関: Cigarette smoking

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an alkaloid poison that occurs in tobacco; used in medicine and as an insecticide
toxic condition caused by the ingestion or inhalation of large amounts of nicotine

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ニコチン(たばこに含まれる無色の毒物)

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/12/19 22:29:27」(JST)

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Nicotine is a potent parasympathomimetic alkaloid found in the nightshade family of plants (Solanaceae) and is a stimulant drug. Nicotine is a nicotinic acetylcholine receptor (nAChR) agonist,^[4]^[5] except at nAChRα9 and nAChRα10 where it acts as an antagonist.^[4] It is made in the roots of and accumulates in the leaves of the nightshade family of plants. Nicotine is found in the leaves of Nicotiana rustica in amounts of 2–14%, the tobacco plant Nicotiana tabacum, Duboisia hopwoodii and Asclepias syriaca.^[6]

It constitutes approximately 0.6–3.0% of the dry weight of tobacco^[7] and is present in the range of 2–7 µg/kg of various edible plants.^[8] It functions as an antiherbivore chemical; consequently, nicotine was widely used as an insecticide in the past^[9]^[10] and neonicotinoids such as imidacloprid are currently widely used.

Nicotine is addictive.^[11] In lesser doses (an average cigarette yields about 2 mg of absorbed nicotine), the substance acts as a stimulant in mammals, while high amounts (50–100 mg) can be harmful.^[12]^[13]^[14] This stimulant effect is a contributing factor to the addictive properties of tobacco smoking. Nicotine's addictive nature includes psychoactive effects, drug-reinforced behavior, compulsive use, relapse after abstinence, physical dependence and tolerance.^[15]

Nicotine is associated with cardiovascular disease, potential birth defects, and poisoning.^[16] In vitro studies have associated it with cancer, but carcinogenicity has not been demonstrated in vivo.^[16] There is inadequate research to demonstrate that nicotine is associated with cancer in humans.^[17] Medicinal nicotine as a tool to quitting smoking has a good safety history.^[18] During pregnancy, there are risks to child later in life for type 2 diabetes, obesity, hypertension, neurobehavioral defects, respiratory dysfunction, and infertility.^[18] Nicotine is regarded as a potentially lethal poison.^[19] It is unlikely that a person would overdose on nicotine through smoking alone.^[20] The use of electronic cigarettes, which are designed to be refilled with nicotine-containing e-liquid, has renewed interest in nicotine overdoses, especially with regard to the possibility of young children ingesting the liquids.^[21]

1 Psychoactive effects
2 Uses
- 2.1 Medical
- 2.2 Enhancing performance
- 2.3 Recreational
3 Adverse effects
- 3.1 Vascular system
- 3.2 Carcinogen
- 3.3 Fetal development
- 3.4 Reinforcement disorders
4 Overdose
5 Pharmacology
- 5.1 Pharmacodynamics
  - 5.1.1 Central nervous system
  - 5.1.2 Sympathetic nervous system
  - 5.1.3 Adrenal medulla
- 5.2 Pharmacokinetics
6 Physical and chemical properties
- 6.1 Occurrence and biosynthesis
- 6.2 Measurement in body fluids
7 History
- 7.1 Chemical identification
8 Society and culture
9 Research
10 See also
11 References
12 Further reading
13 External links

Psychoactive effects

Nicotine's mood-altering effects are different by report: in particular it is both a stimulant and a relaxant.^[22] 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.^[23] Like any stimulant, it may very rarely cause the often uncomfortable akathisia. By reducing the appetite and raising the metabolism, some smokers may lose weight as a consequence.^[24]^[25]

When a cigarette is smoked, nicotine-rich blood passes from the lungs to the brain within seven seconds and immediately stimulates nicotinic acetylcholine receptors; this indirectly promotes the release of many chemical messengers such as acetylcholine, norepinephrine, epinephrine, arginine vasopressin, serotonin, dopamine, and beta-endorphin in parts of the brain.^[26]^[27] Nicotine also extends the duration of positive effects of dopamine and increases sensitivity in brain reward systems.^[28]^[29] Most cigarettes contain 1–3 milligrams of inhalable nicotine.^[30] Studies suggest that when smokers wish to achieve a stimulating effect, they take short quick puffs, which produce a low level of blood nicotine.^[31]

Nicotine is unique in comparison to most drugs, as its profile changes from stimulant to sedative with increasing dosages and use, a phenomenon described by Paul Nesbitt in his doctoral dissertation^[32] and subsequently referred to as "Nesbitt's paradox."^[33]

Uses

Medical

A 21 mg patch applied to the left arm. The Cochrane Collaboration finds that nicotine replacement therapy increases a quitter's chance of success by 50% to 70%.^[34]

The primary therapeutic use of nicotine is in treating nicotine dependence in order to eliminate smoking with the damage it does to health. Controlled levels of nicotine are given to patients through gums, dermal patches, lozenges, electronic/substitute cigarettes or nasal sprays in an effort to wean them off their dependence (though electronic cigarettes are only able to be licensed as medical products in a few jurisdictions, such as the European Union).

Studies have found that these therapies increase the chance of success of quitting by 50 to 70%,^[34] though reductions in the population as a whole have not been demonstrated.^[35]

Enhancing performance

Nicotine is frequently used for its performance-enhancing effects on cognition, alertness and focus.^[36]^[37] It is second only to caffeine as the most widely used nootropic in the world.^{[citation needed]}

Recreational

Nicotine is commonly consumed as a recreational drug for its stimulant effects.^[38] Recreational nicotine products include chewing tobacco, cigars, cigarettes, e-cigarettes, snuff, and snus.

