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Neuropsychopharmacology of nicotine use. Full review.

Brain

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Nicotine is structurally and functionally similar to one of the main mediators of the nervous system — acetylcholine, and therefore it is its agonist: it can affect one of its receptor types — nicotinic acetylcholine receptors (nAChR) - to cause a response. It is important to note, that nAChR is inotropic, which means, when an agonist binds to a receptor, it allows a stream of ions through. The N-type acetylcholine receptor allows mainly Na+ ions to pass, and, to a lesser extent, divalent cations. But it does not pass anions at all. All these ion flows are created with the sole purpose of starting a cascade of reactions, which, in turn, provide an appropriate biological response in any structure that is susceptible to this type of signals. Hence, all the effects of nicotine: it does not act on a specific system or anatomical region of the nervous system, but on one of the most common receptors in the body. It has access to a variety of body structures, and most importantly — to the central nervous system. An important role here is played by the fact that nicotine passes through the blood-brain barrier (BBB) quite easily, since the nitrogen atom in it is tertiary, unlike acetylcholine, in which it is quaternary, and it is not able to penetrate through biological barriers.

Since nicotine has a direct effect on the central nervous system, people began to search for the reason, and they found it. And not even one. Ubiquitous geneticists also had a role: approaching the situation from their side, they found far more than one gene related to the nicotine addiction development. Molecular biologists did not lag behind — found the objects of their attention both in the central nervous system and beyond.

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One of the most popular reasons is the similarity of nicotine with acetylcholine. Most nAChRs in the central nervous system are located presynaptically and modulate the release of acetylcholine, dopamine, serotonin, glutamate, gamma-aminobutyric acid (GABA) and norepinephrine. nAChRs can also be located postsynaptically, for example, on dopaminergic neurons in the ventral tegmental area (VTA). The two most commonly expressed nAChRs in the brain are α4β2 or α7 nAChRs. Stimulation of α4β2 nAChRs located on dopaminergic neurons in the ventral tegmental area turns their neurotransmitter production from the tonic to the phasic mode. This event leads, for example, to an increase in dopamine release in both the adjacent nuclei and the ventral tegmental area, which is the beginning of the mesocortical and mesolimbic dopamine pathways. The ventral tegmental region is widely involved in reward systems, or rather, it is a cluster of many nerve pathways.

Hippocampus.
The hippocampus is a part of the limbic system. It participates in the formation of emotions, attention retention, storing short-term memory and translating it into long-term memory. It also forms spatial memory, due to which we better navigate the terrain and find the shortest path to our destination. At the same time, it performs the opposite functions: forgetting, filtering the necessary from the unnecessary information. It is worth mentioning that one of the early diagnostic signs of Alzheimer's disease is volume loss of the hippocampus tissue. This beautiful structure expresses large amounts of nAchR (synaptic plasticity and long-term activity of the hippocampus are associated with their activation): the effect of nicotine on these receptors mimics the action of a normal mediator. The hippocampus receives cholinergic afferent projections from the dentate gyrus, basal nuclei, frenulum (habenula), and tegmental area. In addition to this, it is shown that glucocorticoid receptors are expressed in the hippocampus, as well as a whole bunch of metabotropic glutamate receptors, divided into AMPA and NMDA depending on their effect, as well as by their effect on excitotoxicity into 3 groups: the first group - mGlu1, mGlu5; the second group - mGlu2, mGlu3; the third group - mGlu4, mGlu6, mGlu7, mGlu8.

Stimulation of these receptors has an exciting effect on neurons, moreover, with an increased content of Ca2+. The density of ionotropic glutamate AMPA and NMDA receptors is even higher there. It is interesting that metabotropic receptors regulate the work of ionotropic ones, activate intracellular signaling cascades leading to the modification of other proteins, for example, ion channels. This can eventually change the excitability of the synapse, for example, by inhibiting neurotransmission, or modulating or even inducing postsynaptic reactions: the first group increases the activity of NMDA receptors and the risk of excitotoxicity, groups 2 and 3 inhibit these processes. Excitotoxicity is a pathological process that leads to damage and death of nerve cells under the influence of neurotransmitters that can hyperactivate NMDA and AMPA receptors. At the same time, the excessive calcium intake into the cell activates a number of enzymes (phospholipases, endonucleases, proteases) that destroy cytosolic structures. Excessive calcium intake also leads to the launch of cell apoptosis, which undoubtedly plays a role in the pathogenesis of various neurodegenerative diseases.

