor effects ofnicotine and the increased risk of clots and clogging.

Therapeutic usesThe primary therapeutic use of nicotine is in treating nicotine dependence in order to eliminate smoking with thedamage 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 oftenreferred to as "Smoker’s Paradoxes".[68] Although in most cases the actual mechanism is understood only poorly ornot at all, it is generally believed that the principal beneficial action is due to the nicotine administered, and thatadministration of nicotine without smoking may be as beneficial as smoking, without the higher risk to health due totar and other ingredients found in tobacco.For instance, recent studies suggest that smokers require less frequent repeated revascularization after percutaneouscoronary intervention (PCI).[68] Risk of ulcerative colitis has been frequently shown to be reduced by smokers on adose-dependent basis; the effect is eliminated if the individual stops smoking.[69] [70] Smoking also appears tointerfere with development of Kaposi's sarcoma in patients with HIV,[71].[72]

Nicotine reduces the chance of Breast cancer among women carrying the very high risk BRCA gene,[73]

preeclampsia,[74] and atopic disorders such as allergic asthma.[75] A plausible mechanism of action in these casesmay be nicotine acting as an anti-inflammatory agent, and interfering with the inflammation-related disease process,as nicotine has vasoconstrictive effects.[76]

Nicotine 8

Tobacco smoke has been shown to contain compounds capable of inhibiting MAO. Monoamine oxidase isresponsible 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.[77] Many suchpapers regarding Alzheimer's disease[78] and Parkinson's Disease[79] have been published. Recent studies find nobeneficial link between smoking and Alzheimer's disease and in some cases, suggest it may actually result in anearlier onset of the disease.[80] [81] [82] [83] However, nicotine has been shown to delay the onset of Parkinson'sdisease in studies involving monkeys and humans.[84] [85] [86]

Recent studies have indicated that nicotine can be used to help adults suffering from autosomal dominant nocturnalfrontal lobe epilepsy. The same areas that cause seizures in that form of epilepsy are responsible for processingnicotine in the brain.[87]

Studies suggest a correlation between smoking and schizophrenia, with estimates near 75% for the proportion ofschizophrenic patients who smoke. Although the nature of this association remains unclear, it was recently arguedthat the increased level of smoking in schizophrenia may be due to a desire to self-medicate with nicotine.[88] [89]

More recent research has found that mildly dependent users got some benefit from nicotine, but not those who werehighly dependent.[90] All of these studies are based only on observation, and no interventional (randomized) studieshave 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 adultswith ADHD.[91]

Nicotine (in the form of chewing gum or a transdermal patch) is being explored as an experimental treatment forOCD. Small studies show some success, even in otherwise treatment-refractory cases.[92] [93] [94]

Research as a potential basis for an antipsychotic agentWhen the metabolites of nicotine were isolated and their effect on first the animal brain and then the human brain inpeople with schizophrenia were studied, it was shown that the effects helped with cognitive and negative symptomsof schizophrenia. Therefore, the nicotinergic agents, as antipsychotics which do not contain nicotine but act on thesame receptors in the brain are showing promise as adjunct antipsychotics in early stages of FDA studies onschizophrenia. The prepulse inhibition (PPI) is a phenomenon in which a weak prepulse attenuates the response to asubsequent startling stimulus. Therefore, PPI is believed to have face, construct, and predictive validity for the PPIdisruption in schizophrenia, and it is widely used as a model to study the neurobiology of this disorder and forscreening antipsychotics.[95] Additionally, studies have shown that there are genes predisposing people withschizophrenia to nicotine use.[96]

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

See also• Nicotiana

• Nicotiana rustica

• Mapacho• Nicotiana tabacum

• Tobacco• Tobacco products

• Nicotinic acid (Niacin)• Drug addiction

Nicotine 9

• Tobacco cessation• Chantix• Zyban• Nicogel• Nicotini• NicVAX• Nicotine gum• Nicotine patch• Nicotine inhaler• Nicotine nasal spray• Snus• Electronic Cigarette

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

References[1] http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2009/ MB_cgi?term=54-11-5& rn=1[2] http:/ / www. whocc. no/ atc_ddd_index/ ?code=N07BA01[3] http:/ / www. whocc. no/ atcvet/ atcvet_index/ ?code=QP53AX13[4] http:/ / pubchem. ncbi. nlm. nih. gov/ summary/ summary. cgi?cid=942[5] http:/ / www. drugbank. ca/ cgi-bin/ show_drug. cgi?CARD=DB00184[6] http:/ / www. chemspider. com/ Chemical-Structure. 80863[7] http:/ / fdasis. nlm. nih. gov/ srs/ srsdirect. jsp?regno=6M3C89ZY6R[8] http:/ / www. emolecules. com/ cgi-bin/ search?t=ex& q=n1cc%28ccc1%29%5BC%40H%5D2N%28C%29CCC2[9] http:/ / pubchem. ncbi. nlm. nih. gov/ search/ ?smarts=n1cc%28ccc1%29%5BC%40H%5D2N%28C%29CCC2[10] http:/ / en. wikipedia. org/ w/ index. php?& diff=cur& oldid=398693012[11] "Determination of the Nicotine Content of Various Edible Nightshades (Solanaceae) and Their Products and Estimation of the Associated

