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'''Nicotine''' is an [[alkaloid]] found in the nightshade family of plants (''Solanaceae'') which constitutes approximately 0.6–3.0% of dry weight of [[tobacco]],<ref name="acs">{{cite web |url=http://pubs.acs.org/cgi-bin/abstract.cgi/jafcau/1999/47/i08/abs/jf990089w.html |title=Determination of the Nicotine Content of Various Edible Nightshades (Solanaceae) and Their Products and Estimation of the Associated Dietary Nicotine Intake |format= |work= |accessdate=2008-10-05}}</ref><ref>{{cite web |url=http://dccps.nci.nih.gov/tcrb/monographs/9/m9_3.PDF |title=Smoking and Tobacco Control Monograph No. 9}}</ref> with biosynthesis taking place in the roots, and accumulating in the leaves. It functions as an antiherbivore chemical with particular specificity to insects; therefore nicotine was widely used as an [[insecticide]] in the past, and currently nicotine analogs such as [[imidacloprid]] continue to be widely used.
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'''Nicotine''' is an [[organic compound]], a [[Pyrrolidine|pyrrolidine-like]] [[alkaloid]] found naturally in the nightshade family of plants, such as [[tobacco]] and tomatoes. It constitutes 0.3 to 5% of the tobacco plant by dry weight, with biosynthesis taking place in the roots, and accumulates in the leaves. It is a potent nerve [[poison]] and is included in many [[insecticide|insecticides]]. In lower concentrations, the substance is a [[stimulant]] and is one of the main factors leading to the habit-forming qualities of [[tobacco smoking]]. Nicotine seems to provide both a [[stimulant]] and a [[depressant]] effect, and it is likely that the effect it has at any time is determined by the mood of the user, the environment and the circumstances of use. Studies have suggested that low doses have a [[depressant]] effect, whilst higher doses have [[stimulant]] effect. Nicotine has limited [[carcinogen]]ic effects, inhibiting the body's ability to destroy potentially cancerous cells. However, nicotine does not promote the development of cancer in healthy cells. In addition to the tobacco plant, nicotine is also found in lower quantities in other members of the ''Solanaceae'' (nightshade) family, which includes tomato, potato, eggplant (aubergine), and green pepper. Nicotine alkaloids are also found in the leaves of the [[coca]] plant.
  
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In low concentrations (an average [[cigarette]] yields about 1&nbsp;mg of absorbed nicotine), the substance acts as a [[stimulant]] in [[mammal]]s and is one of the main factors responsible for the dependence-forming properties of [[tobacco smoking]]. According to the American Heart Association, "Nicotine [[addiction]] has historically been one of the hardest addictions to break." The pharmacological and behavioral characteristics that determine tobacco addiction are similar to those that determine addiction to drugs such as [[heroin]] and [[cocaine]].<ref>[http://www.americanheart.org/presenter.jhtml?identifier=4753 American Heart Association] and Nicotine addiction.</ref>
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== History and name ==
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Nicotine 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 their medicinal use. Nicotine was first isolated from the tobacco plant in 1828 by German chemists Posselt & Reimann.<!--might be in: Magazin der Pharmacie 24. 138. 1828-->{{Fact|date=April 2008}} Its chemical [[empirical formula]] was described by Melsens in 1843,<ref>{{cite journal
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| title = Ueber das Nicotin
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| author = Melsens
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| journal = [[Journal für Praktische Chemie]]
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| volume = 32
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| issue = 1
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| pages = 372–377
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| year = 1844
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| url =
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| doi = 10.1002/prac.18440320155}}</ref> its structure was
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discovered by [[Adolf Pinner]] in 1893, and it was first synthesized by A. Pictet and Crepieux in 1904.{{Fact|date=April 2008}}
   
 
== Chemistry ==
  
== Chemistry ==
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Nicotine is a [[hygroscopic]], oily liquid that is miscible with [[water (molecule)|water]] in its [[base_(chemistry)|base]] form. As a [[nitrogenous base]], nicotine forms [[salt]]s with [[acid]]s that are usually solid and water soluble. Nicotine easily penetrates the [[skin]]. As shown by the physical data, [[free base]] nicotine will burn at a temperature below its boiling point, and its vapors will combust at 95 °C in air despite a low vapor pressure. Because of this, most nicotine is burned when a cigarette is smoked; however, enough is inhaled to cause the body to form a powerful addiction.
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Nicotine is a hygroscopic, oily liquid that is miscible with water in its [[base (chemistry)|base]] form. As a [[nitrogenous base]], nicotine forms [[salt]]s with [[acid]]s that are usually solid and water soluble. Nicotine easily penetrates the [[skin]]. As shown by the physical data, [[Freebase (chemistry)|free base]] nicotine will burn at a temperature below its boiling point, and its vapors will combust at 308K (35°C or 95°F) in air despite a low [[vapor pressure]]. Because of this, most of the nicotine is burned when a cigarette is smoked; however, enough is inhaled to provide the desired effects.
   
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==Pharmacology==
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== Effects on the body ==
  
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===Pharmacokinetics===
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In small doses nicotine has a stimulating effect, increasing activity, alertness and memory. Repeat users report a pleasant relaxing effect. It also increases the [[heart]] rate and [[blood pressure]] and reduces the appetite. In large doses it may cause [[vomit]]ing and [[nausea]]. The [[LD50|LD<sub>50</sub>]] of nicotine (that is, the lethal dosage reported to kill 50% of the population) is 50&nbsp;mg/kg for [[rat]]s and 3&nbsp;mg/kg for [[mice]]. 40&ndash;60 mg can be a lethal dosage for adult human beings. This dose makes it an extremely deadly poision. It is more toxic than many other alkaloids such as [[cocaine]], which has a lethal dose of 1000mg.
  
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As nicotine enters the body, it is distributed quickly through the [[blood]]stream and can cross the [[blood-brain barrier]]. On average it takes about seven seconds for the substance to reach the [[brain]] when inhaled. The half life of nicotine in the body is around two hours.<ref>{{cite web |url=http://jpet.aspetjournals.org/cgi/content/citation/221/2/368 |title=Interindividual variability in the metabolism and cardiovascular effects of nicotine in man}}</ref> The amount of nicotine inhaled with tobacco smoke is a fraction of the amount contained in the tobacco leaves. The amount of nicotine absorbed by the body from smoking depends on many factors, including the type of tobacco, whether the smoke is inhaled, and whether a filter is used. For [[Smokeless tobacco]], [[chewing tobacco]], [[dipping tobacco]] and [[Snuff (tobacco)|snuff]], which are held in the mouth between the lip and gum, or taken in the nose, the amount released into the body tends to be much greater than smoked tobacco. Nicotine is [[metabolized]] in the [[liver]] by [[cytochrome P450]] enzymes (mostly [[CYP2A6]], and also by [[CYP2B6]]). A major metabolite is [[cotinine]].
   
