Effects of Nicotine on Receptors in Different Organs

the฀ metabolism฀ of฀ this฀ transmitter฀ in฀ mesolimbic฀ and฀ nigrostriatal฀ structures฀ [6,฀ 34] .฀ The฀density฀of฀nicotine฀receptors฀is฀higher฀in฀the฀cerebral฀structures฀of฀smokers฀than฀of฀ ฀non-smokers฀and฀in฀contrast฀to฀the฀situation฀following฀nicotine฀infusions,฀the฀smoking฀of฀ single฀cigarettes฀leads฀to฀the฀formation฀of฀additional฀nACh฀receptors,฀preferentially฀in฀the฀ hippocampus,฀gyrus฀rectus฀and฀cerebellar฀cortex฀ [35] . In฀the฀persistent฀presence฀of฀nicotine฀as฀in฀heavy฀smoking,฀up-regulation฀of฀the฀nico- tine฀receptors฀occurs฀in฀numerous฀regions฀of฀the฀brain฀hippocampus,฀neocortex,฀gyrus฀ rectus,฀cerebellar฀cortex,฀median฀raphe฀ [21,฀36–38] ,฀probably฀due฀to฀reduced฀internalisa- tion฀andor฀degradation฀Fig.฀ 4.4 ฀ [39] .฀The฀density฀of฀the฀receptors฀is฀altered฀doubled,฀ but฀not฀their฀afinity฀for฀the฀ligand.฀The฀excess฀nicotine฀is฀probably฀bound฀to฀desensitised฀ or฀inactivated฀receptors฀ [6] . nAChR฀density฀is฀particularly฀high฀in฀the฀nucleus฀accumbens฀ [40] ,฀the฀structure฀which฀ is฀also฀the฀centre฀for฀the฀reward฀system฀and฀plays฀an฀important฀role฀with฀regard฀to฀caloric฀ intake,฀among฀other฀things฀ [41] .฀In฀animal฀experiments,฀dopamine฀is฀released฀by฀nicotine฀ administration.฀Clearly,฀the฀nucleus฀accumbens฀is฀crucial฀for฀the฀development฀of฀depen- dence฀ [34,฀42] .฀The฀combination฀of฀nicotine฀administration฀with฀stimulation฀of฀the฀dop- aminergic฀system,฀especially฀in฀the฀mesoaccumbens,฀seems฀to฀be฀exceptionally฀important฀ in฀that฀there฀is฀a฀regionally฀selective฀down-regulation฀of฀the฀control฀of฀dopaminergic฀neu- rons฀ localised฀ in฀ the฀ mesoaccumbens฀ and฀ these฀ are฀ additionally฀ inhibited฀ by฀ NMDA- glutamate฀receptors฀ [43] .฀It฀is฀suggested฀that฀sensitisation฀is฀related฀to฀enhanced฀burst฀iring฀ of฀mesoaccumbens฀neurons,฀which฀results฀in฀enhancement฀of฀dopamine฀release฀into฀the฀extra- cellular฀space฀and฀hence,฀potentiates฀the฀effect฀on฀extrasynaptic฀dopamine฀receptors฀ [43] .฀ According฀to฀Wise฀and฀Bozarth฀ [44] ,฀the฀dependence-producing฀effect฀of฀nicotine฀and฀other฀ substances฀ is฀ also฀ determined฀ by฀ whether฀ they฀ inluence฀ dopaminergic฀ synapses฀ in฀ the฀ mesolimbic฀system.฀However,฀this฀hypothesis฀is฀not฀without฀its฀opponents฀ [45] .