Adverse effects

Vascular system

Nicotine is associated with cardiovascular disease.^[16] Nicotine increases blood pressure and heart rate.^[39] Nicotine can also induce potentially atherogenic genes in human coronary artery endothelial cells.^[40] Microvascular injury can result through its action on nicotinic acetylcholine receptors (nAChRs).^[41] Nicotine elevates serum cholesterol levels, supports clot formation, and aids in plaque formation by enhancing vascular smooth muscle.^[16]

Carcinogen

Possible side effects of nicotine.^[42]

Although there is insufficient evidence to classify nicotine as a carcinogen, there is an ongoing debate about whether it functions as a tumor promoter.^[43] In vitro studies have associated it with cancer, but carcinogenicity has not been demonstrated in vivo.^[16] There is inadequate research to demonstrate that nicotine is associated with cancer in humans, but there is evidence indicating possible oral, esophageal, or pancreatic cancer risks.^[17] Nicotine replacement therapy has not been shown to be associated with cancer in the real world.^[16] Medicinal nicotine as a tool to quitting smoking has a good safety history.^[18]

While no epidemiological evidence directly supports the notion that nicotine acts as a carcinogen in the formation of human cancer, research has identified nicotine's indirect involvement in cancer formation in animal models and cell cultures.^[44]^[45]^[46] Nicotine increases cholinergic signalling and adrenergic signalling in the case of colon cancer,^[47] thereby impeding apoptosis (programmed cell death), promoting tumor growth, and activating growth factors and cellular mitogenic factors such as 5-lipoxygenase (5-LOX), and epidermal growth factor (EGF). Nicotine also promotes cancer growth by stimulating angiogenesis and neovascularization.^[48]^[49] In one study, nicotine administered to mice with tumors caused increases in tumor size (twofold increase), metastasis (nine-fold increase), and tumor recurrence (threefold increase).^[50] N-Nitrosonornicotine (NNN), classified by the International Agency for Research on Cancer (IARC) as a Group 1 carcinogen, has been shown to form in vitro in amounts less than 0.01% the active substance, when human saliva is incubated with nornicotine.^[51] The IARC has not evaluated pure nicotine or assigned it to an official carcinogenic classification.

Fetal development

In pregnancy, a 2013 review noted that "nicotine is only 1 of more than 4000 compounds to which the fetus is exposed through maternal smoking. Of these, ∼30 compounds have been associated with adverse health outcomes. Although the exact mechanisms by which nicotine produces adverse fetal effects are unknown, it is likely that hypoxia, undernourishment of the fetus, and direct vasoconstrictor effects on the placental and umbilical vessels all play a role. Nicotine also has been shown to have significant deleterious effects on brain development, including alterations in brain metabolism and neurotransmitter systems and abnormal brain development." It also notes that "abnormalities of newborn neurobehavior, including impaired orientation and autonomic regulation and abnormalities of muscle tone, have been identified in a number of prenatal nicotine exposure studies" and that there is weak data associating fetal nicotine exposure with newborn facial clefts, and that there is no good evidence for newborns suffering nicotine withdrawal from fetal exposure to nicotine.^[52]

Effective April 1, 1990, the Office of Environmental Health Hazard Assessment (OEHHA) of the California Environmental Protection Agency added nicotine to the list of chemicals known to cause developmental toxicity.^[53]

Risks to child later in life via nicotine exposure during pregnancy include type 2 diabetes, obesity, hypertension, neurobehavioral defects, respiratory dysfunction, and infertility.^[18] Nicotine crosses the placenta and is found in the breast milk of mothers who smoke as well as mothers who inhale passive smoke.^[11]

Reinforcement disorders

Nicotine dependence involves aspects of both psychological dependence and physical dependence, since discontinuation of extended use has been shown to produce both affective (e.g., anxiety, irritability, craving, anhedonia) and somatic (mild motor dysfunctions such as tremor) withdrawal symptoms.^[1] Withdrawal symptoms can persist for several weeks.^[54] Nicotine has clinically significant cognitive-enhancing effects at low doses, particularly in fine motor skills, attention, and memory. These beneficial cognitive effects may play a role in the maintenance of tobacco dependence.^[54]

Nicotine is addictive.^[11]^[55]^[56] Nicotine activates the mesolimbic pathway and induces long-term ΔFosB expression in the nucleus accumbens when inhaled or injected at sufficiently high doses, but not necessarily when ingested.^[55]^[56]^[57] Consequently, repeated daily exposure (possibly excluding oral route) to nicotine can result in accumbal ΔFosB overexpression, in turn causing nicotine addiction.^[55]^[56]

Overdose

Nicotine is regarded as a potentially lethal poison.^[19] The LD₅₀ of nicotine is 50 mg/kg for rats and 3 mg/kg for mice. 30–60 mg (0.5–1.0 mg/kg) can be a lethal dosage for adult humans.^[12]^[58] However the widely used human LD₅₀ estimate of 0.5–1.0 mg/kg was questioned in a 2013 review, in light of several documented cases of humans surviving much higher doses; the 2013 review suggests that the lower limit causing fatal outcomes is 500–1000 mg of ingested nicotine, corresponding to 6.5–13 mg/kg orally.^[14] Nevertheless, nicotine has a relatively high toxicity in comparison to many other alkaloids such as caffeine, which has an LD₅₀ of 127 mg/kg when administered to mice.^[59]