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===Pharmacodynamics===
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Repeat users of nicotine very often develop a physical dependency to the chemical. A report released on [[May 16]], 1988, by United States Surgeon General C. Everett Koop stated that the [[addiction|addictive]] properties of nicotine are similar to those of [[heroin]] and [[cocaine]]; although many people do not agree with such a comparison.
 
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Nicotine acts on the [[nicotinic acetylcholine receptor]]s, specifically the [[ganglion type nicotinic receptor]] and one [[CNS type nicotinic receptor]]. The former is present in the [[adrenal medulla]] and elsewhere, while the latter is present in the central nervous system (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.
   
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====In CNS====
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Physical withdrawal symptoms include irritability, headaches, anxiety, cognitive disturbances and sleep disruption. These symptoms peak at around 48&ndash;72 [[hour]]s and generally cease after two to six weeks.
  
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By binding to [[nicotinic acetylcholine receptor]]s, nicotine increases the levels of several [[neurotransmitter]]s - acting as a sort of "volume control". It is thought that the increased levels of [[dopamine]] in the [[reward circuit]]s of the [[brain]] is what is responsible for the [[euphoria]]/[[pleasure]], [[relaxation]] and eventual [[addiction]] caused by nicotine consumption.
   
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Studies have shown that other ingredients in inhaled tobacco smoke (as opposed to pure nicotine) inhibit the production of [[monoamine oxidase]] (MAO),<ref>{{cite journal |author=Fowler JS, Volkow ND, Wang GJ, Pappas N, Logan J, MacGregor R, Alexoff D, Wolf AP, Warner D, Cilento R, Zezulkova I |title=Neuropharmacological actions of cigarette smoke: brain monoamine oxidase B (MAO B) inhibition |journal=Journal of addictive diseases |year=1998 |pmid=9549600}}</ref> an [[enzyme]] responsible for breaking down [[monoamine|monoaminergic neurotransmitters]] in the brain (e.g. dopamine, [[norepinephrine]], [[serotonin]], etc.). The compounds responsible for this effect are beta-carboline alkaloids such as [[harmine]] and [[norharmine]].
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Although the amount of nicotine inhaled with tobacco smoke is quite small (most of the substance is destroyed by the heat), it is still sufficient to cause dependence. The amount of nicotine absorbed by the body from smoking depends on many factors, including the type of tobacco, whether the smoke is inhaled, and whether a filter is used. For [[smokeless tobacco]], [[chewing tobacco]], often called Dip, Snuff, or snus, which is held in the mouth between the lip and gum, the amount released into the body tends to be much greater than smoked tobacco.
 
   
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====In PNS====
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As nicotine enters the body, it quickly gets distributed through the [[blood|bloodstream]] and can cross the [[blood-brain barrier]]. On average it takes about seven seconds for the substance to reach the [[brain]]. It acts on the [[nicotinic acetylcholine receptor]]s. In small concentrations it increases the activity of these receptors, among other things leading to an increased flow of [[adrenaline]], a stimulating [[hormone]]. The release of adrenaline causes an increase in heart rate, blood pressure and respiration, as well as higher [[glucose]] levels in the blood. [[Cotinine]] is a break-down product of nicotine which remains in the blood for up to 48 hours and can be used as an indicator of a person's exposure to smoke. In high doses, nicotine will cause a [[depolarizing block]] of the nicotinic acetylcholine receptor, which is the reason for its [[Nicotine Poisoning|toxicity]] and its effectiveness as an [[insecticide]].
  
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Nicotine also activates the [[sympathetic nervous system]],<ref>[http://www.ncbi.nlm.nih.gov/pubmed/8140174?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVBrief Paper published on PubMed]</ref> acting via [[splanchnic nerves]] to the adrenal medulla, stimulates the release of epinephrine. Acetylcholine released by preganglionic sympathetic fibers of these nerves acts on nicotinic acetylcholine receptors, causing the release of epinephrine (and norepinephrine) into the [[bloodstream]].
   
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====In adrenal medulla====
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In addition, nicotine increases [[dopamine]] levels in the reward circuits of the [[brain]]. Studies have shown that smoking tobacco inhibits [[monoamine oxidase]] (MAO), an [[enzyme]] responsible for breaking down [[monoamine|monoaminergic neurotransmitters]] such as dopamine, in the brain. It is currently believed that nicotine by itself does not inhibit the production of [[monoamine oxidase]] (MAO), but that other ingredients in inhaled tobacco smoke are believed to be responsible for this activity. In this way, it generates feelings of pleasure. This reaction is similar to that caused by [[cocaine]] and [[heroin]] and is another reason people keep smoking: to sustain high dopamine levels.
 
  +
By binding to [[ganglion type nicotinic receptor]]s in the adrenal medulla nicotine increases flow of [[adrenaline]] (epinephrine), a stimulating [[hormone]]. By binding to the receptors, it causes cell depolarization and an influx of [[calcium]] through voltage-gated calcium channels. Calcium triggers the [[exocytosis]] of [[Chromaffin cell|chromaffin granules]] and thus the release of [[epinephrine]] (and norepinephrine) into the [[bloodstream]]. The release of [[epinephrine]] (adrenaline) causes an increase in [[heart rate]], [[blood pressure]] and [[respiration]], as well as higher [[blood glucose]] levels<ref name="Marieb" >{{cite book | author = Elaine N. Marieb and Katja Hoehn | title = Human Anatomy & Physiology (7th Ed.) | publisher = Pearson | pages = ? | year = 2007 | id = ISBN 0-805-35909-5}}</ref>
   
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[[Cotinine]] is a byproduct of the metabolism of nicotine which remains in the blood for up to 48 hours. It can therefore be used as an indicator of a person's exposure to smoke.{{Fact|date=October 2008}}
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It has been noted that the majority of people diagnosed with [[schizophrenia]] smoke tobacco. Estimates for the number of schizophrenics that smoke range from 75% to 90%. It was recently argued that the increased level of smoking in schizophrenia may be due to a desire to [[self-medication|self-medicate]] with nicotine. [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12084420]
  
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[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=7864277] More recent research has found the reverse, that it is a risk factor without long-term benefit, used only for its short term effects. [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15738502]
  
   
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==Psychoactive effects==
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Nicotine and its metabolites are being researched for the treatment of a number of disorders, including [[ADHD]], [[Parkinson's Disease]] and [[Alzheimer's]] Disease.
  
