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. Nicotine is a naturally occurring toxic chemical found in tobacco plants. It has a fishy odor when warm. Cigarettes, cigars, other tobacco products, and tobacco smoke contain nicotine. Worker exposure may occur during processing and extraction of tobacco.

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by ellie and reny

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What percent of the population is addicted to nicotine? STATISTICS 

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What percent of the population is addicted to nicotine? STATISTICS 

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By 2019, adjusted nicotine dependence prevalence was 41.27% (95% CI, 39.21%-43.37%) among those aged 18 to 25 years, 50.64% (95% CI, 47.99%-53.30%) among those aged 26 to 34 years, 60.71% (95% CI, 58.27%-63.09%) among those aged 34 to 49 years, and 64.43% (95% CI, 60.98%-67.74%) among those 50 years and older.

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irritation and burning sensation in the mouth and throat

increased salivation

nausea

abdominal pain

vomiting and diarrhea

increase in plasma free fatty acids

increase in the level of catecholamines in the blood

increases your blood pressure

increase in heart rate

dizziness

cough

hypothermia

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What are the main withdrawal symptoms of nicotine?

Having urges or cravings to smoke. ...

Feeling irritated, grouchy, or upset. ...

Feeling jumpy and restless. ...

Having a hard time concentrating. ...

Having trouble sleeping. ...

Feeling hungrier or gaining weight. ...

Feeling anxious, sad, or depressed.

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7 Common Withdrawal Symptoms | Quit Smoking | Tips From Former Smokers | CDC

And What You Can Do About Them

Trying to quit smoking feels different for each person, but almost everyone will have some symptoms of nicotine withdrawal. When you stop, your body and brain have to get used to not having nicotine. This can be uncomfortable, but nicotine withdrawal can't hurt you - unless you give in and have a cigarette!

Over time, withdrawal symptoms will fade as long as you stay smokefree.

Almost everyone who smokes regularly has cravings or urges to smoke when they quit. They may be mild or can sometimes feel overwhelming. Figuring out how to deal with cravings is one of the most important things you can do to stay successful.

Ways to manage: There are LOTS of things you can do to make urges and cravings less of a problem. Quit-smoking medicines can help a lot, and so can other quitting tips. Cravings can be triggered by things that make you think about smoking-like people you smoked with, a place you often smoked, or things you used to do while smoking like having a cup of coffee. Even a thought or a feeling can trigger a craving. But other thoughts can help you get through a craving, like remembering why you are quitting. Remember that you never have to give in to a craving, and that it will always pass.

Use a quit-smoking medicine.

Keep busy and distract yourself.

Be active - some physical activity is better than none!

Spend time with friends who don't smoke.

See other ways to manage withdrawal.

It is very common to feel irritated or grouchy when you quit. Even many people who have never smoked know this is part of quitting. Knowing this is normal can be helpful.

Ways to manage: Remind yourself that you likely feel this way because your body is getting used to being without nicotine. Take a few deep breaths and remind yourself why you're quitting.

Feeling jumpy or restless during the first days or weeks after quitting is normal. Just like your mind gets irritated without nicotine at first, the rest of your body can, too.

Ways to manage: Doing some physical activity can help shake loose your jumpiness. Get up and walk around for a bit if you feel restless. Try cutting back on coffee, tea, and other caffeinated drinks. When you quit smoking, caffeine lasts longer in your body.

You may notice that it is harder to concentrate in the first days after you quit-this is very common.

Ways to manage: Try to cut yourself some slack, especially in the first days after you quit. Try to limit activities that require strong concentration if you can.

It's common to have some trouble sleeping when you first quit smoking. This will get better, but if it is bothering you, talk with your healthcare provider to get help. If you become exhausted from poor sleep, this can make it harder to stay quit.
Ways to manage:

If you drink coffee, tea, or other caffeinated drinks regularly, don't drink them in the late afternoon or evening. When you quit smoking, caffeine lasts longer in your body.

If you are using the nicotine patch, try taking it off an hour before bedtime. Sometimes the nicotine in the patch can affect your sleep.

Try some of the other things that can help you get a good night's sleep:

Don't watch TV or use phones, computers, or e-books in bed.

Make sure your bedroom is quiet, dark, relaxing, and at a comfortable temperature.

Don't eat a heavy meal or drink alcohol right before bed.

Add in some physical activity during the day (but not right before bed).

Go to sleep and wake up around the same time each day, even on weekends.

It's normal for your appetite to increase some when you quit. And your body may not burn calories quite as fast. You may also eat more because of the stress of quitting or to have something to do with your hands and mouth. Food may even be more enjoyable because your senses of smell and taste are not being dulled by all that smoke!

Ways to manage: While some people may gain weight after they quit, it's important for your health to quit sooner than later. Below are a few simple things you can do to help control weight gain after quitting. The bonus is that these things will help you build healthy behaviors for a lifetime of being smokefree!

Snack smart. If you eat between meals, find some healthy, low-calorie foods that still give your mouth and hands something to do, like celery, carrots, or sugar-free mints. You can also keep your hands and mouth busy with a toothpick or a straw.

Be active. Any physical activity is better than none. Even if you don't want to join a gym or take up running, simply going for a walk can have real health benefits!

When you eat, focus on eating. Eating is often something we do in the background while we watch TV or check our phones. When we eat like this, we eat more. When you quit smoking, make a point of removing distractions when you eat. Also try eating a bit slower and focus on enjoying your food. This can help you notice when you are getting full.

If you are worried about gaining weight, a quit coach can help you with other quitting tips, or you can talk with your healthcare provider for help.

People who smoke are more likely to have anxiety or depression than people who don't smoke. Some people feel mood changes for a short time after they quit smoking. Watch for this, especially if you've ever had anxiety or depression.

For some people, smoking may seem like it helps with anxiety or depression, but don't be tricked. Smoking might make you feel better in the short-term, but that's because the nicotine in cigarettes stops the discomfort of withdrawal, not because it is helping with anxiety or depression. There are much better ways to deal with withdrawal symptoms and mood changes than returning to smoking! The good news is that once people have been smoke-free for a few months, their anxiety and depression levels are often lower than when they were smoking.
Ways to manage:

Be Active. Being physically active can help lift your mood. Start small and build up over time. This can be hard to do if you're feeling down. But your efforts will pay off.

Structure your day. Stay busy. Get out of the house if you can.

Connect with other people. Being in touch or talking with others every day can help your mood. Try to connect with people who are supportive of your efforts to quit smoking.

Reward yourself. Do things you enjoy. Even small things add up and help you feel better.

Talk with a healthcare provider. If you don't feel better in a couple weeks, or your symptoms feel unmanageable, it's important to contact a healthcare provider.

What if feelings of depression get worse, or don't get better? You should get help. Talk to your healthcare provider, call the quitline ( 1-800-QUIT-NOW), or seek appropriate emergency help.

Sometimes people who are feeling depressed think about hurting themselves or dying. If you or someone you know is having these feelings, get help now.

Call or text the 988 Suicide & Crisis Lifeline at 988, available 24 hours a day, 7 days a week. Online chatexternal icon is available 24/7.

Call 911 or go to the nearest hospital emergency department for emergency medical treatment.

Don't be alone. Don't leave another person alone if he or she is in crisis.

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centers for disease control and prevention

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The Tips From Former Smokers campaign features real people suffering as a result of smoking and exposure to secondhand smoke.

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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4363846/#:~:text=Nicotine%20on%20direct%20application%20in,after%20cutaneous%20and%20respiratory%20exposure.

