Nicotine is an alkaloid found in the nightshade family of plants (Solanaceae) that acts as a nicotinic acetylcholine agonist and a monoamine oxidase inhibitor[citation needed]. The biosynthesis
takes place in the roots and accumulation occurs in the leaves of the
Solanaceae. It constitutes approximately 0.6–3.0% of the dry weight of tobacco[1] and is present in the range of 2–7 µg/kg of various edible plants.[2] It functions as an antiherbivore chemical; therefore, nicotine was widely used as an insecticide in the past[3][4][5] and nicotine analogs such as imidacloprid are currently widely used.
In low doses (an average cigarette yields about 1 mg of absorbed nicotine), the substance acts as a stimulant in mammals, while high amounts (30–60 mg[6]) can be fatal.[7] This stimulant effect is the main factor responsible for the dependence-forming properties of tobacco smoking. According to the American Heart Association, nicotine addiction has historically been one of the hardest addictions to break, while the pharmacological and behavioral characteristics that determine tobacco addiction are similar to those determining addiction to heroin and cocaine. 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 1.6% per year between the years of 1998 and 2005. This was found for all major market categories of cigarettes.[8]
Research in 2011 has found that nicotine inhibits chromatin-modifying enzymes (class I and II histone deacetylases) which increases the ability of cocaine to cause an addiction.[9]
Currently, nicotine is a permitted pesticide for organic farming because it is derived from a botanical source. Nicotine sulfate sold for use as a pesticide is labeled "DANGER," indicating that it is highly toxic.[5] However, in 2008, the EPA received a request to cancel the registration of the last nicotine pesticide registered in the United States.[15] This request was granted, and after 1 January 2014, this pesticide will not be available for sale.[16]
Nicotine biosynthesis
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
nicotinic acid while the pyrrolidone is derived from N-methyl-Δ1-pyrrollidium cation.[18][19]
Biosynthesis of the two component structures proceeds via two
independent syntheses, the NAD pathway for nicotinic acid 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 nicotinic acid mononucleotide (NaMN). The reaction now proceeds via the NAD salvage cycle to produce nicotinic acid via the conversion of nicotinamide by the enzyme nicotinamidase.
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.
The final step in the synthesis of nicotine is the coupling between N-methyl-Δ1-pyrrollidium cation and nicotinic acid. 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 nicotinic acid 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.[20]
Side effects of nicotine.[21]
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.[22] The elimination half-life of nicotine in the body is around two hours.[23]
The amount of nicotine absorbed by the body from smoking depends on many factors, including the types of tobacco, whether the smoke is inhaled, and whether a filter is used. For chewing tobacco, dipping tobacco, snus 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.[clarification needed][citation needed] 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.[24] Under some conditions, other substances may be formed such as myosmine.[25]
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.[26]
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 responsible for the apparent euphoria and relaxation, and addiction caused by nicotine consumption. 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.[30] Nicotine's selectivity is thought to be due to a particular amino acid difference on these receptor subtypes.[31]
Tobacco smoke contains anabasine, anatabine, and nornicotine.[citation needed] It also contains the monoamine oxidase inhibitors harman and norharman.[32] These beta-carboline compounds significantly decrease MAO activity in smokers.[32][33] MAO enzymes break down monoaminergic neurotransmitters such as dopamine, norepinephrine, and serotonin. It is thought that the powerful interaction between the MAOI's and the nicotine is responsible for most of the addictive properties of tobacco smoking.[34] The addition of five minor tobacco alkaloids increases nicotine-induced hyperactivity, sensitization and intravenous self-administration in rats.[35]
Chronic nicotine exposure via tobacco smoking up-regulates alpha4beta2* nAChR in cerebellum and brainstem regions[36][37] but not habenulopeduncular structures.[38] Alpha4beta2 and alpha6beta2 receptors, present in the ventral tegmental area, play a crucial role in mediating the reinforcement effects of nicotine.[39]
Effect of nicotine on chromaffin cells.