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In addition, the hippocampus expresses orexin receptors of the first type (OX1) (to orexins secreted by the hypothalamus and playing one of the key roles in the regulation of sleep/wakefulness, and also general metabolism), as well as receptors for leptin, so they will be described in the context of the hypothalamus. There are works proving that acute and chronic nicotine intake improves working memory, and the blockade of receptors, on the contrary, causes a weakening of the assimilation and memorization of information in experimental subjects. In addition to these observations, some cognitive symptoms of Alzheimer's disease are improved by the clinical use of acetylcholinesterase inhibitors. However, elevated nicotine levels do not selectively affect nAChRs, and there is evidence of the involvement of both (nicotine and muscarinic) receptors in learning and memory processes.

By hybridization of mRNA, it was found that the α7-and β2-subunits are expressed in greater numbers than the others, although all types of subunits are generally present. At the same time, their expression is higher within the interneurons, however, most of the pyramidal ones turn out to be highly exhibiting these subunits. This is important because it is the composition of nAChRs that dictates their pharmacological properties and determines the course of changes in the membrane potential, including the relative magnitude of changes in intracellular Ca2+. Calcium flow from the outside stimulates its release from intracellular reserves. This is the role of nicotine as a regulator, and if necessary, an amplifier of the neurotransmitter release. Although nAChRs are ion channels for both Na+ and K+, it is an increase in the concentration of intracellular calcium that affects the release of transmitters: there is an increase in glutamate, a decrease in GABA and an increase in the level of adrenaline.

Interestingly, the combination of nicotine-induced presynaptic release of glutamate and postsynaptic depolarization (via nicotine alone) gives a stable and high increase in the concentration of intracellular calcium, which provides the notorious synaptic plasticity.

Ionotropic glutamate AMPA and NMDA receptors are expressed on the postsynaptic neuron, among others. Two forms of NMDA-dependent long-term potentiation (LTP) in the hippocampal synapses of the C1 region can be classified by their sensitivity to protein kinase A (PKA) inhibitors. The level of PKA plays a key role in the formation of long-term memory, which the hippocampus is responsible for. The molecular mechanisms of nicotine's action on memory formation have not yet been fully elucidated, but there are some conclusions: short-term memory is estimated in the time interval up to 2 hours after training, long-term memory is exceeds 4. So, when exposed to nicotine, the level of PKA was measured at different time intervals, and it turned out that it almost did not change from the initial level to 2-3 hours. But just after 4 hours it increased quite sharply. The increase was also recorded after 8 and 24 hours.

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The dependence of the protein kinase A level on the time elapsed since the administration of nicotine (left - posterior hippocampus, right -anterior hippocampus). In the experiment, saline solution and nicotine were administered: ST, NT — administration of saline solution and nicotine followed by training, SH, NH – the introduction of nicotine and saline solution followed by maintenance under normal conditions.

So, it was suggested that nicotine stimulates long-term memory, although it is not very clear exactly how: whether it is focused on short-term memory, which subsequently strengthens the long-term memory, or directly influences the latter. One thing is for sure — nicotine potentiates the accumulation, storage and reproduction of information from long-term memory. This is also proved by measuring the level of extracellularly regulated signaling kinases (ERK½), which, in turn, play one of the main roles in memory formation, and their inhibition does not allow nicotine to modulate the hippocampus, which once again confirms their role in memory formation. So far, all explanations come down to the fact that α4β2 receptors are expressed in large quantities in the hippocampus, passing calcium inside, which not only causes depolarization, but also in some cases serves as an intracellular messenger, activating signaling pathways involving PKA and ERK½, leading to the effects mentioned above.