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Abstract

With the advent of nicotine replacement therapy, the consumption of the nicotine is on the rise. Nicotine is considered to be a safer alternative of tobacco. The IARC monograph has not included nicotine as a carcinogen. However there are various studies which show otherwise. We undertook this review to specifically evaluate the effects of nicotine on the various organ systems. A computer aided search of the Medline and PubMed database was done using a combination of the keywords. All the animal and human studies investigating only the role of nicotine were included. Nicotine poses several health hazards. There is an increased risk of cardiovascular, respiratory, gastrointestinal disorders. There is decreased immune response and it also poses ill impacts on the reproductive health. It affects the cell proliferation, oxidative stress, apoptosis, DNA mutation by various mechanisms which leads to cancer. It also affects the tumor proliferation and metastasis and causes resistance to chemo and radio therapeutic agents. The use of nicotine needs regulation. The sale of nicotine should be under supervision of trained medical personnel.

Keywords: Addiction, cancer, cardiovascular, gastrointestinal, nicotine, respiratory

INTRODUCTION

Tobacco is the leading cause of preventable cancers. WHO estimated around 1.27 billion tobacco users world-wide. Tobacco consumption alone accounts for nearly 5.4 million deaths per year and one billion people may die in this century if global tobacco consumption remained at the current levels.[ 1] An international treaty spearheaded by WHO in 2003 and signed by 170 countries, aims to encourage governments to reduce the production, sales, distribution advertisement and promotion of tobacco products. Despite strong opposition from the Industry, the treaty has been making steady progress in achieving its goal of comprehensive tobacco control around the world.[ 2] As tobacco consumption is being curbed, there is a growing demand for cessation. Pharmacological treatment of nicotine addiction remains an active area of research. There are many nicotine preparations (nicotine gums, patches, e cigarettes and inhalational agents) that are freely available in most parts of the world. These products are being heavily promoted and marketed as magical remedies. Nicotine gums are available in 2 mg and 4 mg preparation that deliver around 1 mg and 3 mg nicotine to the blood stream respectively. E-cigarette, a sophisticated nicotine delivery device, delivers nicotine in a vapor form and it closely mimics the act of smoking. Currently, these products constitute approximately 1% of total nicotine consumption and are showing an increasing trend in most countries.[ 3]

Nicotine is well known to have serious systemic side effects in addition to being highly addictive. It adversely affects the heart, reproductive system, lung, kidney etc. Many studies have consistently demonstrated its carcinogenic potential. [ Table 1 ] The only other known use of nicotine has been as an insecticide since 17 th century.[ 4] After World War II, its use has declined owing to the availability of cheaper, more potent pesticides that are less harmful to mammals. The environment Protection Agency of United States has banned use of nicotine as a pesticide from 1 st January 2014.[ 4] India, one of the largest producer and exporter of nicotine sulphate, has progressively banned its use as agricultural pesticide.[ 5] We undertook this review to evaluate the systemic adverse effects of nicotine.

Table 1

MATERIALS AND METHODS

A computer aided search of the Medline and PubMed databases was done using different combination of the keywords "nicotine," "chemical composition," "history," "metabolism," "addiction," "cancer," "toxic," "endocrine system," "cardiovascular system," "respiratory system," "lung carcinogenesis, "gastrointestinal system," "immune system," "ocular," "cataract," "central nervous system," "renal system," "reproductive system," "menstrual cycle," "oocytes," "foetus,". Initial search buildup was done using "Nicotine/adverse effects" [Mesh], which showed 3436 articles. Articles were analyzed and 90 relevant articles were included in the review. All the animal and human studies that investigated the role of nicotine on organ systems were analyzed. Studies that evaluated tobacco use and smoking were excluded. All possible physiological effects were considered for this review. We did not exclude studies that reported beneficial effects of nicotine. The objective was to look at the effects of nicotine without confounding effects of other toxins and carcinogens present in tobacco or tobacco smoke.

CHEMICAL PROPERTIES AND METABOLISM

Nicotine was first extracted from tobacco by German physicians Wilhelm Heinrich Posselt and Karl Ludwig Reimann. Nicotine, a strong alkaloid, in its pure form is a clear liquid with a characteristic odour. It turns brown on exposure to air. It is water soluble and separates preferentially from organic solvents. It is an amine composed of pyridine and pyrrolidine rings.

Nicotine is a dibasic compound and the availability and absorption in human body depends upon the pH of the solution.[ 7] The absorption can occur through oral mucosa, lungs, skin or gut.[ 6] The increase in pH of a solution causes an increase in concentrations of uncharged lipophilic nicotine, in this form it can actively pass through all biological membranes.[ 7] The addition of slaked lime and catechu to tobacco increases the absorption of nicotine from the oral cavity.

Nicotine once ingested, is absorbed and metabolized by the liver. The metabolic process can be categorized into two phases. In phase I there is microsomal oxidation of the nicotine via multiple pathways.[ 8] This leads to formation of various metabolites like cotinine and nornicotine, demethyl cotinine, trans-3-hydroxy-cotinine and d-(3-pyridyl)-g-methylaminobutyric acid.[ 9, 10] Thereafter in phase II there is N'-and O'-glucuronidation of the metabolites and excretion via urine, feces, bile, saliva, sweat etc.[ 11, 12]5-10% of elimination is by renal excretion of unchanged nicotine, however there is reabsorption from the bladder when the urinary pH is high.[ 14] There is evidence that nitrosation of nicotine in vivo could lead to formation of N-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK).[ 13] which are known to be highly carcinogenic. Inflammation in the oral cavity increases risk of endogenous nitrosation.

MECHANISM OF ACTION

Nicotine acts via 3 major mechanisms, producing physiological and pathological effects on a variety of organ systems.[ 15, 16]

1. Nicotinic acetylcholine receptors (nAChRs) on chromaffin cells via catecholamines.

2. Central nervous system (CNS) stimulation of nAChRs.

Brain imaging studies demonstrate that nicotine acutely increases activity in the prefrontal cortex and visual systems. There is release of a variety of neurotransmitters important in drug-induced reward. Nicotine also causes an increased oxidative stress and neuronal apoptosis, DNA damage, reactive oxygen species and lipid peroxide increase. nAChRs were originally thought to be limited to neuronal cells, however, studies have identified functional nAChRs in tissues outside the nervous system. Actions on nicotinic receptors produce a wide variety of acute and long-term effects on organ systems, cell multiplication and apoptosis, throughout the body.

IMMEDIATE EFFECTS AND TOXICITY

Nicotine on direct application in humans causes irritation and burning sensation in the mouth and throat, increased salivation, nausea, abdominal pain, vomiting and diarrhea.[ 17] Gastrointestinal effects are less severe but can occur even after cutaneous and respiratory exposure.[ 18] Predominant immediate effects as seen in animal studies and in humans consist of increase in pulse rate and blood pressure. Nicotine also causes an increase in plasma free fatty acids, hyperglycemia, and an increase in the level of catecholamines in the blood.[ 19, 20] There is reduced coronary blood flow but an increased skeletal muscle blood flow.[ 20, 22] The increased rate of respiration causes hypothermia, a hypercoagulable state, decreases skin temperature, and increases the blood viscosity.