Nicotine is the natural product of tobacco, having a half-life of 1 to 2 hours. Cotinine is an active metabolite of nicotine that remains in the blood for 18 to 20 hours, making it easier to analyze due to its longer half-life.[43]
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 such as acetylcholine, norepinephrine, epinephrine, vasopressin, histamine, arginine, serotonin, dopamine, autocrine agents, and beta-endorphin.[48] This release of neurotransmitters and hormones is responsible for most of nicotine's effects. Nicotine appears to enhance concentration[49] and memory 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 extends the duration of positive effects of dopamine[50] and increases sensitivity in brain reward systems.[51] Most cigarettes (in the smoke inhaled) contain 1 to 3 milligrams of nicotine.[52]
Research suggests that, when smokers wish to achieve a stimulating effect, they take short quick puffs, which produce a low level of blood nicotine.[53] 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.
Technically, nicotine is not significantly addictive, as nicotine administered alone does not produce significant reinforcing properties.[54] However, after coadministration with an MAOI, such as those found in tobacco, nicotine produces significant behavioral sensitization, a measure of addiction potential. This is similar in effect to amphetamine.[34]
Nicotine gum, usually in 2-mg or 4-mg doses, and nicotine patches are available, as well as smokeless tobacco, nicotine lozenges and electronic cigarettes.
A 21 mg patch applied to the left arm. The Cochrane Collaboration finds that NRT increases a quitter's chance of success by 50 to 70%.[55] But in 1990, researchers found that 93% of users returned to smoking within six months.[56]
A study on rats showed that nicotine exposure abolishes the beneficial and protective effects of estrogen on the hippocampus,[61] an estrogen-sensitive region of the brain involved in memory formation and retention.
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.[63][64][65] Like other physically addictive drugs, nicotine withdrawal causes down-regulation of the production of dopamine and other stimulatory neurotransmitters as the brain attempts to compensate for artificial stimulation. As dopamine regulates the sensitivity of nicotinic acetylcholine receptors decreases. To compensate for this compensatory mechanism, the brain in turn upregulates the number of receptors, convoluting its regulatory effects with compensatory mechanisms meant to counteract other compensatory mechanisms. An example is the increase in norepinephrine, one of the successors to dopamine, which inhibit reuptake of the glutamate receptors,[66] in charge of memory and cognition. The net effect is an increase in reward pathway sensitivity, the opposite of other addictive drugs such as cocaine and heroin, which reduce reward pathway sensitivity.[51] This neuronal brain alteration can persist for months after administration ceases.
A study found that nicotine exposure in adolescent mice retards the growth of the dopamine system, thus increasing the risk of substance abuse during adolescence.[67]
These include attaching the nicotine molecule as a hapten to a protein carrier such as Keyhole limpet hemocyanin or a safe modified bacterial toxin to elicit an active immune response. Often it is added with bovine serum albumin.
Additionally, because of concerns with the unique immune systems of individuals being liable to produce antibodies against endogenous hormones and over the counter drugs, monoclonal antibodies have been developed for short term passive immune protection. They have half-lives varying from hours to weeks. Their half-lives depend on their ability to resist degradation from pinocytosis by epithelial cells.[68][citation needed]
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.[6][69] Nicotine therefore has a high toxicity in comparison to many other alkaloids such as cocaine, which has an LD50
of 95.1 mg/kg when administered to mice. It is unlikely that a person
would overdose on nicotine through smoking alone, although overdose can
occur through combined use of nicotine patches or nicotine gum and
cigarettes at the same time.[7]
Spilling a high concentration of nicotine onto the skin can cause
intoxication or even death, since nicotine readily passes into the
bloodstream following dermal contact.[70]
Historically, nicotine has not been regarded as a carcinogen and the IARC has not evaluated nicotine in its standalone form and assigned it to an official carcinogen group. While no epidemiological evidence supports that nicotine alone acts as a carcinogen in the formation of human cancer, research over the last decade has identified nicotine's carcinogenic potential in animal models and cell culture.[71][72] Nicotine has been noted to directly cause cancer through a number of different mechanisms such as the activation of MAP Kinases.[73] Indirectly, nicotine increases cholinergic signalling (and adrenergic signalling in the case of colon cancer[74]), thereby impeding apoptosis (programmed cell death), promoting tumor growth, and activating growth factors and cellular mitogenic factors such as 5-LOX, and EGF. Nicotine also promotes cancer growth by stimulating angiogenesis and neovascularization.[75][76] 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).[77]
Though the teratogenic properties of nicotine may or may not yet have been adequately researched, women who use nicotine gum and patches during the early stages of pregnancy face an increased risk of having babies with birth defects, according to a study of around 77,000 pregnant women in Denmark. The study found that women who use nicotine-replacement therapy in the first 12 weeks of pregnancy have a 60% greater risk of having babies with birth defects, compared to women who are non-smokers.[citation needed]
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 the state to cause developmental toxicity, for the purposes of Proposition 65.[78]
However, in a few situations, smoking has been observed to apparently be of therapeutic value. These are often referred to as "Smoker’s Paradoxes".[79] 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).[79] 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.[80][81] Smoking also appears to interfere with development of Kaposi's sarcoma in patients with HIV.[82]
Nicotine has a mild laxative effect and can reduce symptoms of ulcerative colitis.