Thus, the transmission of an exciting signal is followed by increase in intracellular calcium, which enhances all the hippocampus functions. Also, the role of nicotine in cognitive processes modulation is determined by the induction of gamma-frequency oscillations in the cortex (30-80 Hz) through nicotine receptors. A similar effect is provided by the activation of kainate receptors: this correlates with improved learning, memory, and attention. At the same time, the stimulation of D3-receptors to dopamine inhibits this rhythm. And in general, their stimulation acts "opposite to" acetylcholine, causing cognitive depression, deterioration of working memory and is generally suspected as one of the causes of Alzheimer's disease, schizophrenia and Parkinson's. Antagonists of these receptors are used in some cases as antipsychotics.

In addition to nAChR, glucocorticoid receptors are expressed in the hippocampus: nicotine activates the sympathetic system, under its influence the adrenal glands are activated, releasing the notorious glucocorticoids. In addition to their well-known roles, such as increasing blood pressure, blood glucose levels and heart rate, there is a more interesting effect: glucocorticoids increase the sensitivity of the myocardium to catecholamines, but at the same time have a systemic effect on catecholamine receptors, with numerous of their ligands, preventing their desensitization. Kainate receptors form ion channels permeable to sodium and potassium ions. The amount of sodium and potassium that can pass through the channel per second (their conductivity) is similar to the channels of the AMPA receptor. However, the rise and fall of postsynaptic potentials generated by the kainate receptor occur more slowly than that of the AMPA receptor. Kainate receptors play a role on extra-synaptic membranes, axons, in particular. Activation of these extra-synaptic receptors leads to action potential facilitation in hippocampal mossy fibers and interneurons. Their activation occurs in the same way as NMDA-a background increase in intracellular calcium due to the nAChRs action, as well as other ionotropic glutamate receptors in general, which, of course, makes the work of neurons more "dynamic".

There is evidence that smoking inhibits MAO, however, it has been shown that other tobacco combustion products inhibit it as well, although it is not obvious which ones. Nevertheless, if nicotine is administered by smoking, the inhibition of MAO is evident either way. Hence, we can talk about the effect even on metabotropic serotonin 5-HT4 receptors, which are present in the hippocampus in a small number. More precisely, we should not talk about the receptors themselves, but about the inhibition of serotonin breakdown, which mediated its effects. There are also many cannabinoid receptors located in the hippocampus. To know more about them, we can refer to a study that showed that the activation of cannabinoid receptors contributes to the increased production of acetylcholine in those neurons where they are expressed together — mainly in the cortex, hippocampus, striatum. Thus, the effect of nicotine causes a decrease in inhibition of hippocampal neurons. Regular exposure to nicotine also causes an increase in the number of receptors. Therefore, when nicotine intake is discontinued, the hippocampus is depressed. As a result, there is a decrease in concentration, attention, memory deterioration, mood failure and metabolic disorders, and disorder of sleep/wake cycles.

Prefrontal cortex.
The dorsal prefrontal cortex is most interconnected with the regions of the brain that are responsible for attention, cognitive activity and motor skills, while the ventral prefrontal cortex is interconnected with the regions of the brain responsible for emotions. The medial prefrontal cortex participates in the generation of the third and fourth phases of slow-wave sleep (these phases are referred to as "deep sleep"), and its atrophy is associated with a reduction in the deep sleep time-total sleep time ratio. This causes deterioration in memory consolidation, i.e., its transfer from short-term to long-term. One of the basic functions of the prefrontal cortex is the complex management of mental and motor activity in accordance with internal goals and plans. It plays a major role in the creation of complex cognitive structures and action plans, decision-making, control and regulation of both internal activities and external ones like social behavior and interaction.