Nicotine is one of the most toxic of all poisons and has a rapid onset of action. Apart from local actions, the target organs are the peripheral and central nervous systems. In severe poisoning, there are tremors, prostration, cyanosis, dypnoea, convulsion, progression to collapse and coma. Even death may occur from paralysis of respiratory muscles and/or central respiratory failure with a LD50 in adults of around 30-60 mg of nicotine. In children the LD50 is around 10 mg.[ 23]

GREEN TOBACCO SICKNESS

This is an acute form of nicotine toxicity that is known to occur due to handling of green tobacco leaves, with symptoms lasting from 12 to 24 h. The acute symptoms include headache, nausea, vomiting, giddiness, loss of appetite, fatigue and tachyarrythmias.[ 24] No significant mortality has been reported due to green tobacco sickness (GTS) but it significantly affects the health of workers in the tobacco industry.[ 25]

NICOTINE ADDICTION

Nicotine is one of the most addicting agent. The US surgeon general (2010) has concluded nicotine to be as addictive as cocaine or heroin. Nicotine interacts with the nicotinic acetyl choline receptors and stimulates the dopaminergic transmission.[ 26] This in turn stimulates the reward centre and is responsible for the mood elevation and apparent improvement in cognitive function.[ 27] With chronic stimulation by nicotine the GABAergic neurons are desensitized and thus lose their inhibitory effect on dopamine.[ 28] This in turn reinforces the addiction by inducing craving. This effect has been shown to affect the CYP2A6 gene and leads to heritable dependence to nicotine. Studies have shown the nicotine dependence to be transmitted maternally and grand maternally by epigenetic mechanism.[ 29]

EFFECTS ON METABOLISM

Nicotine causes catecholamine release and stimulates the autonomic system. There is increased glycogen synthesis due to α-adrenoceptor stimulation. This leads to reduction in the fasting blood glucose levels. It also causes lipolysis thus decreasing body weight. Nicotine affects insulin resistance and predisposes to metabolic syndrome. In an animal study prenatal exposure was toxic to pancreatic β-cell and leads to decreased B cell population, thus increasing the risk of diabetes.[ 30, 31]

NICOTINE AND CANCER

Nicotine forms arachidonic acid metabolites which cause increased cell division. Binding to Bcl-2 and action on vascular endothelial growth factor and cyclooxygenase-2 (COX-2) causes increased cancer proliferation and survival.[ 35, 36] Promotion of tumor angiogenesis accelerates tumor growth which is mediated by β-adrenergic activation and stimulation of nAChRs.[ 35, 37, 28, 39] Nicotine also suppresses apoptosis by phosphorylation mediated extracellular signal regulated kinases of Bcl-2.[ 40, 41] Recent studies show that nicotine, activates nuclear factor kappa B (NF-kB)-dependent survival of cancer cell and proliferation.[ 42]

In normal cells, nicotine can stimulate properties consistent with cell transformation and the early stages of cancer formation, such as increased cell proliferation, decreased cellular dependence on the extracellular matrix for survival, and decreased contact inhibition. Thus, the induced activation of nAChRs in lung and other tissues by nicotine can promote carcinogenesis by causing DNA mutations[ 26] Through its tumor promoter effects, it acts synergistically with other carcinogens from automobile exhausts or wood burning and potentially shorten the induction period of cancers[ 43] [ Table 2 ].

Table 2

LUNG CARCINOGENESIS

A study relates lung carcinogenesis by nicotine due to genetic variation in CYP2B6.[ 44] Its simultaneous exposure with hyperoxia has been found to induce cancer in hamsters.[ 45] Cotinine has been found to promote lung tumorigenesis by inhibiting anti-apoptotic pathway.[ 46] Nuclear translocation of ARB1 gene by nicotine has found in proliferation and progression of nonsmall-cell lung cancer. Several Studies have shown that nicotine has significant role in tumor progression and metastasis via CXCR4 and increased angiogenesis.[ 36, 47] Carriers of the lung-cancer-susceptibility loci in their DNA extract more nicotine. Smokers carrying the gene CHRNA3 and CHRNA5 were found to extract more nicotine and cells were thus exposed to a higher internal dose of carcinogenic nicotine-derived nitrosamines.[ 48] Additionally modulation of the mitochondrial signaling pathway leads to resistance to the chemotherapeutic agents.[ 49]

GASTRO INTESTINAL CARCINOGENESIS

The carcinogenic role may be mediated by the MAPK/COX-2 pathways, α-7 nAchR and β-adrenergic receptor expression, and mi RNAs α-BTX anatagonist.[ 50] Nicotine forms adducts with liver DNA which enhances its mutagenic potential.[ 49, 51, 52] activation of cell-surface receptors by nicotine stimulates downstream kinases that can mediate resistance to chemotherapy. It has been shown by the finding that smokers who continue to smoke during chemotherapy have a worse prognosis. Moreover they also have increased toxicity and lower efficacy of chemo therapeutic drugs.[ 53] Nicotine affects the periostin gene, α-7-nAChR and e-cadherin suppression which explains the mechanism of gastric cancer growth, invasion and metastasis.[ 54, 55] Nicotine negatively impacts tumor biology by promoting angiogenesis, tumor invasion and increased risk of metastasis.[ 53]

PANCREATIC CANCER

BREAST CANCER

Nicotine causes α9-nAChR-mediated cyclin D3 overexpression which might cause transformation of normal breast epithelial cells and induce cancer. Nicotine and cotinine has been found to be present in the breast fluid of lactating women.[ 59] Several studies have found that α9-nAChR mediated mechanism leads to increased tumor growth, metastasis and tumor cells resistant to chemotherapeutic drugs in breast cancer.[ 59, 60]

CARDIOVASCULAR SYSTEM

The acute hemodynamic effects of cigarette smoking or smokeless tobacco are mediated primarily by the sympathomimetic action. The intensity of its hemodynamic effect is greater with rapid nicotine delivery.[ 61] Nicotine causes catecholamine release both locally and systemically leading to an increase in heart rate, blood pressure and cardiac contractility. It reduces blood flow in cutaneous and coronary vessels; and increases blood flow in the skeletal muscles. Due to restricted myocardial oxygen delivery there is reduced cardiac work. In a study, chewing a low dose (4 mg) of nicotine gum by healthy nonsmokers blunted the increase in coronary blood flow that occurs with increased heart rate produced by cardiac pacing.[ 21] Thus, persistent stimulation by nicotine can contribute to Coronary Vascular Disease by producing acute myocardial ischemia. In the presence of coronary disease, myocardial dysfunction can be worsened. In a placebo-controlled experiment that produced transient ischemia in anesthetized dogs myocardial dysfunction was produced at doses, that did not alter heart rate, blood pressure, or blood flow or myocyte necrosis.[ 62]

Nicotinic acetylcholine receptor's actions on vascular smooth muscle proliferation and plaque neovascularization increases the risk of peripheral arterial disorders. In a murine model of hind limb ischemia, short-term exposure to nicotine paradoxically increased capillary density and improved regional blood flow in the ischemic hind limb.[ 35] However, long-term exposure to nicotine for 16 weeks (about one-third of the life span of a mouse) before induction of ischemia obliterated angiogenic response to nicotine.[ 68]

RESPIRATORY SYSTEM

The effects of nicotine on respiratory system are twofold. One, directly by a local exposure of lungs to nicotine through smoking or inhaled nicotine, and second via a central nervous system mechanism. Nicotine plays a role in the development of emphysema in smokers, by decreasing elastin in the lung parenchyma and increasing the alveolar volume. Nicotine stimulates vagal reflex and parasympathetic ganglia and causes an increased airway resistance by causing bronchoconstriction.[ 69] Nicotine alters respiration through its effects on the CNS. The simultaneous effect of bronchoconstriction and apnea increases the tracheal tension and causes several respiratory disorders. In a study microinjection of nicotine were administered to the prebotzinger complex and adjacent nuclei in the brain. The firing pattern of the brain signals and breathing pattern were monitored. There was an increased frequency of bursts and decreased amplitude and a shallow and rapid rhythm of respiration.[ 70]

GASTROINTESTINAL SYSTEM

There is an increased incidence of treatment resistant Helicobacter pylori infection in smokers. It potentiates the effects of toxins of H. pylori by its action on the gastric parietal cells.[ 75] This effect could be due to histamine mediated response of nicotine.

