The Contribution of cocoa additive to cigarette smoking addiction

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Page 52 of 207 RIVM report 650270002 Serotonin concentrations up to 1.76 mg/l, but constriction at 17.6 mg/l (20). see also heart rate heart rate: Serotonin does not appear to regulate blood pressure in the normal animal. However, when platelets become activated in certain disease states, serotonin may increase blood pressure. Serotonin exerts complex effects in the cardiovascular system, including hypotension or hypertension, vasodilatation or vasoconstriction, and/or bradycardia or tachycardia; the eventual response depends primarily on the nature of the serotonin receptors involved. Serotonin produces positive inotropic and chronotropic effects on the heart that are mediated by 5-HT1 receptors. These effects may be blunted by stimulation of 5-HT3 receptors on afferent nerves of baroreceptors and chemoreceptors. 5-HT3 receptors are also present on vagal nerve endings in the coronary chemoreflex, characterized by inhibition of sympathetic outflow and increased activity of the cardiac (efferent) vagus, leading to profound bradycardia and hypotension (6, 21). Renal system diuresis: An intrarenal infusion of serotonin at a dose of 5 µg/min in anesthetized dogs resulted in a biphasic response of renal blood flow which decreased transiently then increased above the control level during prolonged infusion. The prolonged infusion of serotonin also increased urine flow and urinary excretion of Na + . Serotonin may exert its antidiuretic action via a 5-HT1-like receptor in the tubules but the renal hemodynamic changes induced by serotonin may overcome its antidiuretic action and evokes subsequently diuresis (22). saluresis: After direct application of serotonin to the central nervous system (CNS), increases in urinary excretion of Na+ and in the Na + /K + ratio were observed, concomitant with depressor effects. Therefore, central serotoninergic mechanisms are involved in the control of Na+ excretion in the hydrated rat (23). Nervous system central nervous system: Serotonin exerts numerous effects on the CNS through the large family of serotonin receptors. Serotonin plays a role in depression, agression, long term memory, mental fatigue during endurance exercise (24-27). Serotonin is furthermore involved in regulation of sleep, circadian rhythms, food intake (fat and energy intake) and regulation of the BBB (brain blood barrier) function (13, 28, 29). The serotoninergic system is also involved in the nicotine dependency (30, 31). autonomic system: Serotonin can stimulate or inhibit nerves, depending on the site and the type of receptor involved. Activation of 5-HT1 receptors on adrenergic nerve terminals inhibits the release of the norepinephrine elicited by stimulation of the sympathetic nervous system. 5-HT3 receptors located on various sensory neurons mediate a depolarizing response, which may account for the ability of serotonin to cause pain and itching, as well as respiratory stimulation and cardiovascular reflex (6). Serotonin released from intestinal enterochromaffin cells may act either directly on vagal afferents and/or pass to the circulation and
RIVM report 650270002 Page 53 of 207 Serotonin stimulate central emetic centre (32). Other Serotonin has a differential effect on gastric emptying. Low and high doses (0.1, 0.3 and 30 mg/kg, i.p.) significantly inhibited the gastric emptying in rats while doses ranging from 1 to 10 mg/kg, i.p., had no significant effect on the gastric emptying (33). Critical assessment Serotonin has various effects in the body, through the large family of serotonin receptors. Some contradictory results were obtained about the bronchoconstrictory effect of serotonin in humans, but it is concluded that it is unlikely that serotonin serves a significant bronchoconstrictor mediator in man. Serotonin has also a pulmonary hypertension effect on the pulmonary system. Depending on the serotonin level, it exerts complex effects on the cardiovascular system, including hypotension or hypertension, vasodilatation or vasoconstriction, and/or bradycardia or tachycardia. It also has complex effects on the CNS and is involved in the nicotine dependency. Conclusion Serotonin, an endogenous compound, exerts various effects in the body through the large family of serotonin receptors. The inhalation studies of serotonin did not show any significant bronchoconstrictory effect in normal human subjects. Due to its negligible effect on the bronchi in normal human, it is unlikely that the cigarette serotonin will exert any bronchoconstrictory effect. PHARMACOKINETICS There are no oral data available on the pharmacokinetics of exogenous serotonin. Pharmacokinetics data are only available on endogenous serotonin. Absorption No data are available on serotonin uptake from inhalation studies. Bioavailability No data available on bioavailability from exogenous serotonin intake via inhalation. Distribution About 90% of endogenous serotonin (±10 mg) is located in the enterochromaffin cells of the gastrointestinal tract; most of the remainder is present in platelets and the CNS (6). Most of the serotonin in the body is synthesized and stored in enterochromaffin-tissue associated with the gastrointestinal tract, and is released in the blood as a potent vasoconstricting agent, with >90% of it sequestered in platelets. It is also synthesized and released by neurons, serving as a neurotransmitter in both the central and peripheral nervous system (13). Less than 1 % of serotonin in the blood is extracellular (34). Smoking of a single cigarette caused a transient increase in platelet serotonin levels by about 350% in non-smokers, but had no additional effect in smokers. Similarly,
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The Contribution of cocoa additive to cigarette smoking addiction

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