Dietary Nicotine Intake" (http:/ / pubs. acs. org/ cgi-bin/ abstract. cgi/ jafcau/ 1999/ 47/ i08/ abs/ jf990089w. html). . Retrieved 2008-10-05.[12] "Smoking and Tobacco Control Monograph No. 9" (http:/ / dccps. nci. nih. gov/ tcrb/ monographs/ 9/ m9_3. PDF) (PDF). .[13] The Chemical Components of Tobacco and Tobacco Smoke (http:/ / books. google. com/ books?id=RiwSYFgZ2fEC& pg=PA933&

lpg=PA933& dq=nicotine+ widely+ used+ pesticide& source=bl& ots=KaYsWIJLC_& sig=ZnDL_ENqpngDiOWi5ksxaU12TOc& hl=en&ei=7uw_SueFHJSuswPK_YG3AQ& sa=X& oi=book_result& ct=result& resnum=2)

[14] Some Pesticides Permitted in Organic Gardening (http:/ / www. coopext. colostate. edu/ 4DMG/ VegFruit/ organic. htm)[15] "Nicotine Addiction" (http:/ / www. americanheart. org/ presenter. jhtml?identifier=4753), American Hearth Association.[16] Connolly, G. N; Alpert, H. R; Wayne, G. F; Koh, H (2007). "Trends in nicotine yield in smoke and its relationship with design

characteristics among popular US cigarette brands, 1997-2005". Tobacco Control 16 (5): e5. doi:10.1136/tc.2006.019695. PMID 17897974.[17] Henningfield, JE; Zeller, M (2006). ""Nicotine psychopharmacology", research contributions to United States and global tobacco regulation:

A look back and a look forward" (http:/ / www. springerlink. com/ content/ 75462q6mq88g4575/ fulltext. pdf). Psychopharmacology 184(3-4): 286–291. doi:10.1007/s00213-006-0308-4. PMID 16463054. .

[18] Melsens (1844). "Über das Nicotin". Journal für Praktische Chemie 32 (1): 372–377. doi:10.1002/prac.18440320155.[19] Comptes rendus, 1903, 137, p 860 (http:/ / medicolegal. tripod. com/ toxicchemicals. htm)[20] Gause, G. F. (1941). Luyet, B. J.. ed. (http:/ / www. archive. org/ stream/ opticalactivityl00gauz/ opticalactivityl00gauz_djvu. txt). No. 2 of a

series of monographs on general physiology. Normandy, Missouri: Biodynamica. .[21] References and comments are found in image description in Commons.[22] Benowitz NL, Jacob P 3rd, Jones RT, Rosenberg J, NL; Jacob P, 3rd; Jones, RT; Rosenberg, J (1982). "Interindividual variability in the

metabolism and cardiovascular effects of nicotine in man". J Pharmacol Exp Ther 221 (2): 368–72. PMID 7077531.[23] Hukkanen J, Jacob P 3rd, Benowitz NL., J; Jacob P, 3rd; Benowitz, NL (March 2005). "Metabolism and Disposition Kinetics of Nicotine"

(http:/ / pharmrev. aspetjournals. org/ cgi/ content/ full/ 57/ 1/ 79). Pharmacol Rev. 57 (1): 79–115. doi:10.1124/pr.57.1.3. PMID 15734728. .[24] Benowitz NL, Herrera B, Jacob P 3rd., NL; Herrera, B; Jacob P, 3rd (2004). "Mentholated Cigarette Smoking Inhibits Nicotine Metabolism"

(http:/ / jpet. aspetjournals. org/ cgi/ content/ abstract/ 310/ 3/ 1208). J Pharmacol Exp Ther 310 (3): 1208–15. doi:10.1124/jpet.104.066902.PMID 15084646. .

[25] Benowitz NL, Hukkanen J, Jacob P. Nicotine chemistry, metabolism, kinetics and biomarkers. Handb. Exp. Pharmacol. 192: 29-60, 2009.[26] R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 8th edition, Biomedical Publications, Foster City, CA, 2008, pp. 1103-1107.

Nicotine 10

[27] Mündel, T. and Jones, D. A. (2006). "Effect of transdermal nicotine administration on exercise endurance in men.". Exp Physiol 91 (4):705–713. doi:10.1113/expphysiol.2006.033373. PMID 16627574.

[28] Katzung, Bertram G. Basic & Clinical Pharmacology (Basic and Clinical Pharmacology). New York: McGraw-Hill Medical, 2006. pages99-105.

[29] Xinan Xiu, Nyssa L. Puskar, Jai A. P. Shanata, Henry A. Lester & Dennis A. Dougherty.(2009) "Nicotine binding to brain receptors requiresa strong cation– interaction". Nature 458:534-537 PMID 19252481

[30] Herraiz T, Chaparro C (2005). "Human monoamine oxidase is inhibited by tobacco smoke: beta-carboline alkaloids act as potent andreversible inhibitors". Biochem. Biophys. Res. Commun. 326 (2): 378–86. doi:10.1016/j.bbrc.2004.11.033. PMID 15582589.