Nicotine reduces the chance of breast cancer among women carrying the very high risk BRCA gene,[83] preeclampsia,[84] and atopic disorders such as allergic asthma.[85] 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.[86]
Tobacco smoke has been shown to contain compounds capable of inhibiting monoamine oxidase, which is responsible for the degradation of dopamine in the human brain. When dopamine is broken down by MAO-B, neurotoxic by-products are formed, possibly contributing to Parkinson's and Alzheimers disease.[87] Many such papers regarding Alzheimer's disease[88] and Parkinson's Disease[89] have been published. While tobacco smoking is associated with an increased risk of Alzheimer's disease,[90] there is evidence that nicotine itself has the potential to prevent and treat Alzheimer's disease.[91] Nicotine has been shown to delay the onset of Parkinson's disease in studies involving monkeys and humans.[92][93][94] A study has shown a protective effect of nicotine itself on neurons due to nicotine activation of α7-nAChR and the PI3K/Akt pathway which inhibits apoptosis-inducing factor release and mitochondrial translocation, cytochrome c release and caspase 3 activation.[95]
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 responsible for processing nicotine in the brain.[96]
Studies suggest a correlation between smoking and schizophrenia, with estimates near 75% for the proportion of schizophrenic patients who smoke. Although the nature of this association remains unclear, it was recently argued that the increased level of smoking in schizophrenia may be due to a desire to self-medicate with nicotine.[97][98] More recent research has found that mildly dependent users got some benefit from nicotine, but not those who were highly dependent.[99] There are very few research done on this subject, including the research by Duke University Medical Centre which found that nicotine may improve the symptoms of depression in people.[100] Nicotine appears to improve ADHD symptoms. Some studies are focusing on benefits of nicotine therapy in adults with ADHD.[101]
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.[102]
Nicotine (in the form of chewing gum or a transdermal patch) is being explored as an experimental treatment for OCD. Small studies show some success, even in otherwise treatment-refractory cases.[103][104][105]
The relationship between smoking and inflammatory bowel disease is now firmly established but remains a source of confusion among both patients and doctors. It is negatively associated with ulcerative colitis but positively associated with Crohn's disease. In addition, it has opposite influences on the clinical course of the two conditions with benefit in ulcerative colitis but a detrimental effect in Crohn's disease.[106][107]
In low doses (an average cigarette yields about 1 mg of absorbed nicotine), the substance acts as a stimulant in mammals, while high amounts (30–60 mg[6]) can be fatal.[7] This stimulant effect is the main factor responsible for the dependence-forming properties of tobacco smoking. According to the American Heart Association, nicotine addiction has historically been one of the hardest addictions to break, while the pharmacological and behavioral characteristics that determine tobacco addiction are similar to those determining addiction to heroin and cocaine. 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 1.6% per year between the years of 1998 and 2005. This was found for all major market categories of cigarettes.[8]
Research in 2011 has found that nicotine inhibits chromatin-modifying enzymes (class I and II histone deacetylases) which increases the ability of cocaine to cause an addiction.[9]
Contents[hide] |
[edit] History and name
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,and who promoted their medicinal use. The tobacco and seeds were brought to ambassador Nicot from Brazil by Luis de Gois, a Portuguese colonist in São Paulo. 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.[10][11] Its chemical empirical formula was described by Melsens in 1843,[12] its structure was discovered by Adolf Pinner and Richard Wolffenstein in 1893,[13] and it was first synthesized by Amé Pictet and A. Rotschy in 1904.[14][edit] Historical use of nicotine as an insecticide
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 (waste from the tobacco industry) 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.[4]Currently, nicotine is a permitted pesticide for organic farming because it is derived from a botanical source. Nicotine sulfate sold for use as a pesticide is labeled "DANGER," indicating that it is highly toxic.[5] However, in 2008, the EPA received a request to cancel the registration of the last nicotine pesticide registered in the United States.[15] This request was granted, and after 1 January 2014, this pesticide will not be available for sale.[16]
[edit] 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 308 K (35 °C; 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 cause pharmacological effects.[edit] Optical activity