4.3.2 Organ Effects and Toxicity

Nicotine฀stimulates฀sympathetic฀cardiac฀ganglia฀via฀the฀N-receptors,฀leading฀to฀an฀increase฀in฀ heart฀rate฀see฀Table฀ 4.3 .฀This฀effect฀may฀also฀be฀achieved฀by฀paralysis฀of฀฀parasympathetic฀ Release฀of฀adrenaline฀from฀the฀adrenals,฀of฀noradrenaline฀NA฀in฀the฀hypothalamus฀central฀ increase฀in฀sympathetic฀tone฀and฀of฀dopamine฀in฀the฀mesolimbic฀system Increased฀catecholamine฀levels฀in฀the฀bloodstream฀affecting฀blood฀pressure,฀heart฀rate฀and฀ blood฀coagulation฀factors Varying฀increase฀in฀gastric฀acid฀secretion,฀ulcerogenic฀effect฀peptic฀ulcer฀as฀a฀result฀of฀ reduced฀mucosal฀perfusion Stimulant฀effect฀on฀the฀CNS฀low฀doses:฀tremor,฀blunting฀of฀emotions,฀increased฀ability฀to฀ concentrate Stimulant฀effect฀on฀respiration฀via฀the฀carotid฀and฀aortic฀bodies Stimulation฀of฀the฀vomiting฀centre Intoxication:฀circulatory฀collapse,฀depolarisation฀block฀of฀neuromuscular฀transmission,฀ respiratory฀paralysis฀central Table 4.3 ฀฀฀Pharmacological฀effects฀of฀nicotine฀ [46] cardiac฀ganglia฀or฀by฀the฀discharge฀of฀adrenaline฀from฀the฀adrenal฀medulla.฀Conversely,฀ nicotine฀may฀slow฀the฀heart฀rate฀by฀paralysis฀of฀sympathetic฀or฀stimulation฀of฀parasympa- thetic฀cardiac฀ganglia฀or฀by฀a฀combination฀of฀the฀two฀mechanisms.฀These฀opposite฀effects฀฀–฀ in฀some฀respects฀–฀are฀dependent฀on฀dose,฀route฀of฀administration,฀and฀time฀after฀dosing.฀ Small฀nicotine฀doses฀or฀moderate฀smoking฀produce฀a฀slight฀increase฀in฀heart฀rate฀and฀blood฀ pressure. The฀effect฀of฀nicotine฀on฀the฀gastrointestinal฀tract฀is฀intensiied฀by฀acetylcholine,฀cate- cholamines฀and฀peptide฀hormones.฀Gastric฀acid฀secretion฀is฀not฀regularly฀stimulated,฀and฀ yet,฀tobacco฀smoking฀may฀be฀assumed฀to฀possess฀an฀ulcerogenic฀effect.฀Intestinal฀peristal- sis฀is฀clearly฀stimulated฀and฀this฀may฀lead฀to฀multiple฀bowel฀movements฀ [46] ,฀often฀a฀rea- son฀why฀smokers฀do฀not฀want฀to฀do฀without฀their฀morning฀cigarette. Respiration฀is฀stimulated฀and฀the฀vomiting฀centre฀is฀activated฀by฀stimulation฀of฀nAChRs฀ in฀the฀carotid฀and฀aortic฀bodies. Nicotine฀is฀classed฀as฀a฀powerful฀poison฀that฀is฀effective฀in฀almost฀the฀same฀doses฀as฀ prussic฀acid฀HCN.฀For฀an฀individual฀who฀is฀not฀accustomed฀to฀nicotine,฀it฀is฀estimated฀ that฀a฀single฀dose฀of฀60฀mg฀will฀have฀a฀lethal฀effect฀ [47] .฀Relatively฀high฀doses฀of฀nicotine฀ elicit฀convulsions.฀Ingestion฀of฀toxic฀doses฀leads฀to฀central฀stimulation,฀respiratory฀paraly- sis฀and฀circulatory฀collapse.฀Furthermore,฀nicotine฀causes฀depolarisation฀with฀blockade฀of฀ neuromuscular฀ transmission;฀ if฀ the฀ nicotine฀ dose฀ is฀ suficiently฀ high,฀ death฀ may฀ ensue฀ within฀a฀few฀minutes฀due฀to฀respiratory฀paralysis฀see฀Table฀ 4.3 .

4.3.3 Metabolic and Hormonal Effects of Nicotine

Smokers฀are฀known฀to฀have฀a฀lower฀body฀weight฀than฀non-smokers,฀and฀this฀difference฀is฀ overcompensated฀ for฀ following฀ smoking฀ cessation.฀ Weight฀ reduction฀ associated฀ with฀ smoking฀is฀caused฀by฀the฀reduced฀intake฀of฀calories,฀especially฀sweets,฀as฀well฀as฀by฀an฀ increased฀metabolic฀rate฀and฀the฀increased฀secretion฀of฀catecholamines฀from฀the฀adrenal฀ medulla฀and฀steroid฀hormones฀from฀the฀adrenal฀cortex฀ [48] .฀Besides฀apparently฀playing฀a฀ crucial฀role฀in฀these฀reactions฀ [49,฀50] ,฀nicotine฀also฀stimulates฀the฀secretion฀of฀anti-diuretic฀ hormone฀and฀b-endorphin. A฀similar฀reaction฀is฀observed฀in฀terms฀of฀the฀secretion฀of฀anterior฀pituitary฀lobe฀hor- mones฀e.g.฀ACTH฀ [51] ,฀though฀nicotine฀has฀much฀smaller฀effects฀than฀smoking฀per฀se฀in฀ this฀context.฀Moreover,฀in฀female฀smokers,฀differences฀in฀oestrogen฀secretion฀and฀prema- ture฀onset฀of฀menopause฀are฀thought฀to฀be฀related฀to฀smoking฀ [52] .

4.3.4 Central Nervous System Effects of Nicotine

Nicotine฀in฀low฀doses฀stimulates฀the฀CNS,฀an฀effect฀that฀is฀frequently฀accompanied฀by฀a฀ine฀ tremor.฀Emotions฀are฀blunted฀and฀the฀ability฀to฀concentrate฀is฀reported฀to฀be฀enhanced. The฀dependence-producing฀effects฀of฀nicotine฀have฀been฀beyond฀doubt฀now฀for฀a฀num- ber฀of฀years.฀The฀degree฀of฀nicotine฀dependence฀of฀smokers฀can฀be฀deduced฀on฀the฀basis฀of฀