[31] Fowler JS, Volkow ND, Wang GJ, et al. (1998). "Neuropharmacological actions of cigarette smoke: brain monoamine oxidase B (MAO B)inhibition". J Addict Dis 17 (1): 23–34. doi:10.1300/J069v17n01_03. PMID 9549600.

[32] Wüllner U, Gündisch D, Herzog H, et al. (2008). "Smoking upregulates alpha4beta2* nicotinic acetylcholine receptors in the human brain".Neurosci. Lett. 430 (1): 34–7. doi:10.1016/j.neulet.2007.10.011. PMID 17997038.

[33] Walsh H, Govind AP, Mastro R, et al. (2008). "Up-regulation of nicotinic receptors by nicotine varies with receptor subtype". J. Biol. Chem.283 (10): 6022–32. doi:10.1074/jbc.M703432200. PMID 18174175.

[34] Nguyen HN, Rasmussen BA, Perry DC (2003). "Subtype-selective up-regulation by chronic nicotine of high-affinity nicotinic receptors inrat brain demonstrated by receptor autoradiography". J. Pharmacol. Exp. Ther. 307 (3): 1090–7. doi:10.1124/jpet.103.056408.PMID 14560040.

[35] Pons S, Fattore L, Cossu G, et al. (November 2008). "Crucial role of alpha4 and alpha6 nicotinic acetylcholine receptor subunits fromventral tegmental area in systemic nicotine self-administration" (http:/ / www. pubmedcentral. nih. gov/ articlerender. fcgi?tool=pmcentrez&artid=2819191). J. Neurosci. 28 (47): 12318–27. doi:10.1523/JNEUROSCI.3918-08.2008. PMID 19020025. PMC 2819191.

[36] Yoshida T, Sakane N, Umekawa T, Kondo M (Jan 1994). "Effect of nicotine on sympathetic nervous system activity of mice subjected toimmobilization stress" (http:/ / linkinghub. elsevier. com/ retrieve/ pii/ 0031-9384(94)90009-4). Physiol Behav. 55 (1): 53–7.doi:10.1016/0031-9384(94)90009-4. PMID 8140174. .

[37] King G, Yerger VB, Whembolua GL, Bendel RB, Kittles R, Moolchan ET. Link between facultative melanin and tobacco use amongAfrican Americans.(2009). Pharmacol Biochem Behav. 92(4):589-96. doi:10.1016/j.pbb.2009.02.011 PMID 19268687

[38] Elaine N. Marieb and Katja Hoehn (2007). Human Anatomy & Physiology (7th Ed.). Pearson. pp. ?. ISBN 0-805-35909-5.[39] Detection of Cotinine in Blood Plasma by HPLC MS/MS (http:/ / web. mit. edu/ murj/ www/ v08/ v08-Reports/ v08-r2. pdf), MIT

Undergraduate Research Journal, Volume 8, Spring 2003, Massachusetts Institute of Technology[40] Effective Clinical Tobacco Intervention (http:/ / www. ti. ubc. ca/ pages/ letter21. htm), Therapeutics Letter, issue 21, September–October

1997, University of British Columbia[41] Gilbert Lagrue, François Lebargy, Anne Cormier, "From nicotinic receptors to smoking dependence: therapeutic prospects" Alcoologie et

Addictologie Vol. : 23, N° : 2S, juin 2001, pages 39S - 42[42] Jean-Claude Orsini, "Dependence on tobacco smoking and brain systems controlling glycemia and appetite" Alcoologie et Addictologie Vol.

: 23, N° : 2S, juin 2001, pages 28S - 36S[43] Smokers lose their appetite : Media Releases : News : The University of Melbourne (http:/ / uninews. unimelb. edu. au/ articleid_1898. html)[44] Does cigarette smoking cause stress?. Parrott, Andy C. American Psychologist, Vol 54(10), Oct 1999, 817-820. doi:

[10.1037/0003-066X.54.10.817]This citation will be automatically completed in the next few minutes. You can jump the queue or expand by hand (http:/ / en. wikipedia. org/wiki/ Template:cite_doi/ _. 5b10. 1037. 2f0003-066x. 54. 10. 817. 5d)

[45] Chemically Correct: Nicotine (http:/ / www. bodybuilding. com/ fun/ par16. htm), Andrew Novick[46] Rusted, J; Graupner, O'Connell, Nicholls (1994-05-05). "Does nicotine improve cognitive function?" (http:/ / www. springerlink. com/

content/ 75034q53031260j8/ ?p=afde608485604678839ab0e950be77f9& pi=0). Psychopharmacology (Springer-Verlag) (115): 547–549. .Retrieved 2008-11-15.

[47] http:/ / chronicle. uchicago. edu/ 020328/ nicotine. shtml[48] Kenny PJ, Markou A (Jun 2006). "Nicotine self-administration acutely activates brain reward systems and induces a long-lasting increase in

reward sensitivity" (http:/ / www. nature. com/ npp/ journal/ v31/ n6/ full/ 1300905a. html). Neuropsychopharmacology 31 (6): 1203–11.doi:10.1038/sj.npp.1300905. PMID 16192981. .

