Agonists and Antagonists of the nAChR and its Subtypes

mecamylamine฀Box฀ 4.2 ;฀Table฀ 4.2 ,฀which฀has฀IC 50 ฀values฀in฀the฀lower฀µM฀range฀ [25] ;฀ in฀this฀case,฀the฀a7฀nAChR฀subtypes฀react฀somewhat฀less฀sensitively฀than฀the฀a–b฀heter- omers.฀In฀addition,฀N-methyl- d -aspartate฀NMDA฀receptors฀are฀blocked฀at฀concentra- tions฀in฀the฀higher฀µM฀range฀ [26] .฀Similar฀effects฀are฀also฀produced฀by฀other฀ganglionic฀ blocking฀agents,฀such฀as฀hexamethonium,฀decamethonium฀and฀chlorisondamine฀Table฀ 4.2 .฀At฀concentrations฀in฀the฀low฀µM฀range,฀the฀antidepressant฀bupropion฀also฀inhibits฀ various฀nAChR฀subtypes฀a3b2,฀a4b2,฀a7฀in฀the฀rat฀as฀well฀as฀nAChR-mediated฀rubid- ium฀eflux฀of฀a฀human฀cell฀line฀SH-SY5Y฀ [27,฀28] .฀The฀effect฀of฀bupropion฀on฀human฀ cells฀was฀voltage-independent,฀with฀the฀result฀that฀an฀effect฀via฀the฀channel฀lumen฀may฀ be฀ excluded.฀ Further฀ substances฀ with฀ non-competitive฀ effects฀ include฀ the฀ neuroleptic฀ drug฀chlorpromazine฀and฀the฀anaesthetics฀phencyclidine฀and฀ketamine฀ [29] .฀Various฀ste- roid฀hormones,฀such฀as฀฀corticosterone,฀aldosterone,฀oestradiol฀and฀cortisol,฀are฀able฀to฀ inhibit฀neuronal฀nAChR฀subtypes฀from฀a฀human฀cell฀line฀SH-SY5Y฀at฀concentrations฀in฀ the฀upper฀nM฀to฀lower฀µM฀range฀ [30] .฀Progesterone฀inhibits฀the฀a4b2฀nAChR฀subtype฀at฀ concentrations฀of฀only฀9฀µM฀IC 50 ฀ [31,฀32] .฀A฀b-amyloid฀polypeptide 1–42 ฀also฀inhibits฀the฀ a 7฀nAChR฀subtype฀in฀the฀pM฀range฀ [33] ,฀prompting฀speculation฀concerning฀an฀associa- tion฀with฀the฀pathogenesis฀of฀Alzheimer’s฀disease฀and฀the฀role฀of฀nAChRs฀in฀its฀develop- ment.฀Section฀ 7.1 ฀in฀ Chap.฀7 ฀includes฀a฀discussion฀of฀the฀association฀between฀smoking฀ and฀slowing฀of฀the฀progression฀of฀Alzheimer’s฀disease.

4.3 Pharmacology

Like฀acetylcholine,฀nicotine฀stimulates฀receptors฀of฀the฀parasympathetic฀nervous฀system,฀ and฀a฀distinction฀is฀drawn฀between฀nicotinic฀and฀muscarinic฀receptors฀N฀and฀M฀receptors฀ and฀effects.

4.3.1 Effects of Nicotine on Receptors in Different Organs

Nicotine฀predominantly฀stimulates฀presynaptic฀nACh฀receptors,฀thereby฀producing฀an฀excit- atory฀action฀ [4,฀20] .฀If฀these฀receptors฀are฀located฀on฀dopaminergic฀neurons,฀they฀฀promote฀ Box 4.2 ฀฀฀฀Compounds฀with฀nAChR-antagonistic฀eficacy:฀mecamylamine,฀d-tubocurarine H N CH 3 2 H N OH O OCH 3 H O OH Mecamylamine d-Tubocurarine H 3 C H 3 CO CH 3 CH 3 CH 2 CH 3 NHCH 3 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]