The Contribution of cocoa additive to cigarette smoking addiction

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Page 50 of 207 RIVM report 650270002 Serotonin . SMOKING COCOA INTAKE BY EATING BANANA 25 cig. 3 chocolate cocoa (1 % cocoa) bars of 60 g powder (25 g) (100 g) . Serotonin (µg) 15 35 (milk) (4) 18.75 (4) 5000 – 15000 174 (dark) (4) . Little is known about the profile of the pyrolysis/combustion products of serotonin. (3, 11) Conclusion The daily intake of serotonin from cocoa added to cigarettes is marginal compared with that of serotonin intake from other sources, like chocolate or fruit (banana). Assuming similar bioavaibility, the plasma concentration reached after ingestion of serotonin from chocolate sources or plants is expected to be significantly higher, than after exposure from cigarettes. Since, serotonin is an endogenous compound, it is not expected that the inhaled amount will significantly affect the plasma concentration. However, the different route of application via smoking as compared to other sources should be taken into account. Therefore, local effect of serotonin on the respiratory system might be a point of concern. PHARMACODYNAMICS Mechanism of action Over the past ten years, evidence obtained from molecular, biochemical and physiological studies has revealed the existence of fifteen serotonin receptor subtypes, which can be subdivided into seven major families (5-HT1-7 subtypes) (12). Serotonin both stimulates and inhibits nerves and smooth muscles in the cardiovascular, respiratory and gastrointestinal systems. Platelet membrane contains serotonin receptors (5-HT2) that enhance aggregation when stimulated (6). Serotoninergic neurons are found in the brain stem where they are concentrated in the raphe nuclei. Projections from serotonin neurons reach the cortical forebrain, olfactory bulb, septum, hippocampus, thalamus, hypothalamus, basal ganglia (caudate, putamen and globus pallidus), substantia nigra, cerebellum, and spinal cord. Serotonin produces numerous pharmacological effects mainly because of the diversity of its receptors that are either ionotropic (ligand-gated ion channel receptors) or metabotropic (G-protein-coupled receptors). Serotonin is an autacoid that acts both at microdistances as neurotransmitters and at long distances as a hormone. The majority of serotonin receptors are metabotropic G protein-linked. The exception is the 5HT3 receptor, which is ionotropic. This ligand-gated monovalent cation channel is present in high density in the brain region that contains the emetic centre and its antagonists (e.g., ondansetron) are potent anti-emetics. The metabotropic serotonin receptors are important targets in the brain for action of numerous therapeutics including antidepressants, anxiolytic, and antimigraine drugs. By analogy with neural antiacetylcholine receptors these drugs are likely to act as channel blockers. The metabotropic serotonin receptors are linked to either Gpprotein and their activation decreases cAMP synthesis (5-HT1A-F) or to Gs protein, that activates phospholipase C and increases synthesis of IP3 and diacylglycerol (5- HT2A-C). Although there are many high-affinity agonists and antagonists for all subtypes, there are none that are totally selective for one subtype (13).
RIVM report 650270002 Page 51 of 207 Serotonin Pulmonary system breathing frequency: Afferent nerves to the bronchi may be stimulated by serotonin, causing an increase in respiratory rate (6). tidal volume: no data available lung compliance: no data available airway resistance: Serotonin exhibits a broad diversity of effects on airway smooth muscle contraction, which seems to implicate the presence of a wide variety of serotonin receptor subtypes in both airway smooth muscle and efferent nerves and which also appears to be species-dependent. In several animal airways, serotonin acts directly on airway smooth muscle, causing contraction at low doses and relaxation at high doses. Both contraction and relaxation are mediated by stimulation of the 5-HT2A receptor on airway smooth muscle. The effects of serotonin on airway smooth muscle contraction may also be attributed, in part, to the ability of serotonin to modulate the contractile and relaxing response to other neurotransmitters, such as neuropeptides in the sensory nerve endings and acetylcholine in the presynaptic neurons (12). Some serotonin (inhalation) studies performed on animals are described in the literature. The effect and mechanism of action of serotonin was studied in the pulmonary circulation of rabbits. Serotonin (1.76 µg, 8.8 µg and 17.6µg/l) produced a concentration-dependent increase in rabbit pulmonary arterial tension (14). Serotonin aerosols (1.5 ml/min) were generated by a nebulizer, which introduced serotonin aerosol (0.07 – 1.2 mg/ml tidal air) in cats. The pulmonary resistance increased significantly when the serotonin aerosol concentration was higher than ± 0.3 mg/ml (15). Although the effects of serotonin on the pulmonary system have been extensively studied in several animal species, both in vivo and in vitro, the situation is less well established in humans. A possible relationship between serotonin and airway obstruction has been suggested on the basis of the association of wheezing with carcinoid syndrome (tumor of neuroendocrine cells), although it is now obvious that other mediators such as histamine, bradykinin and tachykinins are also released in this pathology (12). Inhaled serotonin does not produce bronchoconstriction in normal human subjects. It has been demonstrated in some studies, however, that inhalation of serotonin causes bronchoconstriction in 10 - 65% of asthmatic patients, whereas another study did not find the bronchoconstrictory effect of serotonin in asthmatics (16). In that study, serotonin up to a maximum concentration of 13.6 g/l had no consistent effect on FEV-1, the maximum expiratory flow at 30 % of vital capacity (V-max-30) or the specific airways conductance (sGaw) in any of the subject groups (asthmatics and nonasthmatics). That study concluded that in contrast to a variety of animals, serotonin is unlikely to serve as a significant bronchoconstrictor mediator in man. Furthermore, an elevated plasma level of 5-HT has been documented in symptomatic asthmatic patients when compared to nonasthmatics. In the former group, the 5-HT level significantly correlated with clinical severity rating and forced expiratory volume in one second (FEV1) (17). Cardiovascular system blood pressure: Serotonin plays a role in primary pulmonary hypertension; probably through the 5- HT1B/1D- and 5-HT2A -receptors (18, 19). Coronary vessels in human subjects showed a biphasic response to intracoronary serotonin infusion: dilation at
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The Contribution of cocoa additive to cigarette smoking addiction

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