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The control functions of the prefrontal cortex are manifested in the differentiation of contradictory thoughts and motives and the choice between them, the differentiation and integration of objects and concepts, the prediction of the consequences of this activity and its adjustment in accordance with the desired result, emotional regulation, volitional control, concentration of attention on the necessary objects. The prefrontal cortex is strongly connected to the limbic system, although it does not quite belong to it: it is more "rational". It sends forbidding signals that help it keep the limbic system under control. In other words, it determines the opportunity to think rationally, and not just with emotions. When there is a decrease in activity or damage in this area of the brain, especially in its left part, the prefrontal cortex is no longer able to properly influence the limbic system, and this can cause an increased predisposition to depression, but only if the limbic system becomes hyperactive. A classic illustration of this can be patients who have suffered a hemorrhage in the left frontal lobe of the brain. Sixty percent of these patients develop severe depression within the first year after a stroke. In this regard, a correlation is revealed between smoking and depression, attention deficit disorder and similar disorders. The prefrontal cortex also has mutual connections with the stem activating system, and the functioning of the prefrontal regions strongly depends on the activation/inhibition balance. The prefrontal cortex is rich in acetylcholine receptors, D4, glutamate and GABA. The fact is that the prefrontal cortex performs many complex functions, they need to be put together and sorted out, so it is worth activating glutamate or acetylcholine somewhere, and to slow them down somewhere else.

Amygdala.
Due to its connections with the hypothalamus, the amygdala affects the endocrine system, as well as reproductive behavior. The functions of the amygdala are associated with the provision of defensive behavior, vegetative, motor, emotional reactions, motivation of conditioned reflex behavior. Obviously, they are directly related to a person's mood, their feelings, instincts, and, possibly, to the memory of recent events. Amygdala reacts with many of its nuclei to visual, auditory, interoceptive, olfactory, skin irritations. All these irritations impact the activity of the amygdala nuclei, i.e. the amygdala nuclei are polysensory. The reaction of the nucleus to external stimuli lasts, as a rule, up to 85 ms, i.e. significantly less than the reaction to such stimuli of the new cortex. The amygdala plays an important role in the formation of emotions.

In humans and animals, this subcortical brain structure is involved in the formation of both negative (fear) and positive emotions (pleasure), in the formation of memory, especially recent and associative. Disorders in the amygdala functioning cause various forms of pathological fear, aggression, depression, post-traumatic shock in people. The amygdala is rich in glucocorticoid receptors and, therefore, is especially sensitive to stress. There are also delta (δ) opioid receptors (DOP) responsible for analgesia, antidepressant effects, physical dependence and kappa-opioid receptors (KOP) that cause aphoria, myosis, inhibition of ADH production. When the opioid receptor is activated, adenylate cyclase is inhibited, which plays an important role in the synthesis of the secondary cAMP messenger (cAMP), as well as in the regulation of ion channels. The closing of potential-dependent calcium channels in the presynaptic neuron leads to a decrease in the release of excitatory neurotransmitters (such as glutamate). And the activation of potassium channels in the postsynaptic neuron leads to hyperpolarization of the membrane. This reduces the sensitivity of the neuron to excitatory neurotransmitters. Systemic administration of nicotine causes the release of endogenous opioids (endorphins, enkephalins and dinorphins).


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In addition, systemic administration of nicotine induces the release of methionine-enkephalin in the dorsal horns of the spinal cord. Thus, nicotine has acute neurophysiological effects, including an antinociceptive effect, and also has the ability to activate the hypothalamic-pituitary-adrenal (HPA) axis. The involvement of the endogenous opioid system in analgesia is mediated by α4β2 and α7 nAChRs, while the activation of the HGH axis is mediated by α4β2, not α7. This leads researchers to believe that the effects of nicotine on endogenous opioid systems are mediated by α7, and not α4β2. The opioid receptor antagonist naloxone (NLX) causes nicotine withdrawal after repeated administration, and NLX-induced nicotine withdrawal is inhibited by the introduction of an opioid receptor antagonist. NLX-induced nicotine withdrawal is also inhibited by the administration of a α7 antagonist, but not a α4β2 antagonist. To sum up, this data indicates that NLX-induced analgesia and the development of physical dependence mediate endogenous opioid systems, through a7 nAchRsF. Glutamate AMPA receptors, as well as receptors for oxytocin, activating the amygdala through its receptors, and the very fact of activating the amygdala, cause the same effects: anxiety reduction and social interactions' promotion, stimulating effect. Interestingly, the receptors for neuropeptide Y modulate the work of GABA and NMDA receptors, which ultimately has the already mentioned stimulating effect.