IMMUNOLOGICAL SYSTEM

Nicotine has been known to be immunosuppressive through central and peripheral mechanisms. It impairs antigen and receptor mediated signal transduction in the lymphoid system leading to decreased immunological response. The T-cell population is reduced due to arrest of cell cycle. Even the macrophage response, which forms the first line defense against tuberculosis becomes dysfunctional and causes increased incidence of tuberculosis.[ 76] The migration of fibroblasts and inflammatory cells to the inflamed site is reduced. There is decreased epithelialization and cell adhesion and thus there is a delayed wound healing as well as increased risk of infection in nicotine exposed individuals.

The action on the hypothalamo-pituitary adrenal axis and autonomic nervous system stimulation via sympathetic and parasympathetic pathways affects the immune system. The adrenocorticotropic hormone (ACTH) secretion pathway and corticotrophin release is affected and this causes immunosuppression.[ 77]

OCULAR SYSTEM

Nicotine promotes pathologic angiogenesis and retinal neovascularization in murine models. It causes age-related macular degeneration in mice.[ 78] In a clinical study, the most virulent form of age-related maculopathy was associated with retinal neovascularization that contributed to visual deterioration. Tobacco smokers are known to be at greater risk of age-related macular degeneration than are nonsmokers.[ 79] In animal model, spraguely Dawley rats with type 1 diabetes treated with nicotine, developed cataract.[ 80] Thus the syngergistic relationship between nicotine and glucose metabolism exaggerating diabetes might cause accelerated cataract formation. There is synergistic relationship between nicotine and glucose metabolism which increases the risk of diabetes mellitus. This might cause accelerated cataract formation.

RENAL SYSTEM

Risk of chronic kidney disease in smokers is high. Cigarette smoking has been found to increase albumin excretion in urine, decrease glomerular filtration rate, causes increased incidence of renal artery stenosis and is associated with an increased mortality in patients with end-stage renal disease. The pathogenesis of renal effects is due to the action of nicotine via COX-2 isoform induction. The COX-2 isoforms causes increased glomerular inflammation, acute glomerulonephritis and ureteral obstruction.[ 81] There is impaired response of kidneys to the increased systemic blood pressure in smokers. This loss of renoprotective mechanism in smokers also leads to pathogenetic effects of nicotine on the renal system.[ 82]

REPRODUCTIVE SYSTEM - MALES

Nitrous oxide liberated from parasympathetico-nergic nerves plays a pivotal role in generating immediate penile vasodilatation and corpus cavernosum relaxation, and NO derived from endothelial cells contributes to maintaining penile erection. Nicotine causes impairment of NO synthesis. This may lead to loss of penile erections and erectile dysfunction.[ 83]

Various animal studies suggest that nicotine causes seminiferous tubules degeneration, disrupts the spermatogenesis and at cellular level, affect germ cell structure and function in males.[ 84] It decreases testosterone levels which is secondary to decreased production of StAR.[ 85] StAR is the protein which plays an important role in testosterone biosynthesis.

REPRODUCTIVE SYSTEM - FEMALE

Menstrual cycle

Nicotine by inhibiting the 21 hydoxylase causes hypoestrogenic state. It shunts the metabolites to formation of androgen. This leads to chronic anovulation and irregular menstrual cycles. Nicotine can predispose the endometrium to inappropriate cytokine production and irregular bleeding.[ 86] There is consistent evidence that increase in follicle-stimulating hormone levels and decreases in estrogen and progesterone that are associated with cigarette smoking in women, is atleast in part due to effects of nicotine on the endocrine system.[ 26]

Effect on oocytes

Nicotine affects the ovaries and alters the production of oocytes in various animal studies. Nicotine-treated oocytes appeared nonspherical with rough surface and torn and irregular zona-pellucida. Nicotine also caused disturbed oocyte maturation. There is a decreased blood flow to the oviducts and thus impaired fertilization.[ 87]

Peri-natal effects

Maternal smoking has always been known to have deleterious effects on the fetal outcome. There is an increased incidence of intrauterine growth restriction, still birth, miscarriages and mental retardation.[ 88] Various animal studies show retarded fetal growth and lower birth weight when treated perinatally with nicotine. The lower levels of ACTH and cortisol due to nicotine are probable reasons for the incidence of lower birth weight in the newborns.[ 89]

Maternal as well as grand maternal smoking has been found to increase risk of pediatric asthma. Another serious and important effect is the transgenic transmission of the addictive pattern.[ 29]

CONCLUSION

Nicotine is the fundamental cause of addiction among tobacco users. Nicotine adversely affects many organs as shown in human and animal studies. Its biological effects are widespread and extend to all systems of the body including cardiovascular, respiratory, renal and reproductive systems. Nicotine has also been found to be carcinogenic in several studies. It promotes tumorigenesis by affecting cell proliferation, angiogenesis and apoptotic pathways. It causes resistance to the chemotherapeutic agents. Nicotine replacement therapy (NRT) is an effective adjunct in management of withdrawal symptoms and improves the success of cessation programs. Any substantive beneficial effect of nicotine on human body is yet to be proven. Nicotine should be used only under supervision of trained cessation personnel therefore its sale needs to be strictly regulated. Needless to say, that research for safer alternative to nicotine must be taken on priority.

Footnotes

Source of Support: Nil

Conflict of Interest: None declared.

REFERENCES

34. International Agency for Research on Cancer. Tobacco smoke and involuntary smoking. IARC Monogr Eval Carcinog Risk Hum. 2007;89:455-7. [ Google Scholar]

64. Villablanca AC. Nicotine stimulates DNA synthesis and proliferation in vascular endothelial cells [ in vitro. J Appl Physiol. 1998;84:2089-98. [ PubMed] Google Scholar]

65. Chalon S, Moreno H, Jr, Benowitz NL, Hoffman BB, Blaschke TF. Nicotine impairs endothelium-dependent dilatation in human veins [ in vivo. Clin Pharmacol Ther. 2000;67:391-7. [ PubMed] Google Scholar]

87. Hammer RE, Mitchell JA, Goldman H. Cellular and Molecular Aspects of Implantation. US: Springer; 1981. Effects of nicotine on concept us cell proliferation and oviductal/uterine blood flow in the rat; pp. 439-42. [ Google Scholar]

Articles from Indian Journal of Medical and Paediatric Oncology : Official Journal of Indian Society of Medical & Paediatric Oncology are provided here courtesy of Wolters Kluwer -- Medknow Publications

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With the advent of nicotine replacement therapy, the consumption of the nicotine is on the rise. Nicotine is considered to be a safer alternative of tobacco. The IARC monograph has not included nicotine as a carcinogen. However there are various studies ...

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Abstract

More than 70% of adolescents report to have smoked a cigarette at least once. At the adolescent stage the brain has not completed its maturation. The prefrontal cortex (PFC), the brain area responsible for executive functions and attention performance, is one of the last brain areas to mature and is still developing during adolescence. Smoking during adolescence increases the risk of developing psychiatric disorders and cognitive impairment in later life. In addition, adolescent smokers suffer from attention deficits, which aggravate with the years of smoking. Recent studies in rodents reveal the molecular changes induced by adolescent nicotine exposure that alter the functioning of synapses in the PFC and that underlie the lasting effects on cognitive function. Here we provide an overview of these recent findings.

