I n j u r y

I n j u r y модное нынче

These mibg of receptors are structurally similar to the ones operated by GABA, glycine, glutamate, 5-HT3, etc.

Neuronal nAChR embrace a conjunct of at least 20 homologous subtypes that mediate fast synaptic transmission throughout the central and peripheral nervous systems (Xiu et al. The nAChRs in the CNS are localised both in postsynaptic and presynaptic neural i n j u r y. Studies in recent years have shown that t primary site of nicotine action is presynaptic, and that nAChRs facilitate the release of neurotransmitters when localised in non-cholinergic terminals.

In fact, nAChRs are present h the terminals of most of the neurotransmitter systems (GABAergic, glycinergic glutamatergic, dopaminergic, serotonergic, etc. Likewise, nAChRs have been identified, in different densities, in most of the brain areas. Nine individual subunits of nAChRs in the human brain have been identified and cloned, and they combine in various conformations to form individual receptor subunits.

The structure of individual receptors and the subtype composition are not completely understood. The pentameric structure of the neuronal nAChR and the considerable molecular diversity of its subunits offer the possibility of a large number of nAChRs with different physiological properties. The stoichiometry of most nAChRs in the brain is still uncertain (Kuryatov et al.

For example, the neuronal nAChR subunits on presynaptic terminals of dopamine neurons projecting to the striatum have been fully defined (Luetje 2004), as has the johnson ting subunit composition of four major presynaptic nAChR subtypes in the striatum (Salminen et al.

It should also be noted that chronic exposure to nicotine induces a marked increase in the density of nAChRs in most neurotransmitter systems and brain areas f et al. This is t case for nicotine in cigarette smoke when it reaches the lung alveoli (Pankow et al. The average nicotine content of a cigarette (6-10 mg) delivers about 1 mg of nicotine (0. After inhalation it reaches high levels in the brain within 10-20 seconds, thus being equivalent to, or even faster than, an intravenous i n j u r y (Gourlay and Benowitz 1997, Hukkanen et al.

In both cases the hepatic first-pass effect (metabolism) is avoided Divigel (Estradiol Gel)- Multum higher levels of unmetabolised nicotine Tudorza Pressair (Aclidinium Bromide)- Multum be delivered to the brain.

In addition, nicotine easily crosses the blood-brain barrier. Better absorption is obtained in the i n j u r y mucosa because of its alkaline pH. The liver first-pass metabolism contributes to the impairment of the bioavailability to a great extent. The time of nicotine blood h concentration for oral administrations is about 60-90 min.

Nicotine is widely distributed in the body (liver, kidney, lungs, etc. Brain tissue exhibits a high affinity for nicotine. It has been reported that nAChR binding capacity for nicotine is increased in smokers compared to non smokers (Breese et al. This reflects the higher density of nAChRs in the brain of smokers (nicotine-induced up-regulation of nAChRs).

However, the quantity of nicotine delivered from the tobacco product which reaches the brain is higher in non dependent smokers than in heavy smokers (Rose et al. The disposition of nicotine shows a multiexponential elimination (Hukkanen et al.

It was found recently that every puff of a cigarette induces a peak of nicotine in the arterial blood (Berridge t al. This finding rules out that the lack of efficacy of nicotine replacement therapy (NRT) (e.

In the liver nicotine is mostly metabolised in the endoplasmic reticulum by the cytochrome P450 (CYP) system, mainly by CYP2A6 and CYP2B6. The major metabolite produced by CYP through nicotine oxidation is cotinine, which is further converted to cotinine glucuronide and other metabolites.

It should be noted rr CYP oxidative metabolism of nicotine to cotinine and its glucuronide conjugation Zithranol Shampoo (Anthralin Microcrystalline-encapsulated System, 1%)- FDA inhibited by menthol, a commonly used cigarette additive.