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Nicotine's [[Mood (psychology)|mood]]-altering effects are different by report. First causing a release of [[glucose]] from the liver and [[epinephrine]] (adrenaline) from the [[adrenal medulla]], it causes [[stimulation]]. Users report feelings of [[relaxation]], [[sharpness]], [[calmness]], and [[alertness]].<ref>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</ref> By reducing the [[appetite]] and raising the [[metabolism]], some [[smoker]]s may [[weight loss|lose weight]] as a consequence.<ref>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</ref><ref>[http://uninews.unimelb.edu.au/articleid_1898.html Smokers lose their appetite : Media Releases : News : The University of Melbourne<!-- Bot generated title -->]</ref>
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When a [[cigarette]] is smoked, nicotine-rich blood passes from the [[lung]]s to the [[brain]] within seven seconds and immediately stimulates the release of many chemical messengers including [[acetylcholine]], [[norepinephrine]], [[epinephrine]], [[vasopressin]], [[arginine]], [[dopamine]], [[autocrine agents]], and [[beta-endorphin]]{{Fact|date=August 2008}}. This results in enhanced pleasure{{Fact|date=August 2008}}, decreased [[anxiety]]{{Fact|date=August 2008}}, and a state of alert [[relaxation]]{{Fact|date=August 2008}}. Nicotine appears to enhance [[attention|concentration]]{{Fact|date=August 2008}} and [[learning]]{{Fact|date=August 2008}} due to the increase of [[acetylcholine]]. It also appears to enhance [[alertness]] due to the increases of [[acetylcholine]] and [[norepinephrine]]. [[Arousal]] is increased by the increase of [[norepinephrine]]. [[Pain]] is reduced by the increases of [[acetylcholine]] and [[beta-endorphin]]. [[Anxiety]] is reduced by the increase of [[beta-endorphin]]. Nicotine also sensitises brain reward systems.<ref>Kenny PJ, Markou A. "Nicotine self-administration acutely activates brain reward systems and induces a long-lasting increase in reward sensitivity". However, these effects are an illusion brought about by Nicotine addiction. What appears to be relaxation, is merely the effect of ending the craving for Nicotine. The longer the periods between Nicotine intake, the greater the illusion of pleasure will be.
  +
''Neuropsychopharmacology'' (2006) 31, 1203–1211.</ref> Most cigarettes (in the smoke inhaled) contain 0.1 to 2.8 milligrams of nicotine.<ref>[http://www.erowid.org/chemicals/nicotine/nicotine_dose.shtml Erowid Nicotine Vault : Dosage<!-- Bot generated title -->]</ref>
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Research suggests that, when smokers wish to achieve a stimulating effect, they take short quick puffs, which produce a low level of blood nicotine.<ref>{{cite book
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| last = Einstein
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| first = Stanley
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| authorlink = Stanley Einstein
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| title = Drug and Alcohol Use: Issues and Factors
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| publisher = [[Springer]]
  +
| date = 1989
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| pages = 101–118
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| isbn = 0306413787
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}}</ref> This stimulates [[action potential|nerve transmission]]. When they wish to relax, they take deep puffs, which produce a high level of blood nicotine, which depresses the passage of [[nerve impulses]], producing a mild sedative effect. At low doses, nicotine potently enhances the actions of [[norepinephrine]] and [[dopamine]] in the brain, causing a drug effect typical of those of [[psychostimulants]]. At higher doses, nicotine enhances the effect of [[serotonin]] and [[opiate]] activity, producing a calming, [[analgesic|pain-killing]] effect. Nicotine is unique in comparison to most [[drug]]s, as its profile changes from [[stimulant]] to [[sedative]]/[[pain killer]] in increasing [[dosage]]s and use.
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[[Image:Nicoderm.JPG||thumb|right|A 21 mg patch applied to the left arm]]
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[[Nicotine gum]], usually in 2-mg or 4-mg doses, and [[nicotine patches]] are available, that do not have all the other ingredients in smoked tobacco.
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==Dependence==
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{{see also|Smoking cessation}}
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Modern [[research]] shows that nicotine acts on the brain to produce a number of effects. Specifically, its addictive nature has been found to show that nicotine activates reward pathways—the circuitry within the brain that regulates feelings of pleasure and euphoria.<ref>[http://www.nida.nih.gov/researchreports/nicotine/nicotine2.html NIDA - Research Report Series - Tobacco Addiction - Extent, Impact, Delivery, and Addictiveness<!-- Bot generated title -->]</ref>
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To reduce the health effects of cigarette smoking, the best thing to do is to quit. Public health authorities do not endorse either smoking fewer cigarettes or switching to lower tar and nicotine brands as a satisfactory way of reducing risk.<ref>[http://www.philipmorrisusa.com/en/cms/Products/Cigarettes/Health_Issues/default.aspx Smoking & Health Issues - Philip Morris USA<!-- Bot generated title -->]</ref>
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[[Dopamine]] is one of the key [[neurotransmitters]] actively involved in the brain. Research shows that by increasing the levels of dopamine within the reward circuits in the brain, nicotine acts as a chemical with intense addictive qualities. In many studies it has been shown to be more addictive than [[cocaine]] and [[heroin]], though chronic treatment has an opposite effect on reward thresholds. Like other physically addictive drugs, nicotine causes down-regulation of the production of dopamine and other stimulatory neurotransmitters as the brain attempts to compensate for artificial stimulation. In addition, the sensitivity of nicotinic acetylcholine receptors decreases. To compensate for this compensatory mechanism, the brain in turn upregulates the number of receptors, convoluting its regulatory effects with compensatory mechanisms meant to counteract other compensatory mechanisms. The net effect is an increase in reward pathway sensitivity, opposite of other drugs of abuse such as cocaine and heroin, which reduce reward pathway sensitivity.<ref> [http://www.nature.com/npp/journal/v31/n6/full/1300905a.html] </ref> This neuronal brain alteration persists for months after administration ceases. Due to an increase in reward pathway sensitivity, nicotine withdrawal is relatively mild compared to ethanol or heroin withdrawal.{{Fact|date=November 2007}} Nicotine also has the potential to cause dependence in many animals other than humans. Mice have been administered nicotine and exhibit [[withdrawal]] reactions when its administration is stopped.{{Fact|date=September 2008}}
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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.<!-- Comment --><ref> Nolley E.P. & Kelley B.M. "[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17129706&query_hl=31&itool=pubmed_docsum Adolescent reward system perseveration due to nicotine: Studies with methylphenidate.]," ''Neurotoxicol Teratol.'', 2006 Oct 4</ref>
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==Toxicology==
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The [[LD50|LD<sub>50</sub>]] of nicotine is 50&nbsp;mg/kg for [[rat]]s and 3&nbsp;mg/kg for [[mouse|mice]]. 40–60 mg (0.5-1.0 mg/kg) can be a lethal dosage for adult humans.<ref>{{cite journal
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| author = Okamoto M., Kita T., Okuda H., Tanaka T., Nakashima T.
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| title = Effects of aging on acute toxicity of nicotine in rats
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| journal = Pharmacol Toxicol.
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| year = 1994
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| volume = 75
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| issue = 1
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| pages = 1–6
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| doi =
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}}</ref><ref>[http://www.inchem.org/documents/pims/chemical/nicotine.htm#PartTitle:7.%20TOXICOLOGY IPCS INCHEM]</ref> This designates nicotine as an extremely deadly [[poison]]. It is more toxic than many other alkaloids such as [[cocaine]], which has an LD<sub>50</sub> of 95.1 mg/kg when administered to mice. Spilling a sufficient concentration of nicotine onto the skin can result in poisoning or even death since Nicotine readily passes into the bloodstream from dermal contact.<ref>Lockhart LP (1933). Nicotine poisoning (letter). Br Med J 1:246-247</ref>
   