Today nicotine is less commonly used in agricultural insecticides, which was a main source of poisoning. More recent cases of poisoning typically appear to be in the form of Green Tobacco Sickness or due to accidental ingestion of tobacco or tobacco products or ingestion of nicotine containing plants.^[60]^[61]^[62] People who harvest or cultivate tobacco may experience Green Tobacco Sickness (GTS), a type of nicotine poisoning caused by dermal exposure to wet tobacco leaves. This occurs most commonly in young, inexperienced tobacco harvesters who do not consume tobacco.^[60]^[63] People can be exposed to nicotine in the workplace by breathing it in, skin absorption, swallowing it, or eye contact. The Occupational Safety and Health Administration (OSHA) has set the legal limit (permissible exposure limit) for nicotine exposure in the workplace as 0.5 mg/m³ skin exposure over an 8-hour workday. The National Institute for Occupational Safety and Health (NIOSH) has set a recommended exposure limit (REL) of 0.5 mg/m³ skin exposure over an 8-hour workday. At levels of 5 mg/m³, nicotine is immediately dangerous to life and health.^[64]

It is unlikely that a person would overdose on nicotine through smoking alone, the US Food and Drug Administration (FDA) states in 2013 "There are no significant safety concerns associated with using more than one OTC NRT at the same time, or using an OTC NRT at the same time as another nicotine-containing product—including a cigarette."^[20]

The recent rise in the use of electronic cigarettes, many forms of which are designed to be refilled with nicotine-containing e-liquid supplied in small plastic bottles, has renewed interest in nicotine overdoses, especially in the possibility of young children ingesting the liquids.^[21] A 2015 report on e-cigarettes by Public Health England noted an "unconfirmed newspaper report of a fatal poisoning of a two-year old child" and two published case reports of children of similar age who had recovered after ingesting e-liquid and vomiting.^[21] They also noted case reports of suicides by nicotine.^[21] Where adults drank liquid containing up to 1,500 mg of nicotine they recovered (helped by vomiting), but an ingestion apparently of about 10,000 mg was fatal, as was an injection.^[21] They commented that "Serious nicotine poisoning seems normally prevented by the fact that relatively low doses of nicotine cause nausea and vomiting, which stops users from further intake."^[21]

Pharmacology

Pharmacodynamics

Central nervous system

Effect of nicotine on dopaminergic neurons.

By binding to nicotinic acetylcholine receptors, nicotine increases the levels of several neurotransmitters – acting as a sort of "volume control." It is thought that increased levels of dopamine in the reward circuits of the brain are a major contributor to the apparent euphoria and relaxation, and addiction caused by nicotine consumption. Nicotine-induced dopamine release occurs via the cholinergic–dopaminergic reward link, which is mediated by the neuropeptide ghrelin in the ventral tegmentum.^[65] Nicotine has a higher affinity for acetylcholine receptors in the brain than those in skeletal muscle, though at toxic doses it can induce contractions and respiratory paralysis.^[66] Nicotine's selectivity is thought to be due to a particular amino acid difference on these receptor subtypes.^[67]

Chronic nicotine use inhibits class I and II histone deacetylases in the striatum; this effect plays a role in addiction.^[68]^[69]

Sympathetic nervous system

Nicotine also activates the sympathetic nervous system,^[70] acting via splanchnic nerves to the adrenal medulla, stimulating the release of epinephrine. Acetylcholine released by preganglionic sympathetic fibers of these nerves acts on nicotinic acetylcholine receptors, causing the release of epinephrine (and noradrenaline) into the bloodstream. Nicotine also has an affinity for melanin-containing tissues due to its precursor function in melanin synthesis or due to the irreversible binding of melanin and nicotine. This has been suggested to underlie the increased nicotine dependence and lower smoking cessation rates in darker pigmented individuals. However, further research is warranted before a definite conclusive link can be inferred.^[71]

Adrenal medulla

Effect of nicotine on chromaffin cells.

By binding to ganglion type nicotinic receptors in the adrenal medulla, nicotine increases flow of adrenaline (epinephrine), a stimulating hormone and neurotransmitter. 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.^[72]

Nicotine has a half-life of 1–2 hours. Cotinine is an active metabolite of nicotine that remains in the blood for 18–20 hours, making it easier to analyze due to its longer half-life.^[73]

Pharmacokinetics

As nicotine enters the body, it is distributed quickly through the bloodstream and crosses the blood–brain barrier reaching the brain within 10–20 seconds after inhalation.^[74] The elimination half-life of nicotine in the body is around two hours.^[75]

The amount of nicotine absorbed by the body from smoking can depend on many factors, including the types of tobacco, whether the smoke is inhaled, and whether a filter is used. However, it has been found that the nicotine yield of individual products has only a small effect (4.4%) on the blood concentration of nicotine,^[76] suggesting "the assumed health advantage of switching to lower-tar and lower-nicotine cigarettes may be largely offset by the tendency of smokers to compensate by increasing inhalation".

Nicotine acts on nicotinic acetylcholine receptors, specifically the α3β4 ganglion type nicotinic receptor, present in the autonomic ganglia and adrenal medulla, and a central nervous system (CNS) α4β2 nicotinic receptor. In small concentrations, nicotine increases the activity of these cholinergic receptors and indirectly on a variety of other neurotransmitters such as dopamine.