In the amygdala, there is a high density of D1 receptors associated with G-proteins and activating adenylate cyclase. They also have postsynaptic inhibition, which is an excellent "fuse" due to the fact that overstimulation of the amygdala in conditions of depression and chronic stress is associated with increased anxiety and aggression. It is precisely because of the formation of emotions in response to the administration of nicotine, and the formation of memory, reactions, reflexes. The amygdala plays an important role in nicotine addiction and mediating its effects.

Hypothalamus.
The last of the most important targets of nicotine in the central nervous system is the hypothalamus. Contact with nicotine activates POMK neurons, which, according to an article in Science, reduces appetite through their activation. Also, POMK neurons are involved in analgesic reactions, which were described above. In addition, nicotine increases the secretion of neuropeptide Y. However, not everything is clear about the neuropeptide, which will be considered below. The hypothalamus also expresses receptors for leptin, for orexins (OX2), and, moreover, it also secretes orexins. Orexins (also known as hypocretins 1 and 2) play a role in regulating appetite, sleep and addiction to certain narcotic substances. If there is a lack of orexins, narcolepsy and obesity develop, despite the fact that there may be appetite loss. If there is an excess of orexins, on the contrary, insomnia and anorexia are present. Orexin activity is also associated with metabolic processes (lipolysis), increased blood pressure, and even with the processes of regulating the menstrual cycle in women and regulating gene expression in sertoli cells in men. They also seem to respond to blood glucose levels.

It has been shown that chronic nicotine intake increases the level of orexins, although it is not apparent how. The authors limit themselves to the opinion that the effect occurs through a α4β2-dependent mechanism, which was revealed by more than one method of immunohistochemistry. The main indicator was the level of MRNA subunits of the nicotine receptor. Personally, I would assume that all of this is due to the activation of orexin neurons (by the way, there are not so many of them, only a few thousand per brain, however, they have projections to other important zones).

It should be mentioned that the intake of nicotine causes the release of norepinephrine from the paraventricular nucleus of the hypothalamus. By the way, the same thing will happen simultaneously in the amygdala through NMDA potentiation and through cascades involving nitric oxide. Since the hypothalamus is very closely connected with the pituitary gland, it will be essential to note, that in experiments on the interaction of the pituitary gland with nicotine, it was finally found out that oxytocin is released separately from vasopressin, and that nicotine specifically causes an increase in the release of the latter. This information was significant for humanity — this explained the unclear effects: intra-carotid or intravenous administration of nicotine was accompanied by an increase in blood pressure, and intraspinal administration of small doses was accompanied by its decrease, we will return to these effects in the next part of the article.