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The [[carcinogen]]ic properties of nicotine in standalone form, separate from tobacco smoke, have not been evaluated by the [[International Agency for Research on Cancer|IARC]], and it has not been assigned to an official carcinogen group. The currently available literature indicates that nicotine, on its own, does not promote the development of [[cancer]] in healthy tissue and has no [[mutagen]]ic properties. Its [[Teratogenesis|teratogenic]] properties have not yet been adequately researched, and while the likelihood of birth defects caused by nicotine is believed to be very small or nonexistent, nicotine replacement product manufacturers recommend consultation with a physician before using a [[nicotine patch]] or [[nicotine gum]] while pregnant or nursing. However, nicotine and the increased acetylcholinic 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 apoptosis 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. Thus nicotine plays an indirect role in [[carcinogenesis]]. It is also important to note that its addictive properties are often the primary motivating factor for [[tobacco smoking]], contributing to the proliferation of cancer.
  
   
 
== Therapeutic uses ==
  
== Therapeutic uses ==
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The primary therapeutic use of nicotine is in treating nicotine dependence. Controlled levels of nicotine are given to a patient through gums, dermal patches, or nasal sprays in an effort to wean them off of their dependence.
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The primary therapeutic use of nicotine is in treating nicotine dependence in order to eliminate [[smoking]] with its risks 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.
   
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However, in a few situations, smoking has been observed to apparently be of therapeutic value to patients.
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Recent studies have indicated that nicotine can be used to help adults suffering from [[autosomal dominant]] [[frontal lobe epilepsy]]. The same areas that cause seizures in that form of [[epilepsy]] are also responsible for processing nicotine in the brain.
  
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These are often referred to as "Smoker’s Paradoxes".<ref name="cohen">
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{{cite journal
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| last = Cohen
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| first = David J.
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| authorlink =
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| coauthors = Michel Doucet, Donald E. Cutlip, Kalon K.L. Ho, Jeffrey J. Popma, Richard E. Kuntz
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| title = Impact of Smoking on Clinical and Angiographic Restenosis After Percutaneous Coronary Intervention
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| journal = Circulation
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| volume = 104
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| issue =
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| pages = 773
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| date = 2001
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| url = http://www.data-yard.net/34/circulation_2001_104_773.htm
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| doi =
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| id =
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| accessdate = 2006-11-06}}
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</ref> 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 (tobacco residue)|tar]] and other ingredients found in [[tobacco]].
   
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For instance, recent studies suggest that smokers require less frequent repeated [[revascularization]] after [[percutaneous coronary intervention]] (PCI).<ref name="cohen"/> Risk of [[ulcerative colitis]] has been frequently shown to be reduced by smokers on a dose-dependent basis; the effect is eliminated if the individual stops smoking.<ref name="ohcm">Longmore, M., Wilkinson, I., Torok, E. Oxford Handbook of Clinical Medicine (Fifth Edition) p. 232</ref><ref>
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{{cite journal
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| last = Green
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| first = JT
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| authorlink =
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| coauthors = Richardson C, Marshall RW, Rhodes J, McKirdy HC, Thomas GA, Williams GT
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| title = Nitric oxide mediates a therapeutic effect of nicotine in ulcerative colitis
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| journal = Aliment Pharmacol Ther
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| volume = 14
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| issue = 11
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| pages = 1429–1434
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| date = November, 2000
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| url = http://www.data-yard.net/22/ncbi.htm
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| doi =
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| pmid =: 11069313
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| accessdate = 2006-11-06}}</ref>
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Smoking also appears to interfere with development of [[Kaposi's sarcoma]],<ref>
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{{cite news
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| last =
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| first =
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| coauthors =
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| title = Smoking Cuts Risk of Rare Cancer
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| work =
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| pages =
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| publisher = UPI
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| date = March 29, 2001
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| url = http://www.data-yard.net/10b/kaposi.htm
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| accessdate = 2006-11-06}}
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</ref>
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[[breast cancer]] among women carrying the very high risk [[BRCA]] gene,<ref>
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{{cite news
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| last = Recer
  +
| first = Paul
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| coauthors =
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| title = Cigarettes May Have an Up Side
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| work =
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| pages =
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| publisher = AP
  +
| date = May 19, 1998
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| url = http://www.forces.org/evidence/files/brea.htm
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| accessdate = 2006-11-06}}
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</ref>
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[[preeclampsia]],<ref>
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{{cite journal
  +
| last = Lain
  +
| first = Kristine Y.
  +
| authorlink =
  +
| coauthors = Robert W. Powers, Marijane A. Krohn, Roberta B. Ness, William R. Crombleholme,
  +
James M. Roberts
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| title = Urinary cotinine concentration confirms the reduced risk of preeclampsia with tobacco exposure
  +
| journal = American Journal of Obstetrics and Gynecology
  +
| volume = 181
  +
| issue = 5
  +
| pages = 908–14
  +
| date = November 1991
  +
| url = http://www.data-yard.net/2/13/ajog.htm
  +
| doi =
  +
| pmid = : 11422156
  +
| accessdate = 2006-11-06}}
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</ref>
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and [[atopy|atopic disorder]]s such as [[allergic asthma]].<ref>
  +
{{cite journal
  +
| last = Hjern
  +
| first = A
  +
| authorlink =
  +
| coauthors = Hedberg A, Haglund B, Rosen M
  +
| title = Does tobacco smoke prevent atopic disorders? A study of two generations of Swedish residents
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| journal = Clin Exp Allergy
  +
| volume = 31
  +
| issue = 6
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| pages = 908–914
  +
| publisher =
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| date = June 2001
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| url = http://www.data-yard.net/30/asthma.htm
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| doi =
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| pmid = : 11422156
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| accessdate = 2006-11-06}}</ref>
  +
A plausible mechanism of action in these cases may be nicotine acting as an [[Inflammation|anti-inflammatory agent]], and interfering with the inflammation-related disease process, as nicotine has vasoconstrictive effects.<ref name="sciam">{{cite journal | author=Lisa Melton | title=Body Blazes | journal=Scientific American | date=June 2006 | pages=p.24 | url=http://www.sciam.com/article.cfm?chanID=sa006&colID=5&articleID=00080902-A2CF-146C-9D1E83414B7F0000}}</ref>
   