Nicotine exposure during adolescence alters acetylcholine and glutamate receptor signaling in the prefrontal cortex, one of the last brain areas to mature. This may help explain altered cognitive function and attention performance in adolescents who smoke.

Adolescence is a truly revolutionary time period in anyone's life, the age of explosive development of both emotional and cognitive sides of the mind. This is the age when passions ignite, when creativity is at its peak, bold and original ideas shake old theories, friendships and first loves are found, and important breakthroughs are made. But adolescence also has a dark side. The uncontrollable emotions create a risk zone for behavioral problems, psychopathology, and addiction. To quote John Ciardi: "You don't have to suffer to be a poet. Adolescence is enough suffering for anyone." Indeed, adolescence also marks a period of increase in the number of suicides, accidents, homicides, mood disorders, unwanted pregnancies, anorexia, bulimia, and substance abuse, such as tobacco smoking ( Resnick et al. 1997; Ozer et al. 2004).

What makes adolescence such a painful period some people are happy to survive? The answer may lie in adolescent brain development. Brain development continues throughout adolescence, although the speed and timing of maturation varies for different brain areas ( Gogtay et al. 2004). Subcortical limbic structures important for emotional processing, such as hypothalamus, midbrain dopamine areas, nucleus accumbens, dorsal and ventral striatum, and amygdala, experience a major developmental boost around the onset of puberty ( Sowell et al. 2003; Casey et al. 2005). Their maturation is important for social and sexual behaviors and is triggered by pubertal hormones. In contrast, development of frontal cortical areas of the brain, responsible for cognitive control over behavior, depends on age and experience and continues throughout adolescence and into adulthood ( Sowell et al. 2003; Giedd 2004). Thus, during adolescence emotional drive has already become very strong, whereas cognitive self-control and adult decision-making strategies still are developing. Thereby, brain development may be responsible for characteristic adolescent traits-uncontrollable mood swings, impulsivity, risk taking, and peer-directed social interactions ( Orr and Ingersoll 1995; Spear 2000; Galvan et al. 2007). Although indispensable for transition from child to independent status of adult, these traits can backfire and cause damage. Indeed, risk-taking behavior, so typical for adolescents, is associated with high rates of mortality and morbidity among young people ( Grunbaum et al. 2004).

The impulsive, peer-influenced nature of adolescent choices leads to another important health risk-experimenting with drugs of abuse. Since nicotine is one of the most socially accepted drugs in our society, the first choice usually falls on tobacco smoking. According to a recent study conducted in 41 countries in Europe and North America, 19% of 15-year-olds smoke at least once a week and 30% report experimenting with cigarettes before the age of 14 ( Currie et al. 2008). Serious health risks of smoking are well known: Smoking leads to millions of premature deaths worldwide and tobacco smoking has been marked as an epidemic disease ( Peto et al. 1999). Nicotine is also a psychoactive and addictive substance that directly acts on brain areas involved in emotional and cognitive processing. Early exposure to nicotine during the transition from child to adult may be harmful, since it may derange the normal course of brain maturation and have lasting consequences for cognitive ability, mental health, and even personality ( Brown et al. 1996; Choi et al. 1997; Richards et al. 2003; Brook et al. 2004; Deas 2006). In this review, we will highlight recent findings that start to uncover causal relations between nicotine exposure during adolescence and cognitive deficits in later life, pinpointing the underlying functional synaptic adaptations in prefrontal networks.

SENSITIVITY TO NICOTINE OF THE ADOLESCENT BRAIN

Comparing smoking behavior of adolescents to that of adults may point to an enhanced sensitivity of the adolescent brain to addictive properties of nicotine. Adolescents report symptoms of dependence even at low levels of cigarette consumption ( Colby et al. 2000; Kandel and Chen 2000). The most susceptible youth lose autonomy over tobacco intake already within 1 or 2 days of first inhaling from a cigarette. Among adolescents the appearance of tobacco withdrawal symptoms and failed attempts to stop smoking can precede daily smoking dependence and appear even before consumption reaches two cigarettes per day ( DiFranza et al. 2007).

The difference in sensitivity to nicotine between adolescents and adults is also reported for laboratory animals ( Slotkin 2002; Adriani et al. 2003). Rats first exposed to nicotine during adolescence self-administer more nicotine than rats exposed in adulthood and these differences in self-administration at first exposure persist into later age ( Levin et al. 2003). Similarly, much lower doses of nicotine or a single injection are sufficient to establish conditioned place preference in adolescent rats, but not in adult animals ( Vastola et al. 2002; Belluzzi et al. 2004; Brielmaier et al. 2007). Thus, paradigms for both self-administration and conditioned place preference in rats suggest that adolescence may be a developmental stage of particular vulnerability to the effects of nicotine exposure.

The vulnerability to rewarding effects of nicotine during adolescence may be explained by adolescent brain development. Structural and functional MRI data show earlier maturation of reward systems and much slower development of prefrontal cognitive control ( Spear 2000; Chambers et al. 2003; Casey et al. 2005; Ernst et al. 2005; Ernst and Fudge 2009). Compared with adults, adolescents are generally more motivated by rewards, are less averse to risks, and are more easily influenced by peers ( Spear 2000; Steinberg 2005; Galvan et al. 2006). The same applies to estimation of health risks of smoking-adolescents have a more optimistic attitude regarding their smoking behavior than adults, believing that they "could smoke for a few years and then quit" if they wished ( Arnett 2000). Lack of mature cognitive control in adolescents makes them also more susceptible to social pressure. The smoking behavior of parents, siblings, and friends leads to a higher risk of smoking among adolescents and this social influence decreases with age ( Vink et al. 2003). Adolescents with ADHD symptoms, whose behavior is even more characterized by impulsive and risk-taking choices, are more likely to experiment with smoking and to become regular tobacco users ( Tercyak et al. 2002; McClernon et al. 2008). Importantly, nicotine may also lead to higher levels of dependence by exerting neurotoxic effects in the prefrontal cortex (PFC) interfering with adolescent cognitive development, executive functioning, and inhibitory control. These effects are particularly evident under stressful or emotionally intense states and are most pronounced when smoking begins during early adolescence ( DeBry and Tiffany 2008).

Taken together, most likely owing to its ongoing development, the adolescent brain is more vulnerable to the effects of nicotine than the adult brain. Adolescents progress faster to nicotine dependence than adults, find nicotine more rewarding, underestimate the risks of smoking, and are more influenced by smoking behavior in their social milieu. This may explain why one of five adolescents smokes regularly and up to 70% of adolescents have experimented with smoking ( Currie et al. 2008; Sidransky 2010). Because nicotine acts directly on the pathways involved in cognitive control, development of the PFC during adolescence may be affected by nicotine exposure. What are the acute consequences of nicotine exposure for neuronal circuits in the PFC of the adolescent brain?

IMMEDIATE EFFECTS OF NICOTINE ON THE ADOLESCENT PREFRONTAL CORTICAL NETWORK

Once nicotine has entered the body, it is distributed quickly through the bloodstream and crosses the blood-brain barrier reaching the brain within 10-20 sec after inhalation ( Le Houezec 2003). Once in the brain, it binds to its target, the nicotinic acetylcholine receptors (nAChR), which take part in cholinergic signaling in the PFC. Twelve genes have been identified encoding neuronal nicotinic receptors (for a review, see Le Novere et al. 2002; Millar and Gotti 2009). In the central nervous system nine α-subunits (α2-α10) and three β-type subunits (β2-β4) are expressed. These subunits assemble in different stoichiometries to form pentameric channels, and subunit compositions of nAChRs vary depending on the brain region (for a review, see Grady et al. 2002; Le Novere et al. 2002; McGehee 2002; Alkondon and Albuquerque 2004; Wonnacott et al. 2005; Mineur and Picciotto 2008; Millar and Gotti 2009). Nicotinic AChRs are cation selective channels that permit the flow of Na⁺, K⁺, and Ca ²⁺ across the membrane, which leads to depolarizing currents and activate neurons ( McGehee and Role 1995; Millar and Gotti 2009).

