Nicotine pathway

L-aspartate oxidase and quinolate synthase, are also partially regulated by NIC loci. These genes are abundantly expressed and induced by Meja only in tobacco roots thus, transcription of genes involved in the aspartate/NAD and nicotine pathways are controlled by common regulatory mechanisms (Katoh and Hashimoto 2004). 

The nucleus accumbens is part of the limbic system. It receives dopaminergic input through the mesolimbic system that originates from cell bodies in the ventral segmental area (A 10 cell group). This mesolimbic dopaminergic pathway is part of the reward pathways. Drugs of abuse (cocaine, amphetamine, opiates or nicotine) have been shown to increase the level of dopamine release in these neurons. 

Nicotinic Acetylcholine Receptor Nicotinic Receptors Nigrostriatal Tract/Pathway Nitrates... 

Figure 25-7. Metabolism of adipose tissue. Hormone-sensitive lipase is activated by ACTH, TSH, glucagon, epinephrine, norepinephrine, and vasopressin and inhibited by insulin, prostaglandin E, and nicotinic acid. Details of the formation of glycerol 3-phosphate from intermediates of glycolysis are shown in Figure 24-2. (PPP, pentose phosphate pathway TG, triacylglycerol FFA, free fatty acids VLDL, very low density lipoprotein.)...

To achieve their different effects NTs are not only released from different neurons to act on different receptors but their biochemistry is different. While the mechanism of their release may be similar (Chapter 4) their turnover varies. Most NTs are synthesised from precursors in the axon terminals, stored in vesicles and released by arriving action potentials. Some are subsequently broken down extracellularly, e.g. acetylcholine by cholinesterase, but many, like the amino acids, are taken back into the nerve where they are incorporated into biochemical pathways that may modify their structure initially but ultimately ensure a maintained NT level. Such processes are ideally suited to the fast transmission effected by the amino acids and acetylcholine in some cases (nicotinic), and complements the anatomical features of their neurons and the recepter mechanisms they activate. Further, to ensure the maintenance of function in vital pathways, glutamate and GABA are stored in very high concentrations (10 pmol/mg) just as ACh is at the neuromuscular junction. 

FIGURE 10.11 Interaction of pathways for degradation of pyridine-2-carboxylate, pyridine-3-carboxylate, and nicotine. (From Neilson, A.H. and Allard, A.-S., The Handbook of Environmental Chemistry, Springer, Heidelberg, 1998. With permission.)... 

As for the aerobic degradation of pyridines, hydroxylation of the heterocyclic ring is a key reaction in the anaerobic degradation of azaarenes by Clostridia. Whereas in Clostridium barkeri, the end products are carboxylic acids, CO2, and ammonium, the anaerobic sulfate-reducing Desulfococcus niacinii degraded nicotinate completely to CO2 (Imhoff-Stuckle and Pfennig 1983), although the details of the pathway remain incompletely resolved. 

The metabolism of nicotinate has been extensively studied in Clostridia and the details of the pathway (Figure 10.20) have been delineated in a series of studies (Kung and Tsai 1971 Kung and... 

Stadtman 1971 Kung et al. 1971). Degradation is initiated by hydroxylation of the ring, and the level of nicotinic acid hydroxylase is snbstantially increased by the addition of selenite to the medinm (Imhoff and Andreesen 1979). Nicotinate hydroxylase from Clostridium barkeri contains molybdenum that is coordinated to seleninm, which is essential for hydroxylase activity (Gladyshev et al. 1994). The most remarkable featnre of the pathway is the mechanism whereby 2-methylene-glntarate is converted into methylitaconate by a coenzyme Bi2-mediated reaction (Knng and Stadtman 1971). 

Ensign JC, SC Rittenberg (1964) The pathway of nicotinic acid oxidation by a Bacillus species. J Biol Chem 239 2285-2291. 

Scheme 1 Synthetic pathway of 6-hydroxy-3-succinoyl-pyridine from (S)-nicotine in tobacco waste utilizing whole cells of a Pseudomonas sp. [39]...

Figure 9.2 Autonomic nerve pathways. All preganglionic neurons release acetylcholine (Ach), which binds to nicotinic receptors (N) on the postganglionic neurons. All postganglionic neurons in the parasympathetic system and some sympathetic postganglionic neurons innervating sweat glands release Ach that binds to muscarinic (M) receptors on the cells of the effector tissue. The remaining postganglionic neurons of the sympathetic system release norepinephrine (NE), which binds to alpha (a) or beta (P) receptors on cells of the effector tissue. The cells of the adrenal medulla, which are modified postganglionic neurons in the sympathetic system, release epinephrine (EPI) and NE into the circulation.

Ferrari, R., Le Novere, N., Picciotto, M.R., Changeux, J.P., Zoli, M. Acute and long-term changes in the mesolimbic dopamine pathway after systemic or local single nicotine injections. Eur. J. Neurosci. 15 1810, 2002. 

Gopalakrishnan, M., Molinari, E., Sullivan, J. Regulation of human 0 ,P2 neuronal nicotinic acetylcholine receptors by cholinergic channel ligands and second messenger pathways. Mol. Pharmacol. 52 524, 1997. 

Fedele, E., Varnier, G., Ansaldo, M.A., Raiteri, M. Nicotine administration stimulates the in vivo N-methyl-D-aspartate receptor/nitric oxide/cyclic GMP pathway in rat hippocampus through glutamate release. Br. J. Pharmacol. 125 1042, 1998. 

These dopaminergic reward pathways are critical for normal survival, since they provide the pleasure drives for eating, drinking and reproduction. However, this system produces similar sensations of pleasure with alcohol, cocaine, heroin, nicotine,... 

The pleasure derived from using tobacco is linked to the stimulation of dopamine-dependent neurotransmitter pathways in the brain, particularly in the meso-limbic system. The precise nature of this link remains controversial, but many of the neurophysiological processes underlying nicotine addiction are common to other addictive drugs with diverse pharmacological actions such as opiates, cannabis, alcohol and cocaine. 

If these changes are also present in central dopaminergic reward pathways, it may be that the allele is linked to impaired perception of reward. It has been suggested that an inherited dopamine deficit could be overcome by nicotine, which stimulates dopamine release thereby restoring dopamine function to normal levels [17]. In this way the polymorphism could confer susceptibility to tobacco use. 

Since nicotine has wide ranging effects on the central nervous system it seems likely that pharmacogenomic effects on the development of nicotine dependence will span several neurotransmitter systems. One study found an association between a polymorphism in dopamine /1-hydroxylase and level of tobacco consumption [20]. This enzyme is important in noradrenaline synthesis and it is tempting to speculate that genetically regulated variations in activity might influence susceptibility to nicotine withdrawal symptoms mediated by noradrenergic pathways, but more information is required on the molecular effects of the polymorphism. 

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