Nicotine is metabolized in the liver by cytochrome P450 enzymes (mostly CYP2A6, and also by CYP2B6). A major metabolite is cotinine. Other primary metabolites include nicotine N'-oxide, nornicotine, nicotine isomethonium ion, 2-hydroxynicotine and nicotine glucuronide.^[77] Under some conditions, other substances may be formed such as myosmine.^[78]

Glucuronidation and oxidative metabolism of nicotine to cotinine are both inhibited by menthol, an additive to mentholated cigarettes, thus increasing the half-life of nicotine in vivo.^[79]

Physical and chemical properties

Nicotine is a hygroscopic, colorless^{[citation needed]} oily liquid that is readily soluble in alcohol, ether or light petroleum. It is miscible with water in its base form between 60 °C and 210 °C. As a nitrogenous base, nicotine forms salts with acids that are usually solid and water-soluble. Its flash point is 95 °C and its auto-ignition temperature is 244 °C.^[81]

Nicotine is readily volatile (vapor pressure 5.5 ㎩ at 25 ℃) and dibasic (K_b1 = 1×10⁻⁶, K_b2 = 1×10⁻¹¹).^[6]

Nicotine is optically active, having two enantiomeric forms. The naturally occurring form of nicotine is levorotatory with a specific rotation of [α]_D = –166.4° ((−)-nicotine). The dextrorotatory form, (+)-nicotine is physiologically less active than (–)-nicotine. (−)-nicotine is more toxic than (+)-nicotine.^[82] The salts of (+)-nicotine are usually dextrorotatory. The hydrochloride and sulphate salts become optically inactive if heated in a closed vessel above 180 °C.^[83]

On exposure to ultraviolet light or various oxidizing agents, nicotine is converted to nicotine oxide, nicotinic acid (vitamin B3), and methylamine.^[83]

Occurrence and biosynthesis

Nicotine biosynthesis

Nicotine is a natural product of tobacco, occurring in the leaves in a range of 0.5 to 7.5% depending on variety.^[84] Nicotine also naturally occurs in smaller amounts in plants from the family Solanaceae (such as potatoes, tomatoes, and eggplant).^[85]

The biosynthetic pathway of nicotine involves a coupling reaction between the two cyclic structures that compose nicotine. Metabolic studies show that the pyridine ring of nicotine is derived from niacin (nicotinic acid) while the pyrrolidone is derived from N-methyl-Δ¹-pyrrollidium cation.^[86]^[87] Biosynthesis of the two component structures proceeds via two independent syntheses, the NAD pathway for niacin and the tropane pathway for N-methyl-Δ¹-pyrrollidium cation.

The NAD pathway in the genus nicotiana begins with the oxidation of aspartic acid into α-imino succinate by aspartate oxidase (AO). This is followed by a condensation with glyceraldehyde-3-phosphate and a cyclization catalyzed by quinolinate synthase (QS) to give quinolinic acid. Quinolinic acid then reacts with phosphoriboxyl pyrophosphate catalyzed by quinolinic acid phosphoribosyl transferase (QPT) to form niacin mononucleotide (NaMN). The reaction now proceeds via the NAD salvage cycle to produce niacin via the conversion of nicotinamide by the enzyme nicotinamidase.^{[citation needed]}

The N-methyl-Δ¹-pyrrollidium cation used in the synthesis of nicotine is an intermediate in the synthesis of tropane-derived alkaloids. Biosynthesis begins with decarboxylation of ornithine by ornithine decarboxylase (ODC) to produce putrescine. Putrescine is then converted into N-methyl putrescine via methylation by SAM catalyzed by putrescine N-methyltransferase (PMT). N-methylputrescine then undergoes deamination into 4-methylaminobutanal by the N-methylputrescine oxidase (MPO) enzyme, 4-methylaminobutanal then spontaneously cyclize into N-methyl-Δ¹-pyrrollidium cation.^{[citation needed]}

The final step in the synthesis of nicotine is the coupling between N-methyl-Δ¹-pyrrollidium cation and niacin. Although studies conclude some form of coupling between the two component structures, the definite process and mechanism remains undetermined. The current agreed theory involves the conversion of niacin into 2,5-dihydropyridine through 3,6-dihydronicotinic acid. The 2,5-dihydropyridine intermediate would then react with N-methyl-Δ¹-pyrrollidium cation to form enantiomerically pure (–)-nicotine.^[88]

Measurement in body fluids

Nicotine can be quantified in blood, plasma, or urine to confirm a diagnosis of poisoning or to facilitate a medicolegal death investigation. Urinary or salivary cotinine concentrations are frequently measured for the purposes of pre-employment and health insurance medical screening programs. Careful interpretation of results is important, since passive exposure to cigarette smoke can result in significant accumulation of nicotine, followed by the appearance of its metabolites in various body fluids.^[89]^[90] Nicotine use is not regulated in competitive sports programs.^[91]

History

Nicotine is named after the tobacco plant Nicotiana tabacum, which in turn is named after the French ambassador in Portugal, Jean Nicot de Villemain, who sent tobacco and seeds to Paris in 1560, presented to the French King,^[92] and who promoted their medicinal use. The tobacco and its seeds were brought to Ambassador Nicot from Brazil by Luis de Gois, a Portuguese colonist in São Paulo.^{[citation needed]}Smoking was believed to protect against illness, particularly the plague.^[92]