[49] Erowid Nicotine Vault : Dosage (http:/ / www. erowid. org/ chemicals/ nicotine/ nicotine_dose. shtml)[50] Einstein, Stanley (1989). Drug and Alcohol Use: Issues and Factors. Springer. pp. 101–118. ISBN 0306413787.[51] Guillem K, Vouillac C, Azar MR, et al. (September 2005). "Monoamine oxidase inhibition dramatically increases the motivation to

self-administer nicotine in rats". J. Neurosci. 25 (38): 8593–600. doi:10.1523/JNEUROSCI.2139-05.2005. PMID 16177026.[52] Villégier AS, Blanc G, Glowinski J, Tassin JP (September 2003). "Transient behavioral sensitization to nicotine becomes long-lasting with

monoamine oxidases inhibitors". Pharmacol. Biochem. Behav. 76 (2): 267–74. doi:10.1016/S0091-3057(03)00223-5. PMID 14592678.[53] Stead LF, Perera R, Bullen C, Mant D, Lancaster T. (2008). "Nicotine replacement therapy for smoking cessation" (http:/ / www2. cochrane.

org/ reviews/ en/ ab000146. html). Cochrane Database of Systematic Reviews Art. No.: CD000146. doi:10.1002/14651858.CD000146.pub3. .Retrieved May 22, 2010.

[54] Millstone, Ken (February 13, 2007). "Nixing the patch: Smokers quit cold turkey" (http:/ / jscms. jrn. columbia. edu/ cns/ 2007-02-13/millstone-coldturkeyquitters. html). Columbia.edu News Service. . Retrieved May 23, 2010.

Nicotine 11

[55] NIDA - Research Report Series - Tobacco Addiction - Extent, Impact, Delivery, and Addictiveness (http:/ / www. nida. nih. gov/researchreports/ nicotine/ nicotine2. html)

[56] http:/ / www. sciencedirect. com/ science?_ob=ArticleURL& _udi=B6WN4-4CCGGN1-9P& _user=10& _coverDate=11%2F30%2F1984&_rdoc=1& _fmt=high& _orig=search& _origin=search& _sort=d& _docanchor=& view=c& _searchStrId=1520587233&_rerunOrigin=scholar. google& _acct=C000050221& _version=1& _urlVersion=0& _userid=10&md5=5e43884bdf1f204eb2356e02096708bc& searchtype=a

[57] Nolley EP, Kelley BM (2007). "Adolescent reward system perseveration due to nicotine: studies with methylphenidate". NeurotoxicolTeratol 29 (1): 47–56. doi:10.1016/j.ntt.2006.09.026. PMID 17129706.

[58] Peterson, Eric C., and Michael Owens. "Designing Immunotherapies to thwart drug abuse." Molecular Interventions June 2009: 119-23.Print.

[59] Okamoto M, Kita T, Okuda H, Tanaka T, Nakashima T (Jul 1994). "Effects of aging on acute toxicity of nicotine in rats". PharmacolToxicol. 75 (1): 1–6. doi:10.1111/j.1600-0773.1994.tb00316.x. PMID 7971729.

[60] IPCS INCHEM (http:/ / www. inchem. org/ documents/ pims/ chemical/ nicotine. htm#PartTitle:7. TOXICOLOGY)[61] http:/ / learn. genetics. utah. edu/ content/ addiction/ drugs/ overdose. html[62] http:/ / www. drugtext. org/ library/ articles/ coffin. htm[63] Lockhart LP (1933). "Nicotine poisoning". Br Med J 1: 246–7. doi:10.1136/bmj.1.3762.246-c.[64] "Toxicology" (http:/ / www. ebasedtreatment. org/ drugs/ treatment/ nicotine/ toxicology). eBasedTreatment. . Retrieved 2008-10-05.[65] http:/ / oehha. ca. gov/ prop65/ prop65_list/ files/ P65single121809. pdf[66] http:/ / www. nature. com/ ijo/ journal/ v25/ n8/ full/ 0801654a. html[67] http:/ / www. ncbi. nlm. nih. gov/ sites/ entrez[68] Cohen, David J.; Michel Doucet, Donald E. Cutlip, Kalon K.L. Ho, Jeffrey J. Popma, Richard E. Kuntz (2001). "Impact of Smoking on

Clinical and Angiographic Restenosis After Percutaneous Coronary Intervention" (http:/ / www. data-yard. net/ 34/circulation_2001_104_773. htm). Circulation 104 (7): 773. doi:10.1161/hc3201.094225. PMID 11502701. . Retrieved 2006-11-06.

[69] Longmore, M., Wilkinson, I., Torok, E. Oxford Handbook of Clinical Medicine (Fifth Edition) p. 232[70] Green JT, Richardson C, Marshall RW, et al. (Nov 2000). "Nitric oxide mediates a therapeutic effect of nicotine in ulcerative colitis" (http:/

/ www3. interscience. wiley. com/ resolve/ openurl?genre=article& sid=nlm:pubmed& issn=0269-2813& date=2000& volume=14&issue=11& spage=1429). Aliment Pharmacol Ther. 14 (11): 1429–34. doi:10.1046/j.1365-2036.2000.00847.x. PMID 11069313. .