In the PFC, nAChR expression is found across all layers ( Gioanni et al. 1999; Poorthuis et al. 2012). nAChRs can alter pyramidal neuron activity by enhancing glutamatergic inputs or by activating postsynaptic receptors directly ( Poorthuis et al. 2009). Hippocampal pyramidal neurons express functional α7 nAChR ( Ji et al. 2001). In motor cortex, somatosensory cortex, and visual cortex layers II-III and layer V pyramidal neurons do not contain nAChRs ( Nicoll et al. 1996; Gil et al. 1997; Xiang et al. 1998; Porter et al. 1999; Gulledge et al. 2007). We find that PFC layers II-III pyramidal cells also do not contain nAChRs, and also glutamatergic inputs to these pyramidal neurons are not modulated by nAChRs. Hence, nAChRs do not augment the output of superficial pyramidal neurons in the PFC.

In contrast, in layer V pyramidal neurons, activation of presynaptic β2* nAChRs on glutamatergic inputs from the thalamus strongly enhances activity of these neurons ( Gioanni et al. 1999; Lambe et al. 2003; Couey et al. 2007; Poorthuis et al. 2012). These presynaptic mechanisms are specific to layer V, as they are absent in layers II-III and moderate in layer VI. This may suggest that nAChR-mediated modulation of thalamic inputs to the PFC is specifically targeting layer V pyramidal neurons, which project to the striatum and hypothalamus ( Gabbott et al. 2005). Nicotinic enhancement of thalamic inputs to the cortex also plays a role in primary sensory areas, where it enhances sensory representation in the cortical target structure ( Penschuck et al. 2002; Disney et al. 2007; Kawai et al. 2007). In addition to presynaptic β2* nAChRs that can augment its activity, layer V pyramidal neurons also contain postsynaptic α7 nAChRs. In contrast to layer V, excitatory glutamatergic inputs to layer VI pyramidal neurons were mildly modulated by nAChRs. These neurons are modulated by β2* nAChRs that are responsible for the strong activation of the layer VI neuronal population ( Kassam et al. 2008; Poorthuis et al. 2012). Layer VI pyramidal neurons in entorhinal cortex also have been reported to be modulated by non-α7 nAChRs, most likely containing β2 subunits ( Tu et al. 2009).

In addition to direct activation of PFC pyramidal neurons by nAChRs, PFC GABAergic interneurons are also directly activated by nAChR stimulation. Interneurons form a highly diverse group of cells with distinct roles in cortical computation ( Kawaguchi 1993; Markram et al. 2004). Fast-spiking cells target the perisomatic region of pyramidal neurons ( Kawaguchi and Kubota 1997; Kawaguchi and Kondo 2002) and are therefore thought to be involved in regulating the activity window of pyramidal neurons. In somatosensory areas fast-spiking cells regulate feedforward inhibition of incoming thalamic inputs ( Sun et al. 2006). Feedforward inhibition in the PFC plays an important role in the integration of hippocampal inputs, which enter the PFC through superficial layers ( Jay and Witter 1991; Tierney et al. 2004). Fast-spiking cells in PFC layers II-III contain α7 nAChRs, as do about half of the fast-spiking cells in layer V ( Poorthuis et al. 2012). nAChR activation on fast-spiking interneurons in PFC layer II/III may alter processing of hippocampal inputs.

Somatostatin-positive cells target distal dendritic regions ( Kawaguchi and Kondo 2002; Silberberg and Markram 2007) and can mediate disynaptic inhibition between pyramidal neurons ( Kapfer et al. 2007; Silberberg and Markram 2007). Regular-spiking and somatostatin-positive cells in PFC layers II-II and V are positive for nAChRs, suggesting that nAChRs play an important role in modulating feedback inhibition among pyramidal neurons in these layers ( Poorthuis et al. 2012).

Increased inhibition through activation of nAChRs expressed by interneurons has been found in many different brain regions ( Jones and Yakel 1997; Xiang et al. 1998; McQuiston and Madison 1999; Alkondon et al. 2000; Ji and Dani 2000; Mansvelder et al. 2002; Gulledge et al. 2007). When activated by nAChR stimulation, interneurons can alter activity and plasticity in pyramidal neurons ( Xiang et al. 1998; Alkondon et al. 2000; Ji and Dani 2000; Ji et al. 2001; Couey et al. 2007). Increased inhibition can lead to blockade of long-term potentiation (LTP) induction in the hippocampus ( Ji et al. 2001) and increase in the threshold for induction of spike-timing-dependent plasticity (STDP) ( Couey et al. 2007). Similar mechanisms may play a role across PFC layers because we find that non-fast-spiking cells in all layers express nAChRs.

UP-REGULATION OF nAChRs AND SYNAPTIC mGluRs IN PREFRONTAL CORTEX BY NICOTINE EXPOSURE DURING ADOLESCENCE

A current hypothesis explaining why adolescents are more vulnerable to nicotine addiction is that nicotine has greater positive effects on adolescents than adults, whereas the negative effects associated with nicotine, such as withdrawal, are smaller in adolescents ( O'Dell 2009). Nicotine administration during, but not following, adolescence has long-lasting effects on cognitive, addictive, and emotional behavior in rats ( Adriani et al. 2003; Iniguez et al. 2008; Counotte et al. 2009, 2011). Furthermore, adolescent animals are more sensitive to nicotine-conditioned place preference than adults and show this at lower nicotine doses ( Vastola et al. 2002; Belluzzi et al. 2004; Shram et al. 2006; Brielmaier et al. 2007; Kota et al. 2009). Adolescent nicotine exposure leads to acute and longer-lasting changes in nAChR binding ( Abreu-Villaca et al. 2003; Doura et al. 2008) and function ( Kota et al. 2009) in brain regions such as cortex and striatum. We recently found that the adolescent rodent brain is more sensitive to nicotinic receptor up-regulation in the medial PFC (mPFC) than adults ( Counotte et al. 2012). Naïve rats show an age-related decrease in ³H-epibatidine labeled high-affinity nicotinic receptors in the mPFC, but not in occipital cortex. Adolescent, but not adult nicotine exposure increases ³H-Epi binding of mPFC receptors on the first day of abstinence following 10 days of nicotine injections. This is paralleled by an mPFC-specific increase in expression of nAChRs containing α4 and β2 (but not α5) subunits. The increased expression of high-affinity nAChRs in adolescents is accompanied by an increase in nicotine-stimulated GABAergic synaptic transmission in the mPFC ( Counotte et al. 2012).

One of the first and most common cellular adaptations following chronic nicotine exposure is the up-regulation of nicotinic receptor levels ( Dani and Bertrand 2007). Especially α4β2 type of nAChRs appears to be selectively up-regulated via posttranslational mechanisms ( Miwa et al. 2011). The up-regulation of α4β2 nAChRs by chronic nicotine treatment has been replicated many times in numerous systems-transfected cell lines, neurons in culture, brain slices, and smokers' brains ( Wonnacott 1990; Fu et al. 2009; Lester et al. 2009; Marks et al. 2011; Miwa et al. 2011). Up-regulation is not accompanied by an increase in nAChR subunit mRNA ( Marks et al. 1992); instead it leads to increased nAChR protein levels resulting from increased assembly and/or decreased degradation of nAChRs ( Marks et al. 2011). Nicotine appears to act intracellularly as a selective pharmacological chaperone of acetylcholine receptor ( Lester et al. 2009). It stabilizes nAChRs during assembly and maturation and this stabilization is most pronounced for the highest-affinity nAChR containing α4β2 subunits. Indeed, we found that specifically high-affinity nicotinic receptors containing the α4 and β2 subunits were up-regulated in the adolescent PFC shortly following nicotine exposure. This up-regulation was paralleled by a functional elevation in nicotine-stimulated GABAergic transmission, indicating that functional surface nAChRs are up-regulated as well ( Counotte et al. 2012).