Tobacco was introduced to Europe in 1559, and by the late 17th century, it was used not only for smoking but also as an insecticide. After World War II, over 2,500 tons of nicotine insecticide were used worldwide, but by the 1980s the use of nicotine insecticide had declined below 200 tons. This was due to the availability of other insecticides that are cheaper and less harmful to mammals.^[10]

Currently, nicotine, even in the form of tobacco dust, is prohibited as a pesticide for organic farming in the United States.^[93]^[94]

In 2008, the EPA received a request, from the registrant, to cancel the registration of the last nicotine pesticide registered in the United States.^[95] This request was granted, and since 1 January 2014, this pesticide has not been available for sale.^[96]

Chemical identification

Nicotine was first isolated from the tobacco plant in 1828 by physician Wilhelm Heinrich Posselt and chemist Karl Ludwig Reimann of Germany, who considered it a poison.^[97]^[98] Its chemical empirical formula was described by Melsens in 1843,^[99] its structure was discovered by Adolf Pinner and Richard Wolffenstein in 1893,^[100]^[101]^[102]^{[clarification needed]} and it was first synthesized by Amé Pictet and A. Rotschy in 1904.^[103]

Society and culture

The nicotine content of popular American-brand cigarettes has slowly increased over the years, and one study found that there was an average increase of 1.78% per year between the years of 1998 and 2005.^[104]

Research

While acute/initial nicotine intake causes activation of nicotine receptors, chronic low doses of nicotine use leads to desensitisation of nicotine receptors (due to the development of tolerance) and results in an antidepressant effect, with research showing low dose nicotine patches being an effective treatment of major depressive disorder in non-smokers.^[105] However, the original research concluded that: "Nicotine patches produced short-term improvement of depression with minor side effects. Because of nicotine's high risk to health, nicotine patches are not recommended for clinical use in depression."^[106]

Though tobacco smoking is associated with an increased risk of Alzheimer's disease,^[107] there is evidence that nicotine itself has the potential to prevent and treat Alzheimer's disease.^[108]

Research into nicotine's most predominant metabolite, cotinine, suggests that some, if not most, of nicotine's psychoactive effects may actually be mediated by complex interactions with cotinine, or perhaps even by cotinine alone rather than strictly by nicotine as conventionally thought.^[109]^[110]

Little research is available in humans but animal research suggests there is potential benefit from nicotine in Parkinson's disease.^[111]

There is tentative evidence that nicotinamides may improve depression.^[112]

References

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Conclusions
ΔFosB is an essential transcription factor implicated in the molecular and behavioral pathways of addiction following repeated drug exposure. The formation of ΔFosB in multiple brain regions, and the molecular pathway leading to the formation of AP-1 complexes is well understood. The establishment of a functional purpose for ΔFosB has allowed further determination as to some of the key aspects of its molecular cascades, involving effectors such as GluR2 (87,88), Cdk5 (93) and NFkB (100). Moreover, many of these molecular changes identified are now directly linked to the structural, physiological and behavioral changes observed following chronic drug exposure (60,95,97,102). New frontiers of research investigating the molecular roles of ΔFosB have been opened by epigenetic studies, and recent advances have illustrated the role of ΔFosB acting on DNA and histones, truly as a ‘‘molecular switch’’ (34). As a consequence of our improved understanding of ΔFosB in addiction, it is possible to evaluate the addictive potential of current medications (119), as well as use it as a biomarker for assessing the efficacy of therapeutic interventions (121,122,124).
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External links

Description of nicotine mechanisms
Erowid Nicotine Vault : Nicotine Material Safety Data Sheet
Thomas, Gareth AO; Rhodes, John; Ingram, John R (2005). "Mechanisms of Disease: Nicotine—a review of its actions in the context of gastrointestinal disease". Nature Clinical Practice Gastroenterology & Hepatology 2 (11): 536–544. doi:10.1038/ncpgasthep0316.
CDC - NIOSH Pocket Guide to Chemical Hazards

UpToDate Contents

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1. 成人における禁煙のための薬物療法 pharmacotherapy for smoking cessation in adults
2. ニコチンの心血管系への影響 cardiovascular effects of nicotine
3. 成人における禁煙マネージメントの概要 overview of smoking cessation management in adults
4. 禁煙の利益とリスク benefits and risks of smoking cessation
5. 授乳中の乳幼児：物質使用障害による抗精神病薬、リチウム、および薬剤への曝露の安全性 breastfeeding infants safety of exposure to antipsychotics lithium and medications for substance use disorders

English Journal

Histopathologycal findings in the ovaries and uterus of albino female rats promoted by co-administration of synthetic steroids and nicotine.