"Peripheral" effects of nicotine.
It is known that nicotine activates the sympathetic system, and, in general, all the following events are predictable: blood pressure increases, heart rate increases, mobility and anxiety increase due to the production of glucocorticoids by the adrenal glands. Meanwhile, glucocorticoids have the property of regulating inflammation and the immune response. They increase neutrophilopoiesis and increase the content of neutrophil granulocytes in the blood. They also enhance the response of the neutrophil cells' development in bone marrow to the growth factors G-CSF and GM-CSF and to interleukins, reduce the damaging effect of radiation and chemotherapy of malignant tumors on the bone marrow and reduce the degree of neutropenia caused by these effects. Due to this, glucocorticoids are widely used in medicine for neutropenia caused by chemotherapy and radiotherapy, and for leukemias and lymphoproliferative diseases. However, this is not the end: acetylcholine is a preganglionic mediator in the sympathetic system, causing the release of adrenaline, and its sympathetic effects. They inhibit the activity of various tissue-destroying enzymes - proteases and nucleases, matrix metalloproteinases, hyaluronidase, phospholipase A2 and others, inhibit the synthesis of prostaglandins, kinins, leukotrienes and other inflammatory mediators from arachidonic acid. They also reduce the permeability of tissue barriers and vascular walls, inhibit the exudation of fluid and protein into the focus of inflammation, the migration of leukocytes to the focus (chemotaxis) and the proliferation of connective tissue in the focus, stabilize cell membranes, inhibit lipid peroxidation, the formation of free radicals in the focus of inflammation and many other processes that play a role in the inflammation development. The manifestation of immunostimulating or immunosuppressive effects depends on the concentration of glucocorticoid hormones in the blood. The fact is that the subpopulation of T-suppressors is significantly more sensitive to the depressing effects of low concentrations of glucocorticoids than the subpopulations of T-helpers and T-killers, as well as B-cells.

It is also worth mentioning that since nicotine has a particular vasoconstrictor effect, some problems may be directly related to insufficient blood supply to the fetus in pregnant women. There is a correlation between smoking during pregnancy and obesity development by child, on average, at the age of 9 years. It is not known whether this is due to the effect of nicotine on the developing hypothalamus and, as a result, hence the disorders of the endocrine system, but so far, this hypothesis is the most common. A confirmed example of the endocrinological effect of nicotine specifically (in all the presented experiments, pregnant / lactating females are injected with nicotine salts in various ways) on the fetus can be the fact that it causes disturbances in the activity of parathyroid cells of the fetus together with an increase in the activity of thyroid cells. Together with the activation of both the mother and fetus sympathetic systems, it can explain why the children of mothers who are exposed to nicotine are often hyperactive, capricious and irritable. This effect remains evident during the first month of life in rats, but no further studies have been conducted.

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Other problems arise associated with hyperactivity at an early age: the activity of neuronal promoter functions is inhibited; child cries excessively, then becomes apathetic and lethargic; pallor; in severe cases, child has sleep deprivation; delayed memory and learning problems (like hyperactivity, asthma in children is also considered to be caused by nicotine. However, it also occurs in children of mothers who experienced stress during pregnancy).

Also, nicotine causes an increase in the number of dopaminergic neurons and dopamine receptors during prenatal period, which is not a positive event for the fetus: after birth, sooner or later (during breastfeeding and after its discontinuation, while mother's nicotine consumption is continued), its intake will be discontinued, the amount of dopamine will decrease and this would be harmful for everyone involved. Mothers exposed to nicotine give birth to children with a reduced body weight. But this is not as interesting as the fact that they also have an increased content of TGF-β and nitric oxide — markers of inflammation. Nitric oxide is presumably released by the mechanism discussed in the article. Also, the delayed consequences include the fact that the offspring of "nicotine users" are more likely to form a hypertensive phenotype: prenatal exposure to nicotine activates the mechanism of DNA methylation, which regulates the expression of angiotensin-II receptor genes (AT-1aR, but not AT-1bR).

Oxidative stress and apoptosis due to nicotine use.
In cigarette smoke, there are nitrogen and carbon monoxides, as well as a lot of other substances (among them there are just substances from the list register of carcinogens). There are also resins, which simply do not allow gas exchange to occur normally in the lungs. Apoptosis specifically occurs due to the activation of caspase-3 by active oxygen forms; by the way, this cascade is successfully blocked by ascorbic acid. Nicotine itself is not on the list of carcinogenic substances, and not only does it not cause apoptosis, it also prevents it. It has a more cytoprotective effect, especially on neurons. Smoking itself is a kind of immunosuppressive factor, and, by suppressing the immune response, the risk of developing various tumors increases.