  +
With regard to [[neurology|neurological diseases]], a large body of evidence suggests that the risks of [[Parkinson's disease]] or [[Alzheimer's disease]] might be twice as high for non-smokers than for smokers.<ref>
  +
{{cite journal
  +
| last = Fratiglioni
  +
| first = L
  +
| authorlink =
  +
| coauthors = Wang HX
  +
| title = Smoking and Parkinson's and Alzheimer's disease: review of the epidemiological studies
  +
| journal = Behav Brain Res
  +
| volume = 113
  +
| issue = 1–2
  +
| pages = 117–120
  +
|date=August 2000
  +
| url = http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10942038&dopt=Citation
  +
| doi =
  +
| pmid = : 10942038
  +
| accessdate = 2006-11-06}}
  +
</ref>
  +
Many such papers regarding Alzheimer's disease<ref>
  +
{{cite web
  +
| last = Thompson
  +
| first = Carol
  +
| authorlink =
  +
| coauthors =
  +
| title = Alzheimer's disease is associated with non-smoking
  +
| work =
  +
| date =
  +
| url = http://www.forces.org/evidence/carol/carol16.htm
  +
| format =
  +
| doi =
  +
| accessdate =2006-11-06}}
  +
</ref>
  +
and Parkinson's Disease<ref>
  +
{{cite web
  +
| last = Thompson
  +
| first = Carol
  +
| authorlink =
  +
| coauthors =
  +
| title = Parkinson's disease is associated with non-smoking
  +
| work =
  +
| date =
  +
| url = http://www.forces.org/evidence/carol/carol36.htm
  +
| format =
  +
| doi =
  +
| accessdate =2006-11-06}}
  +
</ref>
  +
have been published. More recent studies find that there's no beneficial link between smoking and Alzheimer's, and in some cases suggest that it actually results in an earlier onset of the disease.<ref>
  +
{{cite web
  +
| last =
  +
| first =
  +
| authorlink =
  +
| coauthors =
  +
| title = Alzheimer's Starts Earlier for Heavy Drinkers, Smokers
  +
| work =
  +
| publisher= Reuters
  +
| date = 2008-17-04
  +
| url = http://www.reuters.com/article/pressRelease/idUS198346+17-Apr-2008+PRN20080417
  +
| format =
  +
| doi =
  +
| accessdate =2008-27-06}}
  +
</ref><ref>
  +
{{cite web
  +
| last = Peck
  +
| first = Peggy
  +
| authorlink =
  +
| coauthors =
  +
| title = Smoking Significantly Increases Risk of Alzheimer's Disease Among Those Who Have No Genetic Predisposition
  +
| work =
  +
| date = 2002-25-07
  +
| url = http://www.docguide.com/news/content.nsf/news/8525697700573E1885256C010043BDDC?OpenDocument&c=Smoking%20Related%20Disorders&count=10&id=48dde4a73e09a969852568880078c249
  +
| accessdate = 2008-27-06}}
  +
</ref><ref>
  +
{{Citation
  +
| last = Aggarwal
  +
| first =Neelum
  +
| authorlink =
  +
| coauthors = Bienias J.L., Bennett, D.A., et al.
  +
| title = The Relation of Cigarette Smoking to Incident Alzheimer's Disease in a Biracial Urban Community Population
  +
| journal = Neuroepidemiology
  +
| volume = 26
  +
| issue = 3
  +
| pages = 140–146
  +
| date =
  +
| url = http://content.karger.com/ProdukteDB/produkte.asp?Doi=91654
  +
| doi = 2006
  +
| accessdate =2008-27-06}}
  +
</ref><ref>
  +
{{cite web
  +
| last = Lerche Davis,
  +
| first =Jeanie
  +
| authorlink =
  +
| title = Smoking Speeds Dementia, Alzheimer's Disease
  +
| date = 2004-22-03
  +
| url = http://www.webmd.com/smoking-cessation/news/20040322/smoking-speeds-dementia-alzheimers-disease
  +
| accessdate = 2008-27-06}}
  +
</ref>
  +
  +
Recent studies have indicated that nicotine can be used to help adults suffering from [[Autosomal dominant nocturnal frontal lobe epilepsy]]. The same areas that cause seizures in that form of [[epilepsy]] are also responsible for processing nicotine in the brain.<ref>{{cite web |url=http://www.cnsforum.com/commenteditem/3c5dccdc-27fb-4b80-9516-ab81e3e4ea6c/default.aspx |title=Nicotine as an antiepileptic agent in ADNFLE: An n-of-one study}}</ref>
  +
  +
It has been noted that the majority of people diagnosed with [[schizophrenia]] smoke tobacco. Estimates for the number of schizophrenics that smoke range from 75% to 90%. It was recently argued that the increased level of smoking in schizophrenia may be due to a desire to [[self-medication|self-medicate]] with nicotine.<ref>[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12084420 Schizophr. Res. 2002]</ref><ref>[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=7864277 Am. J. Psychiatry 1995]</ref> More recent research has found the reverse, that it is a risk factor without long-term benefit, used only for its short term effects.<ref>[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15738502 Br. J. Psychiatry 2005] </ref> 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.
  +
  +
==Research As a Potential Basis for an Antipsychotic Agent==
  +
  +
However, 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 (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. The prepulse inhibition (PPI) is a phenomenon in which a weak prepulse attenuates the response to a subsequent startling stimulus. Alpha7 nicotinic receptor agonists have reported to reverse the PPI disruption."
  +
Department of Clinical Pharmacology and Pharmacy, Neuroscience, Ehime University Graduate School of Medicine, Shitsukawa, Toon 791-0295, Japan. suemaru@m.ehime-u.ac.jp
  +
  +
Additionally, studies have shown that there are genes predisposing people with schizophrenia to nicotine.
  +
"Evidence of association between smoking and alpha7 nicotinic receptor subunit gene in schizophrenia patients" .De Luca V, Wong AH, Muller DJ, Wong GW, Tyndale RF, Kennedy JL.
  +
Neurogenetics Section, Clarke Site, Centre for Addiction and Mental Health, Department of Psychiatry, Toronto, Ontario, Canada.
  +
  +
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.
  +
  +
Nicotine and its metabolites are being researched for the treatment of a number of disorders, including [[ADHD]], [[Schizophrenia]] and [[Parkinson's Disease]].<ref>{{cite web| url=http://www.reutershealth.com/wellconnected/doc30.html |title=Attention-Deficit Hyperactivity Disorder |year=2001 |month=December |work=Reuters Health |publisher=Reuters |archiveurl=http://web.archive.org/web/20060426105219/http://www.reutershealth.com/wellconnected/doc30.html |archivedate=2006-04-26 |quote=Nicotine improves ADHD symptoms. Although such findings should certainly not encourage anyone to smoke, some studies are focusing on benefits of nicotine therapy in adults with ADHD.}}</ref>
  +
  +
The therapeutic use of nicotine as a means of [[appetite]] control and to promote weight loss is anecdotally supported by many ex-smokers who claim to put on weight after quitting. Studies of nicotine in mice<ref>NIH, online at [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=954834&dopt=Abstract]</ref> suggest it may play a role in weight-loss that is independent of appetite and studies involving the elderly suggest that nicotine affects not only weight loss, but also prevents some weight gain.<ref>Cigarette Smoking and Weight Loss in Nursing Home Residents [http://www.priory.com/med/cigsmoking.htm]</ref>
   