Camargo IC1, Leite GA2, Pinto T2, Ribeiro-Paes JT2.Author information 1Univ Estadual PaulistaUNESP, Biological Sciences Department, Av. Dom Antonio, 2100, Campus Universitário, 19806-900 Assis, SP, Brazil. Electronic address: camargo@assis.unesp.br.2Univ Estadual PaulistaUNESP, Biological Sciences Department, Av. Dom Antonio, 2100, Campus Universitário, 19806-900 Assis, SP, Brazil.AbstractThe use of anabolic androgenic steroids is often associated with the use of other substances, licit or not, such as nicotine present in the tobacco. The present study investigated for the first time the effects of co-administration of synthetic steroids and nicotine on the ovarian and uterine tissue and fertility of adult female rats. Animals were submitted to treatment groups (n=16/group): nandrolone decanoate (ND; 7.5mg/kg BW/week); testosterone mixture (T; 7.5mg/kg BW/week); nicotine (N; 2.0mg/kg BW/day), and co-administration of ND/N, T/N and ND/T/N. The control group received saline solution daily. The injections were administered subcutaneously for 30 consecutive days. Results demonstrated that all androgenized rats exhibited estral acyclicity and there was suppression of reproductive capacity due to notable ovarian and uterine histological changes. Treatments promoted decrease (p<0.05) in the ovarian weight. Uterine weight increased (p<0.05) in the T and T/N groups, in comparison to control group. ND or T co-administered or not to nicotine promoted intense follicular degeneration, with formation of cysts in the ovaries. High levels of circulating androgens in the ND/T/N group induced the presence of ovarian sex cord-stromal tumors of Sertoli cell pattern. Androgenized females presented endometrial changes characterized by papilliferous or pleated luminal epithelium, oedematous and hemorrhagic stroma and presence of gland cysts. In conclusion, the co-administration of three drugs promoted atypical morphological pattern on the ovaries and uterus of female rats.
Experimental and toxicologic pathology : official journal of the Gesellschaft für Toxikologische Pathologie.Exp Toxicol Pathol.2014 Jul;66(4):195-202. doi: 10.1016/j.etp.2014.01.005. Epub 2014 Feb 18.
The use of anabolic androgenic steroids is often associated with the use of other substances, licit or not, such as nicotine present in the tobacco. The present study investigated for the first time the effects of co-administration of synthetic steroids and nicotine on the ovarian and uterine tissue
PMID 24556002

Basolateral amygdala CB1 cannabinoid receptors mediate nicotine-induced place preference.

Hashemizadeh S1, Sardari M1, Rezayof A2.Author information 1Department of Animal Biology, School of Biology and Center of Excellence in Phylogeny of Living Organisms, College of Science, University of Tehran, Tehran, Iran.2Department of Animal Biology, School of Biology and Center of Excellence in Phylogeny of Living Organisms, College of Science, University of Tehran, Tehran, Iran; School of Cognitive Sciences, Institute for Research in Fundamental Sciences (IPM), Tehran, Iran. Electronic address: rezayof@khayam.ut.ac.ir.AbstractIn the present study, the effects of bilateral microinjections of cannabinoid CB1 receptor agonist and antagonist into the basolateral amygdala (intra-BLA) on nicotine-induced place preference were examined in rats. A conditioned place preference (CPP) apparatus was used for the assessment of rewarding effects of the drugs in adult male Wistar rats. Subcutaneous (s.c.) administration of nicotine (0.2mg/kg) induced a significant CPP, without any effect on the locomotor activity during the testing phase. Intra-BLA microinjection of a non-selective cannabinoid CB1/CB2 receptor agonist, WIN 55,212-2 (0.1-0.5μg/rat) with an ineffective dose of nicotine (0.1mg/kg, s.c.) induced a significant place preference. On the other hand, intra-BLA administration of AM251 (20-60ng/rat), a selective cannabinoid CB1 receptor antagonist inhibited the acquisition of nicotine-induced place preference. It should be considered that the microinjection of the same doses of WIN 55,212-2 or AM251 into the BLA, by itself had no effect on the CPP score. The administration of a higher dose of AM251 (60ng/rat) during the acquisition decreased the locomotor activity of animals on the testing phase. Interestingly, the microinjection of AM251 (20 and 40ng/rat), but not WIN55,212-2 (0.1-0.5μg/rat), into the BLA inhibited the expression of nicotine-induced place preference without any effect on the locomotor activity. Taken together, these findings support the possible role of endogenous cannabinoid system of the BLA in the acquisition and the expression of nicotine-induced place preference. Furthermore, it seems that there is a functional interaction between the BLA cannabinoid receptors and nicotine in producing the rewarding effects.
Progress in neuro-psychopharmacology & biological psychiatry.Prog Neuropsychopharmacol Biol Psychiatry.2014 Jun 3;51:65-71. doi: 10.1016/j.pnpbp.2014.01.010. Epub 2014 Jan 24.
In the present study, the effects of bilateral microinjections of cannabinoid CB1 receptor agonist and antagonist into the basolateral amygdala (intra-BLA) on nicotine-induced place preference were examined in rats. A conditioned place preference (CPP) apparatus was used for the assessment of reward
PMID 24468643

Initial responses to the first dose of nicotine in novel smokers: The role of exposure to environmental smoking and genetic predisposition.