The processes of dysplasia develop in patients with the history of smoking due to the fact that the resins settle on the walls of the bronchi, alveoli, gas exchange becomes difficult — and then the cells begin to proliferate. Moreover, there is a study showing that if a person continues to smoke during chemotherapy/radiotherapy, the effectiveness of treatment is significantly reduced due to nicotine-induced resistance. By suppressing the immune system, nicotine and other tobacco combustion products increase the risk of proliferation of already existing cancer cells, wherever they are. In addition, tumor cells mainly live off glycolysis, so vasoconstriction causes hypoxia of the organ, its function impairment, while cancer cells thrive there. The most common cancer in smokers is lung cancer because it is where the main combustion products settle, besides nicotine.

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Among other things, the effect of nicotine on the immune system is of great interest. You can find various statements on this subject, which can easily confuse you. Let's try to figure it out nicotine reduces systemic immunity, but raises local immunity — for example, nicotine is used for Crohn's disease, that is, colitis caused by the toxin Clostridium Difficile (but not from ileitis), raising the level of IL-4, substance P and other pro-inflammatory peptides. But in case of burns, it reduces the amount of pro-inflammatory cytokines, which are formed excessively in thermal injuries (we mean control groups that had burns of at least 30% of the body surface, so that the pro-inflammatory reaction had a systemic character). Toll-like receptors play an important role in the development of sepsis, it was found out by intraperitoneal administration of nicotine (400 µg/kg) that it inhibits these receptors through a7nAchR by activating phosphoinositide-3 kinase. Although, whether this is good or bad in the presence of infection is debatable. By means of the same a7nAchR, surprisingly enough, it reduces the course of obesity.

In addition, smoking diabetics/obese people are less likely to have ulcerative colitis, which also appears as a result of local inflammation. In the same anti-inflammatory way, through α7nAchR, it protects the kidneys from ischemia, reducing the amount of tumor necrosis factor alpha, various chemokines, and also preventing neutrophil infiltration. Despite this, the question of the birth of children with an increased content of inflammatory markers remains open.

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As for genetics, current data indicates that nicotine can regulate the expression of genes / proteins involved in various functions, such as ERK1/2, CREB and C-FOS, and also modulate some biochemical pathways, for example, with mitogen — activated protein kinase A (MARK), signaling of phosphatidylinositol phosphatase, a signaling growth factor, and ubiquitin-proteasome pathways. The three genes associated with nicotine addiction are estrogen receptor 1 (ESR1), arrestin beta 1 (ARRB1) and ARRB2. ESR1, as a specific nuclear sex hormone receptor, is widely distributed in the dopaminergic neurons of the midbrain and can modulate the release of neurotransmitters of the brain's reward system. In addition, ESR1 also plays an important role in the process of apoptosis. ARRB1 and ARRB2 are widely used as building proteins. They can regulate several intracellular signaling proteins involved in cell proliferation and differentiation, and play an critical role in the mitogenic and anti-apoptotic properties of nicotine. Experiments were conducted on rats with exposure to nicotine, and then abrupt discontinuation of its intake (3.2 mg / kg / day, 14 days): intact females showed anxiety and increase in expression of the CRF, UCN and DRD1 genes. During nicotine administration, intact females showed a decrease in CRF-R1, CRF-R2, Drd3, Esr2 gene expression and an increase in CRF-BP. This pattern of results was absent in females with ovariectomy.

These processes are localized in the nucleus accumbens. In other words, when nicotine administration was discontinued, stress-associated genes were activated in the nucleus accumbens. The relationship to nicotine is also quite significantly determined by a single-nucleotide polymorphism in the rs16969968 gene, a gene encoding the α5 subunit of the acetylcholine receptor. The subjects were asked to regularly smoke cigarettes containing nicotine (0.60 mg) and placebo (<0.05 mg). Homozygotes carrying the analyzed allele (G: G) showed a significantly reduced puff volume, while carriers of polymorphic alleles (A: G or A: A) inhaled an equivalent volume of both placebo and real cigarettes. The data obtained suggests that the volume of a puff may be a more useful objective phenotypic criterion than the number of cigarettes per day.
 
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