[71] http:/ / jnci. oxfordjournals. org/ content/ 94/ 22/ 1712. full[72] {{cite JNCI J Natl Cancer Inst (2002) 94 (22): 1712-1718. "Smoking Cuts Risk of Rare Cancer" (http:/ / www. data-yard. net/ 10b/ kaposi.

htm). UPI. March 29, 2001. . Retrieved 2006-11-06.[73] Recer, Paul (May 19, 1998). "Cigarettes May Have an Up Side" (http:/ / www. forces. org/ evidence/ files/ brea. htm). Associated Press. .

Retrieved 2006-11-06.[74] Lain, Kristine Y.; Robert W. Powers, Marijane A. Krohn, Roberta B. Ness, William R. Crombleholme, James M. Roberts (Nov 1991).

"Urinary cotinine concentration confirms the reduced risk of preeclampsia with tobacco exposure" (http:/ / www. data-yard. net/ 2/ 13/ ajog.htm). American Journal of Obstetrics and Gynecology 181 (5): 908–14. PMID 11422156. . Retrieved 2006-11-06.

[75] Hjern, A; Hedberg A, Haglund B, Rosen M (June 2001). "Does tobacco smoke prevent atopic disorders? A study of two generations ofSwedish residents" (http:/ / www. data-yard. net/ 30/ asthma. htm). Clin Exp Allergy 31 (6): 908–14. doi:10.1046/j.1365-2222.2001.01096.x.PMID 11422156. . Retrieved 2006-11-06.

[76] Lisa Melton (June 2006). "Body Blazes" (http:/ / www. sciam. com/ article. cfm?chanID=sa006& colID=5&articleID=00080902-A2CF-146C-9D1E83414B7F0000). Scientific American: 24. .

[77] Fratiglioni, L; Wang HX (Aug 2000). "Smoking and Parkinson's and Alzheimer's disease: review of the epidemiological studies". BehavBrain Res 113 (1–2): 117–20. doi:10.1016/S0166-4328(00)00206-0. PMID 10942038.

[78] Thompson, Carol. "Alzheimer's disease is associated with non-smoking" (http:/ / www. forces. org/ evidence/ carol/ carol16. htm). .Retrieved 2006-11-06.

[79] Thompson, Carol. "Parkinson's disease is associated with non-smoking" (http:/ / www. forces. org/ evidence/ carol/ carol36. htm). .Retrieved 2006-11-06.

[80] "Alzheimer's Starts Earlier for Heavy Drinkers, Smokers" (http:/ / www. reuters. com/ article/ pressRelease/ idUS198346+ 17-Apr-2008+PRN20080417). Reuters. 2008-04-17. . Retrieved 2008-06-27.

[81] Peck, Peggy (2002-07-25). "Smoking Significantly Increases Risk of Alzheimer's Disease Among Those Who Have No GeneticPredisposition" (http:/ / www. docguide. com/ news/ content. nsf/ news/ 8525697700573E1885256C010043BDDC?OpenDocument&c=Smoking Related Disorders& count=10& id=48dde4a73e09a969852568880078c249). . Retrieved 2008-06-27.

[82] Aggarwal NT, Bienias JL, Bennett DA, et al. (2006). "The relation of cigarette smoking to incident Alzheimer's disease in a biracial urbancommunity population". Neuroepidemiology 26 (3): 140–6. doi:10.1159/000091654. PMID 16493200.

[83] Lerche Davis,, Jeanie (2004-03-22). "Smoking Speeds Dementia, Alzheimer's Disease" (http:/ / www. webmd. com/ smoking-cessation/news/ 20040322/ smoking-speeds-dementia-alzheimers-disease). . Retrieved 2008-06-27.

[84] DeNoon, Daniel (2006-08-11). "Nicotine Slows Parkinson's Disease" (http:/ / www. webmd. com/ parkinsons-disease/ news/ 20060811/nicotine-slows-parkinsons-disease). . Retrieved 2009-12-27.

[85] Peck, Peggy (2002-07-25). "Smoking Significantly Increases Risk of Alzheimer's Disease Among Those Who Have No GeneticPredisposition" (http:/ / www. nutraingredients. com/ Research/ More-vitamin-B6-linked-to-lower-Parkinson-s-risk). . Retrieved 2009-12-27.

Nicotine 12

[86] Fox, Maggie (2007-10-24). "Nicotine may ease Parkinson's symptoms: U.S. study" (http:/ / www. reuters. com/ article/idUSN2431402020071024). Reuters. . Retrieved 2009-12-27.

[87] "Nicotine as an antiepileptic agent in ADNFLE: An n-of-one study" (http:/ / www. cnsforum. com/ commenteditem/3c5dccdc-27fb-4b80-9516-ab81e3e4ea6c/ default. aspx). .

[88] de Leon J, Tracy J, McCann E, McGrory A, Diaz FJ (Jul 2002). "Schizophrenia and tobacco smoking: a replication study in another USpsychiatric hospital" (http:/ / linkinghub. elsevier. com/ retrieve/ pii/ S092099640100192X). Schizophr Res. 56 (1-2): 55–65.doi:10.1016/S0920-9964(01)00192-X. PMID 12084420. .