Schuck K1, Otten R, Engels RC, Kleinjan M.Author information 1a Behavioural Science Institute, Radboud University Nijmegen , Nijmegen , The Netherlands.AbstractBackground: Sensitivity to initial smoking constitutes an early predictor of the risk of dependence. We investigated the role of exposure to smoking (by parents, siblings, and peers) and reward-related candidate gene polymorphisms (OPRM1 A118G, DRD2 TaqlA and DRD4 bp VNTR) in adolescents' responses to initial smoking. Methods: We used cross-sectional survey data and saliva samples from 171 Dutch students who had never inhaled on a cigarette (mean age: 13.9 years). The outcome measure was adolescents' self-reported responses to initial smoking. Results: Exposure to peer smoking was associated with increased liking (OR = 1.74, CI = 1.13-2.70) and more pleasant sensations (β = .21, p = .01). Exposure to maternal smoking was associated with less unpleasant sensations (β = -.20, p = .01). Adolescents carrying the G-variant of the OPRM1 A118G polymorphism were more likely to report liking (OR = 2.50, CI = 1.09-5.73) and adolescents homozygous for the C-variant of the DRD2 TaqlA polymorphism reported less unpleasant sensations (β = .18, p = .04). Conclusion: Although preliminary, these findings suggest that exposure to environmental smoking and polymorphisms in the OPRM1 and DRD2 gene may affect initial sensitivity to nicotine, an early phenotype of the risk of dependence. In the future, collaborative efforts to combine data from multiple studies in meta-analyses are needed to improve accuracy of estimated effects in genetic studies.
Psychology & health.Psychol Health.2014 Jun;29(6):698-716. doi: 10.1080/08870446.2014.884222. Epub 2014 Feb 17.
Background: Sensitivity to initial smoking constitutes an early predictor of the risk of dependence. We investigated the role of exposure to smoking (by parents, siblings, and peers) and reward-related candidate gene polymorphisms (OPRM1 A118G, DRD2 TaqlA and DRD4 bp VNTR) in adolescents' response
PMID 24446757

Japanese Journal

Association Between KCNJ6 (GIRK2) Gene Polymorphism rs2835859 and Post-operative Analgesia, Pain Sensitivity, and Nicotine Dependence

Nishizawa Daisuke,Fukuda Ken-ichi,Kasai Shinya [他]
Journal of pharmacological sciences 126(3), 253-263, 2014-11
NAID 40020271361

研究・症例ニコチンパッチを使用した禁煙外来患者における禁煙達成阻害因子の検討 : うつを基礎疾患とする患者に注目して

小原智美,川井治之,柿本みはる [他]
日本胸部臨床 73(10), 1237-1242, 2014-10
NAID 40020224431

個人輸入たばこ及び同銘柄の国産たばこに含まれるタール・ニコチン・一酸化炭素及びたばこ特異的ニトロソアミンの分析

稲葉洋平,大久保忠利,内山茂久 [他]
日本衛生学雑誌 = Japanese journal of hygiene 69(3), 205-210, 2014-09
NAID 40020229579

Related Pictures

★リンクテーブル★

リンク元	「薬物濫用」「ニコチン」「nicotinic」
拡張検索	「nicotine dependence」「nicotine sulfate」

「薬物濫用」

NFPA 704; "fire diamond"
	1 4 0
	The fire diamond hazard sign for nicotine.

Nicotine
Systematic (IUPAC) name
	(S)-3-[1-Methylpyrrolidin-2-yl]pyridine
Clinical data
Trade names	Nicorette, Nicotrol
AHFS/Drugs.com	monograph
Pregnancy; category	AU: D; US: D (Evidence of risk); ;
Legal status	AU: Unscheduled; CA: Unscheduled; NZ: Unscheduled; UK: Unscheduled; US: Unscheduled; UN: Unscheduled; EU: Unscheduled;
Dependence; liability	Physical: low–moderate; Psychological: moderate–high
Addiction; liability	High
Routes of; administration	Inhalation; insufflation; oral – buccal, sublingual, and ingestion; transdermal; rectal,
Pharmacokinetic data
Bioavailability	20 to 45% (oral), 53% (intranasal), 68% (transdermal)
Protein binding	<5%
Metabolism	Hepatic
Metabolites	Cotinine
Biological half-life	1-2 hours; 20 hours active metabolite
Excretion	Urine (10-20% (gum), pH-dependent; 30% (inhaled); 10-30% (intranasal))
Identifiers
CAS Number	54-11-5
ATC code	N07BA01 QP53AX13
PubChem	CID: 89594
IUPHAR/BPS	2585
DrugBank	DB00184
ChemSpider	80863
UNII	6M3C89ZY6R
KEGG	D03365
ChEBI	CHEBI:18723
ChEMBL	CHEMBL3
PDB ligand ID	NCT (PDBe, RCSB PDB)
Chemical data
Formula	C10H14N2
Molecular mass	162.23 g/mol
	SMILES CN(CCC1)[C@@H]1C2=CC=CN=C2 ;
	InChI InChI=1S/C10H14N2/c1-12-7-3-5-10(12)9-4-2-6-11-8-9/h2,4,6,8,10H,3,5,7H2,1H3/t10-/m0/s1 ; Key:SNICXCGAKADSCV-JTQLQIEISA-N ;
Physical data
Density	1.01 g/cm3
Melting point	−79 °C (−110 °F)
Boiling point	247 °C (477 °F)
(what is this?) (verify)

　　[★]

英: drug abuse, substance abuse
同: 薬物乱用
関: 薬物依存、薬物嗜癖、物質乱用、物質依存症、薬物使用、接着剤吸引

薬物使用が身体に及ぼす効果

濫用 substance abuse：a pattern of abnormal substance use that leads to impairment of occupational, physical, or social functioning(BBS.73)
依存 substance dependence：ub stance abuse puls withdrawal symptoms, tolerance, or a pattern of repetitive use(BBS.73)
離脱 withdrawal：the development of physical or pschological symptoms after the reduction or cessation of intake of a substance(BBS.73)
耐性 tolerance：the need for increased amounts of the substance to achieve the same positive psychological effect(BBS.73)
交差耐性 cross-tolerance：the development of tolerance to one substance as the result of using another substance(BBS.73)