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.[17] The salts of (+)-nicotine are usually dextrorotatory.[edit] Biosynthesis
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 nicotinic acid mononucleotide (NaMN). The reaction now proceeds via the NAD salvage cycle to produce nicotinic acid via the conversion of nicotinamide by the enzyme nicotinamidase.
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.
The final step in the synthesis of nicotine is the coupling between N-methyl-Δ1-pyrrollidium cation and nicotinic acid. 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 nicotinic acid 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.[20]
[edit] Pharmacology
[edit] Pharmacokinetics
The amount of nicotine absorbed by the body from smoking depends on many factors, including the types of tobacco, whether the smoke is inhaled, and whether a filter is used. For chewing tobacco, dipping tobacco, snus 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.[clarification needed][citation needed] 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.[24] Under some conditions, other substances may be formed such as myosmine.[25]
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.[26]
[edit] Detection of use
[edit] Medical detection
Nicotine can be quantified in blood, plasma, or urine to confirm a diagnosis of poisoning or to facilitate a medicolegal death investigation. Urinary or salivary cotinine concentrations are frequently measured for the purposes of pre-employment and health insurance medical screening programs. Careful interpretation of results is important, since passive exposure to cigarette smoke can result in significant accumulation of nicotine, followed by the appearance of its metabolites in various body fluids.[27][28] Nicotine use is not regulated in competitive sports programs, yet the drug has been shown to have a significant beneficial effect on athletic endurance in subjects who have not used nicotine before.[29][edit] Pharmacodynamics
Nicotine acts on the nicotinic acetylcholine receptors, specifically the ganglion type nicotinic receptor and one CNS 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.[edit] In the central nervous system
Tobacco smoke contains anabasine, anatabine, and nornicotine.[citation needed] It also contains the monoamine oxidase inhibitors harman and norharman.[32] These beta-carboline compounds significantly decrease MAO activity in smokers.[32][33] MAO enzymes break down monoaminergic neurotransmitters such as dopamine, norepinephrine, and serotonin. It is thought that the powerful interaction between the MAOI's and the nicotine is responsible for most of the addictive properties of tobacco smoking.[34] The addition of five minor tobacco alkaloids increases nicotine-induced hyperactivity, sensitization and intravenous self-administration in rats.[35]
Chronic nicotine exposure via tobacco smoking up-regulates alpha4beta2* nAChR in cerebellum and brainstem regions[36][37] but not habenulopeduncular structures.[38] Alpha4beta2 and alpha6beta2 receptors, present in the ventral tegmental area, play a crucial role in mediating the reinforcement effects of nicotine.[39]
[edit] In the sympathetic nervous system
Nicotine also activates the sympathetic nervous system,[40] 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. 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.[41]
[edit] In adrenal medulla
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.[42]Nicotine is the natural product of tobacco, having a half-life of 1 to 2 hours. Cotinine is an active metabolite of nicotine that remains in the blood for 18 to 20 hours, making it easier to analyze due to its longer half-life.[43]
[edit] Psychoactive effects
Nicotine's mood-altering effects are different by report: in particular it is both a stimulant and a relaxant.[44] 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.[45] Like any stimulant, it may very rarely cause the often catastrophically uncomfortable neuropsychiatric effect of akathisia. By reducing the appetite and raising the metabolism, some smokers may lose weight as a consequence.[46][47]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 such as acetylcholine, norepinephrine, epinephrine, vasopressin, histamine, arginine, serotonin, dopamine, autocrine agents, and beta-endorphin.[48] This release of neurotransmitters and hormones is responsible for most of nicotine's effects. Nicotine appears to enhance concentration[49] and memory 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 extends the duration of positive effects of dopamine[50] and increases sensitivity in brain reward systems.[51] Most cigarettes (in the smoke inhaled) contain 1 to 3 milligrams of nicotine.[52]
Research suggests that, when smokers wish to achieve a stimulating effect, they take short quick puffs, which produce a low level of blood nicotine.[53] 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.