 
== See also ==
  
== See also ==
Line 81: Line 351:
 
*[[Nicotine withdrawal]]
  
*[[Nicotine withdrawal]]
 
*[[Psychoactive drug]]
  
*[[Psychoactive drug]]
  +
*[[Smoking cessation]]
 
*[[Tobacco smoking]]
  
*[[Tobacco smoking]]
  +
  +
  +
==References==
  +
{{reflist|colwidth=35em}}
  +
  +
  +
== Further reading ==
  +
* Nicotine Therapy for ADNFLE: [http://www.cnsforum.com/commenteditem/3c5dccdc-27fb-4b80-9516-ab81e3e4ea6c/default.aspx "Nicotine as an antiepileptic agent in ADNFLE: An n-of-one study"]
  +
* Minna, John D.: [http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=151841 "Nicotine exposure and bronchial epithelial cell nicotinic acetylcholine receptor expression in the pathogenesis of lung cancer"]
  +
* [[James Fallon|Fallon, J.H.]], et al. (2005) Gender: A major determinant of brain response to nicotine. International Journal of Neuropharmacology. 8:1–10. [http://journals.cambridge.org/action/displayAbstract?fromPage=online&aid=282494]
  +
* West, Kip A., et al.: [http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=151834 "Rapid Akt activation by nicotine and a tobacco carcinogen modulates the phenotype of normal human airway epithelial cells"]
  +
* [http://www.nida.nih.gov/researchreports/nicotine/nicotine.html National Institute on Drug Abuse]
  +
*Erowid information on tobacco[http://www.erowid.org/plants/tobacco/tobacco.shtml]
   
 
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Latest revision as of 17:38, 7 October 2015

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Nicotine
Chemical name (S)-3-(1-methyl-2-pyrrolidinyl)pyridine
Chemical formula C10H14N2
Molecular mass 162.23 g/mol
Density 1.01 g/ml
Melting point -79 °C
Boiling point 247 °C
Auto-ignition temperature 240 °C
Flash Point 95 °C
Vapour Pressure 0.006 kPa at 25 °C
CAS number 54-11-5
SMILES [H][C@@]2(N(C)CCC2)c1cccnc1
Chemical structure of nicotine3D model of the nicotine molecule
Except where noted otherwise, data are given for
materials in their standard state (at 25 °C, 100 kPa)
Infobox disclaimer and references

Nicotine is an alkaloid found in the nightshade family of plants (Solanaceae) which constitutes approximately 0.6–3.0% of dry weight of tobacco,[1][2] with biosynthesis taking place in the roots, and accumulating in the leaves. It functions as an antiherbivore chemical with particular specificity to insects; therefore nicotine was widely used as an insecticide in the past, and currently nicotine analogs such as imidacloprid continue to be widely used.

In low concentrations (an average cigarette yields about 1 mg of absorbed nicotine), the substance acts as a stimulant in mammals and is one of the main factors responsible for the dependence-forming properties of tobacco smoking. According to the American Heart Association, "Nicotine addiction has historically been one of the hardest addictions to break." The pharmacological and behavioral characteristics that determine tobacco addiction are similar to those that determine addiction to drugs such as heroin and cocaine.[3]

History and name

Nicotine 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 their medicinal use. Nicotine was first isolated from the tobacco plant in 1828 by German chemists Posselt & Reimann.[How to reference and link to summary or text] Its chemical empirical formula was described by Melsens in 1843,[4] its structure was discovered by Adolf Pinner in 1893, and it was first synthesized by A. Pictet and Crepieux in 1904.[How to reference and link to summary or text]

Chemistry

Nicotine is a hygroscopic, oily liquid that is miscible with water in its base form. As a nitrogenous base, nicotine forms salts with acids that are usually solid and water soluble. Nicotine easily penetrates the skin. As shown by the physical data, free base nicotine will burn at a temperature below its boiling point, and its vapors will combust at 308K (35°C or 95°F) in air despite a low vapor pressure. Because of this, most of the nicotine is burned when a cigarette is smoked; however, enough is inhaled to provide the desired effects.

Pharmacology

Pharmacokinetics

As nicotine enters the body, it is distributed quickly through the bloodstream and can cross the blood-brain barrier. On average it takes about seven seconds for the substance to reach the brain when inhaled. The half life of nicotine in the body is around two hours.[5] The amount of nicotine inhaled with tobacco smoke is a fraction of the amount contained in the tobacco leaves. The amount of nicotine absorbed by the body from smoking depends on many factors, including the type of tobacco, whether the smoke is inhaled, and whether a filter is used. For Smokeless tobacco, chewing tobacco, dipping tobacco and snuff, which are held in the mouth between the lip and gum, or taken in the nose, the amount released into the body tends to be much greater than smoked tobacco. Nicotine is metabolized in the liver by cytochrome P450 enzymes (mostly CYP2A6, and also by CYP2B6). A major metabolite is cotinine.

Pharmacodynamics

Nicotine acts on the nicotinic acetylcholine receptors, specifically the ganglion type nicotinic receptor and one CNS type nicotinic receptor. The former is present in the adrenal medulla and elsewhere, while the latter is present in the central nervous system (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 CNS

By binding to nicotinic acetylcholine receptors, nicotine increases the levels of several neurotransmitters - acting as a sort of "volume control". It is thought that the increased levels of dopamine in the reward circuits of the brain is what is responsible for the euphoria/pleasure, relaxation and eventual addiction caused by nicotine consumption.

Studies have shown that other ingredients in inhaled tobacco smoke (as opposed to pure nicotine) inhibit the production of monoamine oxidase (MAO),[6] an enzyme responsible for breaking down monoaminergic neurotransmitters in the brain (e.g. dopamine, norepinephrine, serotonin, etc.). The compounds responsible for this effect are beta-carboline alkaloids such as harmine and norharmine.

In PNS

Nicotine also activates the sympathetic nervous system,[7] acting via splanchnic nerves to the adrenal medulla, stimulates the release of epinephrine. Acetylcholine released by preganglionic sympathetic fibers of these nerves acts on nicotinic acetylcholine receptors, causing the release of epinephrine (and norepinephrine) into the bloodstream.