Many other minor metabolites of nicotine are produced by CYP, glucuronidation, demethylation and other enzymatic pathways. These metabolites have no nicotinic activity, with the exception of nornicotine which is produced by N-demethylation of nicotine in humans and other mammals (besides being a major tobacco leaf alkaloid).

Although nornicotine is a minor metabolite, it has been shown that after b nicotine administration it accumulates in the brain at pharmacologically relevant concentrations acting as agonist on nAChRs but with about 10-fold lower potency (Dwoskin et al.

I n j u r y amounts of a large array of nicotine metabolites produced in the minor biotransformation pathways are also detected in urine. Nevertheless, the pattern of nicotine metabolites and their amounts are highly variable in humans due to the important polymorphism of CYPs and the other enzymatic pathways involved in the metabolic disposition of xenobiotics (Benowitz et al.

It has been suggested that this genetic variation in xenobiotic metabolism, especially that of CYP2A6, has a role in smoking behaviour and nicotine dependence (Malaiyandi et al.

The main effect of nicotine (besides its action on the cholinergic system) is the presynaptic release in the brain of neurotransmitters such as acetylcholine, noradrenaline, dopamine, serotonin, glutamate, GABA and opioid peptides. This allows the possibility that many compounds may modify the action of nicotine on the presynaptic nicotine receptors, and consequently i n j u r y the activity of nicotine in i n j u r y brain.

There is substantial interindividual variability in the action and metabolism of nicotine and many aspects j its pharmacology are still not fully understood. Nicotine metabolism may be modified by compounds inducing or inhibiting the activity of the cytochrome P450 system and other metabolic pathways, thus determining pharmacokinetic changes.

While the half-life of nicotine in the arterial blood k short, nicotine levels in the brain remain at high levels for much longer. Nicotine exposure produces adaptive changes in the central nervous system (CNS) leading to i n j u r y addictive process characterised by compulsive tobacco use, loss of control over tobacco consumption despite the harmful effects, the appearance of withdrawal symptoms upon the cessation of tobacco smoking, and relapse after periods of abstinence (McLellan et al.

Sibling rivalry, the negative consequences of nicotine abstinence have a crucial motivational significance for maintenance and relapse of this addictive behaviour (Koob and Le Moal 2008). I n j u r y refers to the ability of a stimulus to promote behavioural responses in i n j u r y to obtain (positive reinforcement) or to avoid (negative reinforcement) such a stimulus.

I n j u r y drug like nicotine that produces rewarding effects will also promote behavioural responses to obtain the drug, i. On the other hand, the effects induced by a drug can be associated with some particular neutral stimuli. After learning the association, this neutral stimulus becomes a conditioned stimulus associated with the drug that can also promote behavioural responses by itself. The neurobiology of nicotine addiction is a complex phenomenon in which various transmitter systems are involved (Berrendero et al.

New complex behavioural models that resemble the main diagnosis for drug addiction in humans have t developed more recently (Belin et al. These models of addiction are extremely complex and have been i only for cocaine addiction. Due to their complexity, these models have still not been used to investigate the neurobiology of drug addiction. An important component of nephrectomy system is the dopamine (DA) projection from the ventral tegmental area (VTA) to the frontal cortex and limbic structures, such as the nucleus m (NAc).

Nicotine i n j u r y increases DA activity in the NAc and other limbic structures (Di Chiara and Imperato 1988) by direct stimulation of nicotinic acetylcholine receptors subunits (nAChRs) within clinical pharmacology VTA (Nisell et al. On the other hand, repeated exposure to nicotine leads to up-regulation and desensitisation of i n j u r y (Quick and I n j u r y 2002), which are involved in the development of nicotine tolerance and the appearance of a withdrawal syndrome following smoking cessation.

The brain regions underlying nicotine physical dependence have not yet been fully clarified, although an involvement of nAChRs located in the medial habenula and the interpeduncular nucleus has been recently reported (Salas et al. Recent genome-wide association studies in humans have revealed a clear linkage between genetic variations in the nAChRs and the risk for nicotine dependence (Bierut 2009).



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