Technically, nicotine is not significantly addictive, as nicotine administered alone does not produce significant reinforcing properties.[54] However, after coadministration with an MAOI, such as those found in tobacco, nicotine produces significant behavioral sensitization, a measure of addiction potential. This is similar in effect to amphetamine.[34]
Nicotine gum, usually in 2-mg or 4-mg doses, and nicotine patches are available, as well as smokeless tobacco, nicotine lozenges and electronic cigarettes.
[edit] Side Effects
Nicotine increases blood pressure and heart rate in humans.[57] Nicotine can stimulate abnormal proliferation of vascular endothelial cells, similar to that seen in atherosclerosis.[58] Nicotine induces potentially atherogenic genes in human coronary artery endothelial cells.[59] Nicotine could cause microvascular injury through its action on nicotinic acetylcholine receptors (nAChRs),[60] however other mechanisms are also likely at play.A study on rats showed that nicotine exposure abolishes the beneficial and protective effects of estrogen on the hippocampus,[61] an estrogen-sensitive region of the brain involved in memory formation and retention.
[edit] Dependence and withdrawal
 |
This article needs additional citations for verification. (April 2012) |
See also: Smoking cessation
Modern research
shows that nicotine acts on the brain to produce a number of effects.
Specifically, research examining its addictive nature has been found to
show that nicotine activates the mesolimbic pathway ("reward system") – the circuitry within the brain that regulates feelings of pleasure and euphoria.[62]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.[63][64][65] Like other physically addictive drugs, nicotine withdrawal causes down-regulation of the production of dopamine and other stimulatory neurotransmitters as the brain attempts to compensate for artificial stimulation. As dopamine regulates the sensitivity of nicotinic acetylcholine receptors decreases. To compensate for this compensatory mechanism, the brain in turn upregulates the number of receptors, convoluting its regulatory effects with compensatory mechanisms meant to counteract other compensatory mechanisms. An example is the increase in norepinephrine, one of the successors to dopamine, which inhibit reuptake of the glutamate receptors,[66] in charge of memory and cognition. The net effect is an increase in reward pathway sensitivity, the opposite of other addictive drugs such as cocaine and heroin, which reduce reward pathway sensitivity.[51] This neuronal brain alteration can persist for months after administration ceases.
A study found that nicotine exposure in adolescent mice retards the growth of the dopamine system, thus increasing the risk of substance abuse during adolescence.[67]
[edit] Immunology prevention
Because of the severe addictions and the harmful effects of smoking, vaccination protocols have been developed. The principle is under the premise that if an antibody is attached to a nicotine molecule, it will be prevented from diffusing through the capillaries, thus making it less likely that it ever affects the brain by binding to nicotinic acetylcholine receptors.These include attaching the nicotine molecule as a hapten to a protein carrier such as Keyhole limpet hemocyanin or a safe modified bacterial toxin to elicit an active immune response. Often it is added with bovine serum albumin.