In adrenal medulla

By binding to ganglion type nicotinic receptors in the adrenal medulla nicotine increases flow of adrenaline (epinephrine), a stimulating hormone. By binding to the receptors, it causes cell depolarization and an influx of calcium through voltage-gated calcium channels. Calcium triggers the exocytosis of chromaffin granules and thus the release of epinephrine (and norepinephrine) into the bloodstream. The release of epinephrine (adrenaline) causes an increase in heart rate, blood pressure and respiration, as well as higher blood glucose levels[8]

Cotinine is a byproduct of the metabolism of nicotine which remains in the blood for up to 48 hours. It can therefore be used as an indicator of a person's exposure to smoke.[How to reference and link to summary or text]

Psychoactive effects

Nicotine's mood-altering effects are different by report. First causing a release of glucose from the liver and epinephrine (adrenaline) from the adrenal medulla, it causes stimulation. Users report feelings of relaxation, sharpness, calmness, and alertness.[9] By reducing the appetite and raising the metabolism, some smokers may lose weight as a consequence.[10][11]

When a cigarette is smoked, nicotine-rich blood passes from the lungs to the brain within seven seconds and immediately stimulates the release of many chemical messengers including acetylcholine, norepinephrine, epinephrine, vasopressin, arginine, dopamine, autocrine agents, and beta-endorphin[How to reference and link to summary or text]. This results in enhanced pleasure[How to reference and link to summary or text], decreased anxiety[How to reference and link to summary or text], and a state of alert relaxation[How to reference and link to summary or text]. Nicotine appears to enhance concentration[How to reference and link to summary or text] and learning[How to reference and link to summary or text] due to the increase of acetylcholine. It also appears to enhance alertness due to the increases of acetylcholine and norepinephrine. Arousal is increased by the increase of norepinephrine. Pain is reduced by the increases of acetylcholine and beta-endorphin. Anxiety is reduced by the increase of beta-endorphin. Nicotine also sensitises brain reward systems.[12] Most cigarettes (in the smoke inhaled) contain 0.1 to 2.8 milligrams of nicotine.[13]

Research suggests that, when smokers wish to achieve a stimulating effect, they take short quick puffs, which produce a low level of blood nicotine.[14] This stimulates nerve transmission. When they wish to relax, they take deep puffs, which produce a high level of blood nicotine, which depresses the passage of nerve impulses, producing a mild sedative effect. At low doses, nicotine potently enhances the actions of norepinephrine and dopamine in the brain, causing a drug effect typical of those of psychostimulants. At higher doses, nicotine enhances the effect of serotonin and opiate activity, producing a calming, pain-killing effect. Nicotine is unique in comparison to most drugs, as its profile changes from stimulant to sedative/pain killer in increasing dosages and use.

File:Nicoderm.JPG

A 21 mg patch applied to the left arm

Nicotine gum, usually in 2-mg or 4-mg doses, and nicotine patches are available, that do not have all the other ingredients in smoked tobacco.

Dependence

See also: Smoking cessation

Modern research shows that nicotine acts on the brain to produce a number of effects. Specifically, its addictive nature has been found to show that nicotine activates reward pathways—the circuitry within the brain that regulates feelings of pleasure and euphoria.[15]

To reduce the health effects of cigarette smoking, the best thing to do is to quit. Public health authorities do not endorse either smoking fewer cigarettes or switching to lower tar and nicotine brands as a satisfactory way of reducing risk.[16]

Dopamine is one of the key neurotransmitters actively involved in the brain. Research shows that by increasing the levels of dopamine within the reward circuits in the brain, nicotine acts as a chemical with intense addictive qualities. In many studies it has been shown to be more addictive than cocaine and heroin, though chronic treatment has an opposite effect on reward thresholds. Like other physically addictive drugs, nicotine causes down-regulation of the production of dopamine and other stimulatory neurotransmitters as the brain attempts to compensate for artificial stimulation. In addition, the sensitivity of nicotinic acetylcholine receptors decreases. To compensate for this compensatory mechanism, the brain in turn upregulates the number of receptors, convoluting its regulatory effects with compensatory mechanisms meant to counteract other compensatory mechanisms. The net effect is an increase in reward pathway sensitivity, opposite of other drugs of abuse such as cocaine and heroin, which reduce reward pathway sensitivity.[17] This neuronal brain alteration persists for months after administration ceases. Due to an increase in reward pathway sensitivity, nicotine withdrawal is relatively mild compared to ethanol or heroin withdrawal.[How to reference and link to summary or text] Nicotine also has the potential to cause dependence in many animals other than humans. Mice have been administered nicotine and exhibit withdrawal reactions when its administration is stopped.[How to reference and link to summary or text]

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.[18]

Toxicology

The LD50 of nicotine is 50 mg/kg for rats and 3 mg/kg for mice. 40–60 mg (0.5-1.0 mg/kg) can be a lethal dosage for adult humans.[19][20] This designates nicotine as an extremely deadly poison. It is more toxic than many other alkaloids such as cocaine, which has an LD50 of 95.1 mg/kg when administered to mice. Spilling a sufficient concentration of nicotine onto the skin can result in poisoning or even death since Nicotine readily passes into the bloodstream from dermal contact.[21]


Therapeutic uses

The primary therapeutic use of nicotine is in treating nicotine dependence in order to eliminate smoking with its risks 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 to patients. These are often referred to as "Smoker’s Paradoxes".[22] 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 and other ingredients found in tobacco.

For instance, recent studies suggest that smokers require less frequent repeated revascularization after percutaneous coronary intervention (PCI).[22] Risk of ulcerative colitis has been frequently shown to be reduced by smokers on a dose-dependent basis; the effect is eliminated if the individual stops smoking.[23][24] Smoking also appears to interfere with development of Kaposi's sarcoma,[25] breast cancer among women carrying the very high risk BRCA gene,[26] preeclampsia,[27] and atopic disorders such as allergic asthma.[28] A plausible mechanism of action in these cases may be nicotine acting as an anti-inflammatory agent, and interfering with the inflammation-related disease process, as nicotine has vasoconstrictive effects.[29]

With regard to neurological diseases, a large body of evidence suggests that the risks of Parkinson's disease or Alzheimer's disease might be twice as high for non-smokers than for smokers.[30] Many such papers regarding Alzheimer's disease[31] and Parkinson's Disease[32] have been published. More recent studies find that there's no beneficial link between smoking and Alzheimer's, and in some cases suggest that it actually results in an earlier onset of the disease.[33][34][35][36]

Recent studies have indicated that nicotine can be used to help adults suffering from Autosomal dominant nocturnal frontal lobe epilepsy. The same areas that cause seizures in that form of epilepsy are also responsible for processing nicotine in the brain.[37]

It has been noted that the majority of people diagnosed with schizophrenia smoke tobacco. Estimates for the number of schizophrenics that smoke range from 75% to 90%. It was recently argued that the increased level of smoking in schizophrenia may be due to a desire to self-medicate with nicotine.[38][39] More recent research has found the reverse, that it is a risk factor without long-term benefit, used only for its short term effects.[40] 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.