[89] de Leon J, Dadvand M, Canuso C, White AO, Stanilla JK, Simpson GM (Mar 1995). "Schizophrenia and smoking: an epidemiologicalsurvey in a state hospital" (http:/ / ajp. psychiatryonline. org/ cgi/ pmidlookup?view=long& pmid=7864277). Am J Psychiatry 152 (3): 453–5.PMID 7864277. .

[90] Aguilar MC, Gurpegui M, Diaz FJ, de Leon J (Mar 2005). "Nicotine dependence and symptoms in schizophrenia: naturalistic study ofcomplex interactions". Br J Psychiatry 186: 215–21. doi:10.1192/bjp.186.3.215. PMID 15738502.

[91] "Attention-Deficit Hyperactivity Disorder" (http:/ / adam. about. com/ reports/ 000030_1. htm). . Retrieved 21 September 2009.[92] Pasquini M, Garavini A, Biondi M (January 2005). "Nicotine augmentation for refractory obsessive-compulsive disorder. A case report".

Prog. Neuropsychopharmacol. Biol. Psychiatry 29 (1): 157–9. doi:10.1016/j.pnpbp.2004.08.011. PMID 15610960.[93] Lundberg S, Carlsson A, Norfeldt P, Carlsson ML (November 2004). "Nicotine treatment of obsessive-compulsive disorder". Prog.

Neuropsychopharmacol. Biol. Psychiatry 28 (7): 1195–9. doi:10.1016/j.pnpbp.2004.06.014. PMID 15610934.[94] Tizabi Y, Louis VA, Taylor CT, Waxman D, Culver KE, Szechtman H (January 2002). "Effect of nicotine on quinpirole-induced checking

behavior in rats: implications for obsessive-compulsive disorder" (http:/ / linkinghub. elsevier. com/ retrieve/ pii/ S0006322301012070). Biol.Psychiatry 51 (2): 164–71. doi:10.1016/S0006-3223(01)01207-0. PMID 11822995. .

[95] Suemaru K, Kohnomi S, Umeda K, Araki H., K; Kohnomi, S; Umeda, K; Araki, H (2008). "Alpha7 nicotinic receptor agonists havereported to reverse the PPI disruption" (in Japanese). Nihon Shinkei Seishin Yakurigaku Zasshi 28 (3): 121–6. PMID 18646597.

[96] De Luca V, Wong AH, Muller DJ, Wong GW, Tyndale RF, Kennedy JL.(2004). "Evidence of association between smoking and alpha7nicotinic receptor subunit gene in schizophrenia patients" . Neuropsychopharmacology 29(8):1522-6. PMID 15100704

Further reading• Bilkei-Gorzo A, Rácz I, Michel K, Darvas M, Rafael Maldonado López, Zimmer A. (2008). "A common genetic

predisposition to stress sensitivity and stress-induced nicotine craving". Biol. Psychiatry 63 (2): 164–71.doi:10.1016/j.biopsych.2007.02.010. PMID 17570348.

• Willoughby JO, Pope KJ, Eaton V (Sep 2003). "Nicotine as an antiepileptic agent in ADNFLE: an N-of-onestudy" (http:/ / www3. interscience. wiley. com/ resolve/ openurl?genre=article& sid=nlm:pubmed&issn=0013-9580& date=2003& volume=44& issue=9& spage=1238). Epilepsia 44 (9): 1238–40.doi:10.1046/j.1528-1157.2003.11903.x. PMID 12919397.

• Minna JD (Jan 2003). "Nicotine exposure and bronchial epithelial cell nicotinic acetylcholine receptor expressionin the pathogenesis of lung cancer" (http:/ / www. pubmedcentral. nih. gov/ articlerender. fcgi?tool=pmcentrez&artid=151841). J Clin Invest. 111 (1): 31–3. doi:10.1172/JCI17492. PMID 12511585. PMC 151841.

• Fallon JH, Keator DB, Mbogori J, Taylor D, Potkin SG (Mar 2005). "Gender: a major determinant of brainresponse to nicotine" (http:/ / journals. cambridge. org/ action/ displayAbstract?fromPage=online& aid=282494).Int J Neuropsychopharmacol. 8 (1): 17–26. doi:10.1017/S1461145704004730. PMID 15579215.

• West KA, Brognard J, Clark AS, et al. (Jan 2003). "Rapid Akt activation by nicotine and a tobacco carcinogenmodulates the phenotype of normal human airway epithelial cells" (http:/ / www. pubmedcentral. nih. gov/articlerender. fcgi?tool=pmcentrez& artid=151834). J Clin Invest. 111 (1): 81–90. doi:10.1172/JCI16147.PMID 12511591. PMC 151834.