Additionally, because of concerns with the unique immune systems of individuals being liable to produce antibodies against endogenous hormones and over the counter drugs, monoclonal antibodies have been developed for short term passive immune protection. They have half-lives varying from hours to weeks. Their half-lives depend on their ability to resist degradation from pinocytosis by epithelial cells.[68][citation needed]
[edit] Toxicology
See also: Nicotine poisoning
| NFPA 704 |
|---|
Historically, nicotine has not been regarded as a carcinogen and the IARC has not evaluated nicotine in its standalone form and assigned it to an official carcinogen group. While no epidemiological evidence supports that nicotine alone acts as a carcinogen in the formation of human cancer, research over the last decade has identified nicotine's carcinogenic potential in animal models and cell culture.[71][72] Nicotine has been noted to directly cause cancer through a number of different mechanisms such as the activation of MAP Kinases.[73] Indirectly, nicotine increases cholinergic signalling (and adrenergic signalling in the case of colon cancer[74]), thereby impeding apoptosis (programmed cell death), promoting tumor growth, and activating growth factors and cellular mitogenic factors such as 5-LOX, and EGF. Nicotine also promotes cancer growth by stimulating angiogenesis and neovascularization.[75][76] 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).[77]
Though the teratogenic properties of nicotine may or may not yet have been adequately researched, women who use nicotine gum and patches during the early stages of pregnancy face an increased risk of having babies with birth defects, according to a study of around 77,000 pregnant women in Denmark. The study found that women who use nicotine-replacement therapy in the first 12 weeks of pregnancy have a 60% greater risk of having babies with birth defects, compared to women who are non-smokers.[citation needed]
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 the state to cause developmental toxicity, for the purposes of Proposition 65.[78]
[edit] Therapeutic uses
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.However, in a few situations, smoking has been observed to apparently be of therapeutic value. These are often referred to as "Smoker’s Paradoxes".[79] 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).[79] 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.[80][81] Smoking also appears to interfere with development of Kaposi's sarcoma in patients with HIV.[82]
Nicotine has a mild laxative effect and can reduce symptoms of ulcerative colitis.
Nicotine reduces the chance of breast cancer among women carrying the very high risk BRCA gene,[83] preeclampsia,[84] and atopic disorders such as allergic asthma.[85] 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.[86]
Tobacco smoke has been shown to contain compounds capable of inhibiting monoamine oxidase, which is responsible for the degradation of dopamine in the human brain. When dopamine is broken down by MAO-B, neurotoxic by-products are formed, possibly contributing to Parkinson's and Alzheimers disease.[87] Many such papers regarding Alzheimer's disease[88] and Parkinson's Disease[89] have been published. While tobacco smoking is associated with an increased risk of Alzheimer's disease,[90] there is evidence that nicotine itself has the potential to prevent and treat Alzheimer's disease.[91] Nicotine has been shown to delay the onset of Parkinson's disease in studies involving monkeys and humans.[92][93][94] A study has shown a protective effect of nicotine itself on neurons due to nicotine activation of α7-nAChR and the PI3K/Akt pathway which inhibits apoptosis-inducing factor release and mitochondrial translocation, cytochrome c release and caspase 3 activation.[95]
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 responsible for processing nicotine in the brain.[96]
Studies suggest a correlation between smoking and schizophrenia, with estimates near 75% for the proportion of schizophrenic patients who smoke. Although the nature of this association remains unclear, it was recently argued that the increased level of smoking in schizophrenia may be due to a desire to self-medicate with nicotine.[97][98] More recent research has found that mildly dependent users got some benefit from nicotine, but not those who were highly dependent.[99] There are very few research done on this subject, including the research by Duke University Medical Centre which found that nicotine may improve the symptoms of depression in people.[100] Nicotine appears to improve ADHD symptoms. Some studies are focusing on benefits of nicotine therapy in adults with ADHD.[101]
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.[102]
Nicotine (in the form of chewing gum or a transdermal patch) is being explored as an experimental treatment for OCD. Small studies show some success, even in otherwise treatment-refractory cases.[103][104][105]
The relationship between smoking and inflammatory bowel disease is now firmly established but remains a source of confusion among both patients and doctors. It is negatively associated with ulcerative colitis but positively associated with Crohn's disease. In addition, it has opposite influences on the clinical course of the two conditions with benefit in ulcerative colitis but a detrimental effect in Crohn's disease.[106][107]