Research As a Potential Basis for an Antipsychotic Agent

However, 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 (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. The prepulse inhibition (PPI) is a phenomenon in which a weak prepulse attenuates the response to a subsequent startling stimulus. Alpha7 nicotinic receptor agonists have reported to reverse the PPI disruption." Department of Clinical Pharmacology and Pharmacy, Neuroscience, Ehime University Graduate School of Medicine, Shitsukawa, Toon 791-0295, Japan. suemaru@m.ehime-u.ac.jp

Additionally, studies have shown that there are genes predisposing people with schizophrenia to nicotine. "Evidence of association between smoking and alpha7 nicotinic receptor subunit gene in schizophrenia patients" .De Luca V, Wong AH, Muller DJ, Wong GW, Tyndale RF, Kennedy JL. Neurogenetics Section, Clarke Site, Centre for Addiction and Mental Health, Department of Psychiatry, Toronto, Ontario, Canada.

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.

Nicotine and its metabolites are being researched for the treatment of a number of disorders, including ADHD, Schizophrenia and Parkinson's Disease.[41]

The therapeutic use of nicotine as a means of appetite control and to promote weight loss is anecdotally supported by many ex-smokers who claim to put on weight after quitting. Studies of nicotine in mice[42] suggest it may play a role in weight-loss that is independent of appetite and studies involving the elderly suggest that nicotine affects not only weight loss, but also prevents some weight gain.[43]

See also


References

  1. ↑ Determination of the Nicotine Content of Various Edible Nightshades (Solanaceae) and Their Products and Estimation of the Associated Dietary Nicotine Intake. URL accessed on 2008-10-05.
  2. ↑ Smoking and Tobacco Control Monograph No. 9.
  3. ↑ American Heart Association and Nicotine addiction.
  4. ↑ Melsens (1844). Ueber das Nicotin. Journal für Praktische Chemie 32 (1): 372–377.
  5. ↑ Interindividual variability in the metabolism and cardiovascular effects of nicotine in man.
  6. ↑ Fowler JS, Volkow ND, Wang GJ, Pappas N, Logan J, MacGregor R, Alexoff D, Wolf AP, Warner D, Cilento R, Zezulkova I (1998). Neuropharmacological actions of cigarette smoke: brain monoamine oxidase B (MAO B) inhibition. Journal of addictive diseases.
  7. ↑ Paper published on PubMed
  8. ↑ Elaine N. Marieb and Katja Hoehn (2007). Human Anatomy & Physiology (7th Ed.), ?, Pearson. ISBN 0-805-35909-5.
  9. ↑ 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
  10. ↑ 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
  11. ↑ Smokers lose their appetite : Media Releases : News : The University of Melbourne
  12. ↑ Kenny PJ, Markou A. "Nicotine self-administration acutely activates brain reward systems and induces a long-lasting increase in reward sensitivity". However, these effects are an illusion brought about by Nicotine addiction. What appears to be relaxation, is merely the effect of ending the craving for Nicotine. The longer the periods between Nicotine intake, the greater the illusion of pleasure will be. Neuropsychopharmacology (2006) 31, 1203–1211.
  13. ↑ Erowid Nicotine Vault : Dosage
  14. ↑ Einstein, Stanley (1989). Drug and Alcohol Use: Issues and Factors, 101–118, Springer.
  15. ↑ NIDA - Research Report Series - Tobacco Addiction - Extent, Impact, Delivery, and Addictiveness
  16. ↑ Smoking & Health Issues - Philip Morris USA
  17. ↑ [1]
  18. ↑ Nolley E.P. & Kelley B.M. "Adolescent reward system perseveration due to nicotine: Studies with methylphenidate.," Neurotoxicol Teratol., 2006 Oct 4
  19. ↑ Okamoto M., Kita T., Okuda H., Tanaka T., Nakashima T. (1994). Effects of aging on acute toxicity of nicotine in rats. Pharmacol Toxicol. 75 (1): 1–6.
  20. ↑ IPCS INCHEM
  21. ↑ Lockhart LP (1933). Nicotine poisoning (letter). Br Med J 1:246-247
  22. ↑ 22.0 22.1 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. Circulation 104: 773.
  23. ↑ Longmore, M., Wilkinson, I., Torok, E. Oxford Handbook of Clinical Medicine (Fifth Edition) p. 232
  24. ↑ Green, JT, Richardson C, Marshall RW, Rhodes J, McKirdy HC, Thomas GA, Williams GT (November, 2000). Nitric oxide mediates a therapeutic effect of nicotine in ulcerative colitis. Aliment Pharmacol Ther 14 (11): 1429–1434.
  25. ↑ includeonly>"Smoking Cuts Risk of Rare Cancer", UPI, March 29, 2001. Retrieved on 2006-11-06.
  26. ↑ includeonly>Recer, Paul. "Cigarettes May Have an Up Side", AP, May 19, 1998. Retrieved on 2006-11-06.
  27. ↑ Lain, Kristine Y., Robert W. Powers, Marijane A. Krohn, Roberta B. Ness, William R. Crombleholme, James M. Roberts (November 1991). Urinary cotinine concentration confirms the reduced risk of preeclampsia with tobacco exposure. American Journal of Obstetrics and Gynecology 181 (5): 908–14.
  28. ↑ Hjern, A, Hedberg A, Haglund B, Rosen M (June 2001). Does tobacco smoke prevent atopic disorders? A study of two generations of Swedish residents. Clin Exp Allergy 31 (6): 908–914.
  29. ↑ Lisa Melton (June 2006). Body Blazes. Scientific American: p.24.
  30. ↑ Fratiglioni, L, Wang HX (August 2000). Smoking and Parkinson's and Alzheimer's disease: review of the epidemiological studies. Behav Brain Res 113 (1–2): 117–120.
  31. ↑ Thompson, Carol Alzheimer's disease is associated with non-smoking. URL accessed on 2006-11-06.
  32. ↑ Thompson, Carol Parkinson's disease is associated with non-smoking. URL accessed on 2006-11-06.
  33. ↑ Alzheimer's Starts Earlier for Heavy Drinkers, Smokers. Reuters. URL accessed on 2008-27-06.
  34. ↑ Peck, Peggy Smoking Significantly Increases Risk of Alzheimer's Disease Among Those Who Have No Genetic Predisposition. URL accessed on 2008-27-06.
  35. ↑ Aggarwal, Neelum; Bienias J.L., Bennett, D.A., et al., "The Relation of Cigarette Smoking to Incident Alzheimer's Disease in a Biracial Urban Community Population", Neuroepidemiology 26 (3): 140–146, doi:2006, http://content.karger.com/ProdukteDB/produkte.asp?Doi=91654, retrieved on 2008-27-06 
  36. ↑ Lerche Davis,, Jeanie Smoking Speeds Dementia, Alzheimer's Disease. URL accessed on 2008-27-06.
  37. ↑ Nicotine as an antiepileptic agent in ADNFLE: An n-of-one study.
  38. ↑ Schizophr. Res. 2002
  39. ↑ Am. J. Psychiatry 1995
  40. ↑ Br. J. Psychiatry 2005
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  42. ↑ NIH, online at [2]
  43. ↑ Cigarette Smoking and Weight Loss in Nursing Home Residents [3]


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