• National Institute on Drug Abuse (http:/ / www. nida. nih. gov/ researchreports/ nicotine/ nicotine. html)• Erowid information on tobacco (http:/ / www. erowid. org/ plants/ tobacco/ tobacco. shtml)

Nicotine 13

External links• Description of nicotine mechanisms (http:/ / www. howstuffworks. com/ nicotine. htm)

Article Sources and Contributors 14

Article Sources and ContributorsNicotine  Source: http://en.wikipedia.org/w/index.php?oldid=400112890  Contributors: 100110100, 24champion, 7pof7, A5, AAA!, ALoopingIcon, AThing, Acdx, Adashiel, Afluent Rider,Agnosticaphid, Alansohn, AlexRochon, AlexanderPico, AlexiusHoratius, All.ya.little.triksters, Alphax, Ambreenkazmi, Anastrophe, AndreNatas, Ansell, Antjben, Anypodetos, Apothecia,Aramgutang, Arcadian, Archfalhwyl, Ariel., AriesPrincess, Atif.t2, AtomicCactus, Atorpey, Atteppo, Avnjay, AxelBoldt, Azazell0, BBird, BL, Badger Drink, Badhotra, BananaFiend, Barek,Bassbonerocks, Bayhemp, Beao, Beefnut, Beetstra, Benjah-bmm27, BennyD, Biglovinb, Bill52270, Binary TSO, BlackAce48, Bmarett, Bmwild, Bobo192, Bogsat, Bongwarrior, BorisTM, Brec,Brendan19, Brianga, BrienIsSexy4, Brockert, Brokenfixer, Bruce39, Bthomas001, Bwmcmaste, C6541, Cacycle, Caliga10, Calvin 1998, CambridgeBayWeather, Can't sleep, clown will eat me,Capricorn42, Card, CardinalDan, Carl.bunderson, Carlosp123, Casforty, Causa sui, Cflm001, Chem-awb, ChemNerd, Chinasaur, Chocolateboy, Chuckysaul, Closedmouth, Cometstyles,Confuzion, Corp1117, Correogsk, Countchoc, CovenantD, CrazyChemGuy, Crazycomputers, Crxssi, Crystallina, Curps, Curtmack, CyberSach, Cyrius, D, D0nj03, DMacks, DPham4, DVD R W,Daevatgl, Dakinijones, Dancter, Daniel5127, Danielkueh, Dark-side-of-moon, Dascripter, DeadEyeArrow, Deany12345, Dekisugi, Delldot, Delta G, Deor, DerHexer, Dfrg.msc, Dirkbb,Discospinster, Dlohcierekim, Dmarquard, DogcatcherDrew, Donarreiskoffer, Download, Dr.K., Dragice, Drphilharmonic, Drumlinedude, Duja, EagleFan, Eastlaw, EddEdmondson, Edgar181,Eequor, EgonWillighagen, EhJJ, El3ctr0nika, ElBenevolente, Electrickoolaid, Elkman, Enviroboy, Epbr123, Eric-Wester, Erikthunder, Everyking, Everything Else Is Taken, Ewlyahoocom,Extremophile, Eye.earth, Falcon8765, Falk Lieder, Fdskjs, Fdssdf, Fireaxe888, Fluidhomefront, Flyguy649, Footballfan190, Forever24ilove, Fragglet, Frahnie, Fremsley, FreplySpang, Fribbler,Fuzzform, Fvasconcellos, Gabbe, Gale Jackson, Gamsarah, Geedubber, Gene Nygaard, Gentgeen, Georgevtucker, Gilliam, Gimboid13, Gobonobo, Gogo Dodo, GooberGobbler, Googie man,GraemeL, Graham king 3, Graham87, Grayshi, GregorB, Gregshortall, Gsmgm, Gustavb, Gwernol, Gyrofrog, Gzuckier, Gökhan, HJ Mitchell, Hadal, HaeB, Happysailor, Harthacnut, Hazillow,Hdt83, Heah, HexaChord, Hirohisat, Hopur52009, Howlandvh, Hqb, II MusLiM HyBRiD II, Ich, IconicMarlboro, Idontknow610, Iladvocate, Iluvmeandbookz, Im.a.lumberjack, Imersion,Ineffable3000, Invalidreality, Iridescent, Irishguy, IronGargoyle, Isangaft220, Ixfd64, J.delanoy, J04n, JFreeman, Ja3en, Jack834834834, Jan eissfeldt, Jauhienij, Javsav, Jaxl, Jaysweet, Jeff G.,Jfdwolff, Jfurr1981, Jh51681, Jijie, Jimmy joe joeseph, JinJian, Jlam4911, John, John Riemann Soong, JohnCD, JohnnyTwain, Jooyoonchung, Jpoelma13, Jrockley, Jsellick100, Jumbuck,Jusdafax, JustAGal, Jusyc, Jv821, K10wnsta, Kansas Sam, Karl Stas, Karl-Henner, Kartano, Keilana, Kerowyn, Khukri, King of Hearts, Kipala, Knowledge Seeker, Korky Day, KorsteN, Kpjas,Kpstewart, Krellis, Kristen1613, KristinaHanspers, Lakers, LarryGilbert, Lavidia, LeilaniLad, Lenoxus, Leptictidium, Leslieterada, Liamdaly620, Liftarn, Linkspamremover, Linnilou7,LittleHow, LittleOldMe, Lofilt, Looie496, Loonymonkey, Luna Santin, MJ94, MPerel, Madhero88, Madman, Marbee, Maria mdv, Mark Zinthefer, Marqueed, MarsRover, Martial75, MartinKozák, Martinor, MattKingston, MauriceReeves, Mav, MaxEspinho, Maximus Rex, Mayooranathan, Mcsven, Mdpatrick, Meand, Medos2, Merope, Merqurial, Metalhead1994, Metalhead94,MichaelJanich, Mikael Häggström, Mike19772007, Mikevick, Milamber au, Mindjuicer, Miniyazz, Mirgrim, Moira harrington, Mona, Mononomic, Montrealais, Mouse Nightshirt, Mouserunner,Mr Bungle, Mr. Stabs, Mr0t1633, Mrmiscellanious, Mstroeck, Muchie11791, Muslim4eva, Muugokszhiion, Mvv1827, Myanw, NYKevin, Nandesuka, Necromankas, Negaluke, Neptunius, NickMichael, NickW557, Niubrad, Nucleophilic, Nutriveg, OAC, Oasisbob, Ohnoitsjamie, Okiefromokla (old), Olivier, Onorem, Owen, Ozzykhan, Paknightpa, Paleorthid, Palica, ParisianBlade,Pascal666, Peabody80, Persephone12, PhilKnight, Philip Trueman, Philliesfan035, Phlegat, Physchim62, Pieter1, Pinkadelica, PinkcessAR, Pjc51, Plasticup, Pogue, Pol098, Pontificalibus, Popole Chien, Proquence, Protious, Pyrzqxgl, Quantpole, RDBrown, RG2, RJFJR, Raburton, Radon210, Ralph pr, Rave23, Razorflame, Rbaselt, Reillyd, Rich Farmbrough, Richard001, Rjwilmsi,Rockjet, Rodhullandemu, RoyBoy, Rumping, SKEpptic, SWAdair, SYSS Mouse, Saadpralard, Sagaciousuk, Sameer94, Sapfan, ScAvenger, Sceptre, Schaefer, Scheinwerfermann,Schmausschmaus, Septegram, Seven of Nine, Sfiller, Shaddack, Shiznick, Silentlight, Silly rabbit, SimonP, SkankBitch, Slakr, Slapazoid, Sliggy, Slyguy, Smalljim, SmartGuy, Smooth O,SmthManly, Snowolf, Someguy1221, Soporaeternus, Spiritia, Stephenb, Stone, Sturm55, Sub40Hz, Suboptimal Username, Surly Dwarf, Susan Mason, SusanLesch, Sverdrup, TUF-KAT,Tarquin, Techman224, Teles, Thaddeusjwhoopie, Thatguyflint, The Anome, The Rambling Man, The Right Honourable, The Thing That Should Not Be, The sock that should not be, Theundertow, Thehelpfulone, Thingg, Thoric, Thorne, TimVickers, TimeLord mbw, Tom X. Tobin, Tom harrison, TomasBat, Torria78, Travis.Thurston, Trimp, Trusilver, Tryptofish, Tsanth,Tschwenn, TwinsMetsFan, UberMan5000, Ucanlookitup, Underwatercolor, Vanderesch, Vanished User 1004, Velvetron, Vicki Rosenzweig, Vidsp48, VigilancePrime, Vipinhari, Vivin,Vrenator, Waninge, Wapcaplet, Wasell, Wavelength, Whiskey in the Jar, Willking1979, Willtron, Wimt, WojPob, Woodyblues, Woohookitty, Xcomradex, Yarnalgo, Yashgaroth, Yath, Yayay,Yidisheryid, Yosri, Zefryl, Zenohockey, Zionicman, Zrenner, Zvi Zig, 1149 ,طبلا يلع نسح anonymous edits