Given that pyramidal neurons and excitatory projections in layers II/III of the PFC do not express nAChRs ( Poorthuis et al. 2012) the functional consequence of α4β2 nAChR up-regulation on interneurons in layers II/III will be an increased inhibitory transmission in superficial PFC layers. In the deep layers of the PFC, β2 subunits are expressed by both interneurons, as well as layer VI pyramidal neurons and excitatory inputs to layer V pyramidal neurons. An up-regulation of these receptors will lead to a combined increase in activation of pyramidal neurons and interneurons. It follows that during chronic nicotine exposure of the adolescent PFC, the pattern of activity in the prefrontal network may gradually shift toward activation of excitatory neurons in deep layers in the context of increased overall inhibition. This may affect plasticity and refinement of cortical connections ( Couey et al. 2007), and because β2-containing nAChRs in the medial PFC control attention performance ( Guillem et al. 2011), it may have functional implications for maturation and function of the prefrontal network.

In addition to an up-regulation of nAChRs, we recently found in a large-scale iTRAQ-based proteomics screen of synaptic protein levels in the PFC that metabotropic glutamatergic receptors type 2 (mGluR2) are significantly up-regulated during adolescent nicotine exposure ( Fig. 1 ) ( Counotte et al. 2011). These receptors are located presynaptically on glutamatergic synapses and their activation reduces the probability of glutamate release. Thereby, an up-regulation of mGluR2 receptor levels diminishes activity of excitatory glutamatergic synapses in the PFC. Thus, increases in functional nAChR on inhibitory neurons and increased nicotine-stimulated excitation in deep layers of the PFC may be counteracted by reduced excitatory synaptic activity mediated by increased mGluR2 activity.

LONG-TERM CONSEQUENCES OF NICOTINE EXPOSURE DURING ADOLESCENCE

Several studies indicate that smoking during adolescence is associated with disturbances in working memory and attention as well as reduced PFC activation ( Jacobsen et al. 2005, 2007; Musso et al. 2007). Although these studies focus on the short-term effects of adolescent smoking on cognition, they show that impaired cognitive processing in PFC already takes place during this age. Importantly, the history of smoking duration in years is correlated with the extent of diminished PFC activity, indicating a progression of deleterious effects of nicotine which may last into later life ( Musso et al. 2007). Smoking is a prospective risk factor for impaired cognitive function in later life; heavy smoking predicts incident cognitive impairment and decline ( Cervilla et al. 2000; Richards et al. 2003) and middle-aged smokers have a lower psychomotor speed and cognitive flexibility compared to never smokers ( Kalmijn et al. 2002). Several studies have shown that adolescent tobacco use is associated with later risk of developing mental and behavioral problems such as major depressive disorder, agoraphobia, panic disorder, addiction to other substances, antisocial personality disorder, or academic problems ( Brown et al. 1996; Brook et al. 1998, 2002; Johnson et al. 2000; McGee et al. 2000; Ellickson et al. 2001).

Animal studies have shown that exposure during adolescence induces stronger changes in gene expression in the PFC than during other periods of development and adulthood ( Schochet et al. 2005, 2008; Polesskaya et al. 2007). The adolescent PFC shows maximal nicotine response in gene regulation involved in vesicle release, signal transduction, cytoskeleton dynamics, and transcription, suggesting the role of chronic nicotine exposure in initiating long-term structural and functional adaptations ( Polesskaya et al. 2007). The activity of specific early response genes (arc and c-fos) used as a marker for the functional activation of neurons was found to be elevated in adolescent PFC after nicotine exposure ( Leslie et al. 2004; Schochet et al. 2005).

The expression of key molecules involved in plasticity is also altered in the PFC by adolescent nicotine exposure. Acute nicotine induces increases in the expression of the dendritically targeted dendrin mRNA in PFC of adolescent but not adult animals. Dendrin is an important component of cytoskeletal modifications at the synapse and therefore can lead to unique plasticity changes in the adolescent PFC ( Schochet et al. 2008). Lasting synaptic adaptations involve activation of intracellular signaling pathway and such enzymes as extracellular regulated protein kinase (ERK) and cAMP response element binding protein (CREB). Specifically in the PFC, increases in phosphorylation of both these enzymes were found after repeated nicotine exposure ( Brunzell et al. 2003). Also changes in macromolecular constituents indicative of cell loss (reduced DNA) and altered cell size (protein/DNA ratio) can be seen in cortical regions of rodents after adolescent nicotine treatment ( Trauth et al. 2000).

Although these findings only describe direct changes after nicotine exposure, altered expression of genes involved in neuroplasticity can lead to structural changes in PFC neurons that last into adulthood. Indeed, repeated nicotine exposure also changes the structure of neurons in medial PFC: it increases both dendritic length and spine density ( Brown and Kolb 2001). Long-term changes were observed in dendritic morphology of specific subpopulations of pyramidal neurons and these structural changes depended on the age of drug exposure ( Bergstrom et al. 2008).

Also on the behavioral level, nicotine during adolescence leads to persisting deficits. Adolescent, but not adult, nicotine treatment reduces accuracy of correct stimulus detection in a visuospatial attentional task, with an increase in premature and time-out responding. This suggests impaired attention and lack of impulsive control, which is part of normal adolescent maturation ( Counotte et al. 2009). Similar nicotine-induced deficits have been found in a serial pattern learning paradigm ( Fountain et al. 2008).

Taken together, these studies in rodents show that nicotine exposure during adolescence induces significant changes in gene expression and neuronal morphology in PFC. Thus, nicotine does not only change cholinergic signaling by altering nicotinic receptor levels in the adolescent PFC, but can also lead to secondary adaptations involving structural and functional changes in cognition. What are the changes that underlie the changes in cognitive performance?

LASTING SYNAPTIC ADAPTATIONS IN THE PFC THAT AFFECT COGNITIVE PERFORMANCE IN LATER LIFE

In adult rodents that were exposed to nicotine during adolescence only a handful of proteins show long-term adaptations following adolescent nicotine exposure that persisted into later life. Nicotinic AChR levels in the PFC returned to baseline 5 weeks following adolescent nicotine exposure ( Counotte et al. 2012). In contrast, mGluR2 levels show a strong down-regulation at this time ( Counotte et al. 2011). Reduced mGluR2 function in medial PFC synapses resulted in impaired attention performance. Stimulating mGluR2s with specific agonists improved attention performance in animals that were exposed to nicotine during adolescence ( Counotte et al. 2011). Interestingly, the association between changes in mGluR2 signaling and nicotine exposure is not limited to the PFC. Also in other brain areas involved in reward processing such as ventral tegmental area (VTA) and the nucleus accumbens (NAcc) lasting adaptations in mGluR2 function follow nicotine exposure and were found to affect rewarding properties of nicotine ( Helton et al. 1997; Kenny et al. 2003; Kenny and Markou 2004; Liechti et al. 2007). In these brain areas, activation of mGlu2/3 receptors decreases nicotine self-administration ( Liechti et al. 2007), and they play an important role in the development of drug dependence and the expression of the negative affective state observed during withdrawal ( Kenny and Markou 2004). However, the role of group II mGlu receptors in withdrawal appears complex and most likely depends on changes in multiple brain areas.