薬物

1. 中枢神経興奮薬(覚醒剤を含む) stimulants　　身体依存はないとされている

カフェイン caffeine
ニコチン nicotine
amphetamines　精神依存有り。身体依存無し

アンフェタミン amphetamine　精神依存有り。身体依存無し。耐性は連用で出現
デキストロアンフェタミン dextroamphetamine Dexedrine
メタンフェタミン methamphetamine Desoxyn speed ice ヒロポン　精神依存有り。身体依存無し。耐性は連用で出現　　←　以前、日本で多く使われた
メチルフェニデート methylphenidate Ritalin
methylene dioxymethamphetamine MDMA ecstasy

コカイン cocaine crack freebase　精神依存有り。身体依存無し　精神依存生じやすい。耐性発現殆ど無し　コカ

2. sedatives

alcohol　　精神依存有り。身体依存有り。
barbiturates
benzodiazepines

⇔flumazenil Mazicon Romazicon

3. opioids

morphine　精神依存・身体依存有り　けし
heroin　精神依存・身体依存が強い。耐性発現早い。離脱症状激しい
codeine
pethidine
fentanyl
methadone
l-alpha-acetylmethadol acetate LAMM
buprenorphine Temgesic

4. hallucinogens and related agents

cannabis(marijuana(tetrahydrocannabinol THC,hashish)　精神依存有り。身体依存無し　精神依存軽度。耐性は長期使用で軽度出現　大麻草
lysergic acid diethylamide LSD
phencyclidine PCP angel dust
psilocybin
mescaline

精神依存、身体依存

	精神依存	身体依存
コカイン、アンフェタミン類(アンフェタミン、メチルフェタミン)、大麻	○
麻薬(モルヒネ、ヘロイン、コデイン)、バルビツール酸系(フェノバルビタール、チオペンタール)、アルコール	○	○

「ニコチン」

　　[★]

英: nicotine
ラ: nicotinum
商: ニコレット、ニコチネルTTS
関: 他に分類されない治療を主目的としない医薬品

作用

喫煙などにより体内に取り込まれたニコチンはニコチン性受容体に作用する。　→　アセチルコリン受容体

自律神経節に作用、、、結果として血圧を上昇させる。

臨床関連

ニコチン中毒

「nicotinic」

　　[★]

ニコチン性の、ニコチンの

関: nicotine、nicotine sulfate

「nicotine dependence」

　　[★]

ニコチン依存、ニコチン依存症

関: tobacco dependence、tobacco use disorder

「nicotine sulfate」

　　[★]

硫酸ニコチン

関: nicotine、nicotinic

[Dependence-withdrawal-1] D'Souza MS, Markou A (2011). "Neuronal mechanisms underlying development of nicotine dependence: implications for novel smoking-cessation treatments". Addict Sci Clin Pract 6 (1): 4–16. PMC 3188825. PMID 22003417. Withdrawal symptoms upon cessation of nicotine intake: Chronic nicotine use induces neuroadaptations in the brain’s reward system that result in the development of nicotine dependence. Thus, nicotine-dependent smokers must continue nicotine intake to avoid distressing somatic and affective withdrawal symptoms. Newly abstinent smokers experience symptoms such as depressed mood, anxiety, irritability, difficulty concentrating, craving, bradycardia, insomnia, gastrointestinal discomfort, and weight gain (Shiffman and Jarvik, 1976; Hughes et al., 1991). Experimental animals, such as rats and mice, exhibit a nicotine withdrawal syndrome that, like the human syndrome, includes both somatic signs and a negative affective state (Watkins et al., 2000; Malin et al., 2006). The somatic signs of nicotine withdrawal include rearing, jumping, shakes, abdominal constrictions, chewing, scratching, and facial tremors. The negative affective state of nicotine withdrawal is characterized by decreased responsiveness to previously rewarding stimuli, a state called anhedonia.

[2] Cosci, F; Pistelli, F; Lazzarini, N; Carrozzi, L (2011). "Nicotine dependence and psychological distress: outcomes and clinical implications in smoking cessation.". Psychology research and behavior management 4: 119–28. doi:10.2147/prbm.s14243. PMID 22114542.

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Conclusions
ΔFosB is an essential transcription factor implicated in the molecular and behavioral pathways of addiction following repeated drug exposure. The formation of ΔFosB in multiple brain regions, and the molecular pathway leading to the formation of AP-1 complexes is well understood. The establishment of a functional purpose for ΔFosB has allowed further determination as to some of the key aspects of its molecular cascades, involving effectors such as GluR2 (87,88), Cdk5 (93) and NFkB (100). Moreover, many of these molecular changes identified are now directly linked to the structural, physiological and behavioral changes observed following chronic drug exposure (60,95,97,102). New frontiers of research investigating the molecular roles of ΔFosB have been opened by epigenetic studies, and recent advances have illustrated the role of ΔFosB acting on DNA and histones, truly as a ‘‘molecular switch’’ (34). As a consequence of our improved understanding of ΔFosB in addiction, it is possible to evaluate the addictive potential of current medications (119), as well as use it as a biomarker for assessing the efficacy of therapeutic interventions (121,122,124).

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