Image Sources, Licenses and Contributorsfile:Nicotine.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Nicotine.svg  License: Public Domain  Contributors: User:Harbinfile:Nicotine-3D-vdW.png  Source: http://en.wikipedia.org/w/index.php?title=File:Nicotine-3D-vdW.png  License: Public Domain  Contributors: Benjah-bmm27, Ies, KemikungenFile:Yes check.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Yes_check.svg  License: Public Domain  Contributors: User:Gmaxwell, User:WarXFile:Side effects of nicotine.png  Source: http://en.wikipedia.org/w/index.php?title=File:Side_effects_of_nicotine.png  License: Public Domain  Contributors: Mikael HäggströmFile:NicotineDopaminergic WP1602.png  Source: http://en.wikipedia.org/w/index.php?title=File:NicotineDopaminergic_WP1602.png  License: Creative Commons Attribution-Sharealike 3.0 Contributors: Kristina HanspersFile:NicotineChromaffinCells WP1603.png  Source: http://en.wikipedia.org/w/index.php?title=File:NicotineChromaffinCells_WP1603.png  License: Creative Commons Attribution-Sharealike3.0  Contributors: Kristina HanspersImage:Nicoderm.JPG  Source: http://en.wikipedia.org/w/index.php?title=File:Nicoderm.JPG  License: Creative Commons Attribution 2.5  Contributors: BorgQueen, RegBarc, 2 anonymousedits

LicenseCreative Commons Attribution-Share Alike 3.0 Unportedhttp:/ / creativecommons. org/ licenses/ by-sa/ 3. 0/