Although the sequence of events linking mGluR2 adaptations to nAChR activation is unknown, it seems that the reasons for its up- and down-regulation pattern after adolescent nicotine exposure may lie in its function. Metabotropic GluR2 receptors are located on presynaptic glutamatergic terminals where they are activated by glutamate spillover to inhibit glutamate release ( Mateo and Porter 2007). It was shown that activation of mGluR2s can also regulate release of other neurotransmitters: it can inhibit GABA release via a presynaptic mechanism ( Bradley et al. 2000; Pilc et al. 2008). Given the inhibitory role of mGluR2 in neurotransmitter release, its function seems to counteract that of nAChR, which enhances both excitatory and inhibitory synaptic transmission ( Lambe et al. 2003; Couey et al. 2007; Poorthuis et al. 2012). The short-term effects of adolescent nicotine exposure most likely involve enhanced levels of inhibition in prefrontal network. Accordingly, we found an initial and transient up-regulation of inhibitory mGluR2 receptor directly following nicotine exposure during adolescence ( Counotte et al. 2011), which would contribute to the same effect.

In general, factors that lead to enhanced excitation can cause alterations in mGluR2 transmission and cause cognitive deficits ( Melendez et al. 2004; Pozzi et al. 2011). Enhanced glutamate release in PFC was found to be associated with attention deficit and loss of impulse control ( Pozzi et al. 2011). MGluR2 agonists are effective in improving cognitive deficits if enhanced glutamate release is caused by NMDA receptor antagonists ( Pozzi et al. 2011). Furthermore, the important role of prefrontal mGluR2 signaling in cognition is stressed by its link to brain disorders such as depression and schizophrenia. Activation of this receptor has even been proposed as a novel treatment approach for these disorders ( Gupta et al. 2005; Palucha and Pilc 2005; Pilc et al. 2008; Conn et al. 2009). Thus, mGluR2 signaling seems to be a good candidate for shaping cognitive behavior and its impairment leads to disturbances in cognitive function.

At the level of synapse function, alterations in mGluR2 levels affect short-term synaptic plasticity in later life. Short-term depression (STD) is reduced in adult animals as a result of nicotine exposure during adolescence ( Counotte et al. 2011). In control animals, blocking mGluR2 signaling with mGluR2 antagonists also results in reduced STD. Reduced mGluR2 signaling after nicotine exposure has a similar effect on STD as mGluR2 block by antagonist ( Fig. 1 ). Thereby, mGluR2 may act as an inhibitory feedback mechanism in conditions of excessive excitation and high glutamate release, as occurs when a neuron fires a train of action potentials. Especially at high-frequency stimulation the effect of mGluR2 on STD was most prominent at excitatory synapses on layer V pyramidal neurons in the PFC. The lasting reduction of mGluR2 levels and function after adolescent nicotine exposure leads to reduced inhibitory feedback on pyramidal cells and reduces the regulatory role of this receptor in short-term plasticity. Most likely, activation of mGluR2s affects presynaptic calcium channel function as was found in the calyx of Held, by direct electrophysiological recordings from presynaptic terminals ( Takahashi et al. 1996). Agonists of mGluRs suppressed high voltage-activated P/Q-type calcium channels in the presynaptic terminal, thereby inhibiting transmitter release ( Takahashi et al. 1996). Because presynaptic Ca ²⁺ dynamics play a key role in short-term plasticity ( Zucker and Regehr 2002), decrease in Ca ²⁺ current may explain mGluR-dependent modulation of STD.

STD may equip the synapse with low-pass filtering properties, by which the synapse will pass on the first of stimulus in a train of stimuli unaltered, whereas the rest are attenuated. In this manner it shapes the information transfer by synaptic networks and gives rise to sensory and behavioral phenomena ( Zucker 1989). For example, in the somatosensory cortex of rat, in vivo whole-cell recordings in cortical neurons during whisker deflection directly showed that synaptic depression of thalamic input to the cortex contributes to rapid adaptation of sensory responses ( Chung et al. 2002). Selective attention, the ability of an organism to filter out relevant information in the face of distractors, can build on just such a synaptic process. Layer V pyramidal neurons in PFC handle diverse incoming information from mediodorsal thalamus and from local neurons, and these connections are important in mediating executive functions such as, for example, working memory ( Floresco et al. 1999). STD on this level may represent a higher level of sensory adaptation that can be expressed as decreased levels of attention and responsiveness. Reduced short-term plasticity after nicotine exposure compromises the ability of prefrontal neurons to efficiently filter out irrelevant information.

CONCLUDING REMARKS

The prefrontal cortex, the brain area responsible for executive functions and attention performance, is one of the last brain areas to mature and is still in the process of developing during adolescence. This places the adolescent brain in a vulnerable state of imbalance, susceptible to the influence of psychoactive substances such as nicotine. In prefrontal networks nicotine modulates information processing on multiple levels by activating and desensitizing nicotine receptors on different cell types and in this way affects cognition. The adolescent brain is particularly sensitive to the effects of nicotine. Studies in human subjects indicate that smoking during adolescence increases the risk of developing psychiatric disorders and cognitive impairment in later life. In addition, adolescent smokers suffer from attention deficits, which aggravate with the years of smoking.

From studies in the rodent brain it is becoming clear that on the short-term, adolescent, but not adult, nicotine exposure increases the expression of nAChRs containing α4 and β2 subunits in the medial PFC, which leads to an increase in nicotine-induced GABAergic synaptic transmission. In addition, mGluR2 levels on presynaptic glutamatergic terminals in the PFC are increased, causing a reduction in glutamatergic synapse strength ( Fig. 1 ). Changes in nAChR levels are reversible: In the adult rodent brain, weeks after nicotine levels have subsided, nAChR levels in the PFC return to baseline levels. In contrast, at this stage, mGluR2 levels have reduced significantly below baseline levels, thereby altering mGluR2 signaling during short-term plasticity and hampering attention performance. This reduction in mGluR2 signaling underlies the reduced attention performance observed in animals after nicotine exposure during adolescence ( Counotte et al. 2011).

New questions and opportunities arise from these recent findings. The long-term adaptations involving mGluR2s can have profound implications for network functioning and affect more complex levels of information processing. A consequence of increased glutamatergic transmission in adult PFC caused by reduced mGluR2 function could be the impairment of other types of plasticity than STD, such as mechanisms of long-term plasticity. Changes in inhibitory tonus and excitatory transmission following adolescent nicotine exposure may have different short- and long-term effects on long-term plasticity.

Another interesting question would be whether mGluR2 signaling is involved in a broader spectrum of attention impairments with different etiology. If change in mGluR2 signaling is a common underlying mechanism for attention malfunction it would make it a suitable pharmacological target for therapy.

ACKNOWLEDGMENTS

H.D.M. received funding from the FP7 program SynSys, the European Research Council (ERC), NWO (917.76.360), the NeuroBasic consortium, VU University board, and Neuroscience Campus Amsterdam (NCA).

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Articles from Cold Spring Harbor Perspectives in Medicine are provided here courtesy of Cold Spring Harbor Laboratory Press

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Short- and Long-Term Consequences of Nicotine Exposure during Adolescence for Prefrontal Cortex Neuronal Network Function

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More than 70% of adolescents report to have smoked a cigarette at least once. At the adolescent stage the brain has not completed its maturation. The prefrontal cortex (PFC), the brain area responsible for executive functions and attention performance, ...