Molecular Biological Aspects of Dependence

that฀nicotine฀dependence฀unfolds฀via฀the฀same฀dopamine฀reactions฀as฀amphetamine฀and฀ cocaine฀dependence฀ [44] .฀However,฀since฀nicotine฀displays฀protracted฀activity฀via฀several฀ receptors,฀these฀become฀desensitised฀in฀the฀course฀of฀long-term฀administration฀ [6] . In฀addition,฀nicotine฀stimulates฀the฀release฀of฀NA฀from฀regions฀of฀the฀ventral฀hippocam- pus฀that฀are฀innervated฀from฀the฀locus฀coeruleus.฀Here,฀too,฀the฀nAChRs฀are฀isoforms฀that฀ are฀desensitised฀by฀the฀permanent฀presence฀of฀nicotine฀ [77] . The฀continuous฀delivery฀of฀nicotine฀leads฀to฀a฀regional฀reduction฀in฀5-HT฀synthesis฀and฀ concentration฀in฀the฀hippocampus฀ [78] .฀Post-mortem฀studies฀in฀human฀brains฀hippocam- pus฀from฀heavy฀smokers฀also฀reveal฀reduced฀concentrations฀of฀5-HT฀and฀its฀metabolite฀ 5-hydroxyindoleacetic฀acid;฀however,฀this฀is฀not฀the฀case฀in฀the฀cerebral฀and฀cerebellar฀ cortex฀or฀the฀medulla฀oblongata.฀The฀density฀of฀5-HT 1A ฀receptors,฀but฀not฀of฀5-HT 2 ฀recep- tors,฀was฀selectively฀increased฀in฀the฀hippocampal฀tissue฀of฀smokers฀ [77] .฀Even฀though฀this฀ situation฀has฀not฀been฀fully฀elucidated,฀anxiety฀stimuli฀in฀humans฀also฀lead฀to฀increased฀ 5-HT฀release฀in฀the฀brain฀and฀conversely,฀anxiolytic฀agents฀can฀suppress฀this฀release฀ [79] .฀ Since฀nicotine฀also฀lowers฀5-HT฀excess฀in฀the฀hippocampus,฀this฀might฀explain฀the฀anxi- olytic฀effects฀of฀nicotine฀in฀some฀ [80,฀81] ,฀but฀not฀all฀experimental฀models฀ [82] .฀Effective฀ anxiolytic฀drugs฀act฀primarily฀on฀conduction฀pathways฀in฀the฀dorsal฀raphe฀nucleus,฀the฀con- nection฀to฀the฀frontal฀brain฀and฀the฀amygdala฀ [75] ,฀whereas฀nicotine฀acts฀on฀the฀medial฀ Fig. 4.10 ฀฀฀Schematic฀illustration฀of฀the฀brain฀regions฀responsible฀for฀the฀development฀of฀dependence฀ reactions฀and฀the฀sites฀of฀action฀of฀nicotine฀in฀the฀mesolimbic฀dopaminergic฀system฀ [73] raphe฀nucleus,฀which฀radiates฀out฀to฀the฀dorsal฀hippocampus฀and฀stimulates฀the฀conduction฀ pathways฀emanating฀from฀the฀dorsal฀raphe฀nucleus฀in฀the฀process฀ [83] .฀The฀increased฀5-HT฀ release฀ from฀ neurons,฀ which฀ innervate฀ the฀ dorsal฀ hippocampus฀ from฀ the฀ medial฀ raphe฀ nucleus,฀may฀be฀responsible฀for฀a฀relative฀resistance฀to฀emotional฀and฀other฀stress฀reactions฀ and฀ may฀ play฀ an฀ important฀ role฀ in฀ the฀ neuropathology฀ of฀ depression฀ [84,฀ 85] .฀ In฀ fact,฀ depressive฀patients฀smoke฀more฀frequently฀than฀healthy฀individuals,฀suggesting฀an฀antide- pressant฀effect฀in฀these฀patients฀see฀Sect.฀7.1.5฀in฀ Chap.฀7 ฀ [86] .฀The฀inverse฀conclusion฀ that฀antidepressants฀such฀as฀bupropion฀and฀nortriptyline฀might฀be฀useful฀in฀principle฀for฀ smoking฀cessation฀therapy฀has฀been฀demonstrated฀in฀studies฀reported฀elsewhere฀in฀this฀ book฀see฀ Chap.฀11 .฀It฀remains฀to฀be฀seen,฀however,฀whether฀these฀products฀will฀prove฀ their฀usefulness฀in฀smoking฀cessation฀therapy. Various฀studies฀indicate฀that฀nicotine฀also฀acts฀on฀opioid฀receptors.฀Endogenous฀opi- oids฀are฀released฀in฀response฀to฀nicotine฀absorption฀ [87] .฀For฀example,฀nicotine฀pro- duces฀an฀analgesic฀effect฀in฀the฀mouse฀that฀can฀be฀antagonised฀with฀naloxone฀ [88] .฀In฀ humans,฀opiate฀consumption฀and฀the฀craving฀to฀smoke฀are฀frequently฀associated,฀with฀ each฀potentiating฀the฀other,฀and฀cigarette฀consumption฀increases฀during฀heroin฀or฀metha- done฀self-administration฀ [89,฀90] .฀To฀date,฀however,฀a฀number฀of฀studies฀have฀failed฀to฀ establish฀whether฀morphine฀antagonists฀might฀lead฀to฀more฀prolonged฀smoking฀cessa- tion฀ [91] ,฀a฀problem฀that฀awaits฀further฀investigation฀in฀the฀years฀to฀come฀see฀Sect.฀ 11.3.7฀in฀ Chap.฀11 . Nicotine฀ administration฀ in฀ animal฀ studies฀ leads฀ to฀ the฀ release฀ of฀ GABA฀ from฀ the฀ interneurons฀of฀hippocampal฀structures฀ [92] .฀Vigabatrin฀administration฀increases฀GABA฀ levels,฀whereas฀extracellular฀glutamate฀and฀dopamine฀overlow฀are฀decreased฀ [93,฀94] .

4.5.3 Genetic Aspects

Genetic฀aspects฀appear฀to฀be฀less฀important฀than฀environmental฀factors฀parents,฀school฀ groups,฀education,฀religious฀involvement,฀attitude฀of฀society,฀advertising฀in฀the฀develop- ment฀of฀nicotine฀dependence฀ [95,฀96] .฀By฀contrast,฀heavy฀smoking฀or฀the฀inability฀to฀stop฀ smoking฀can฀no฀longer฀be฀explained฀in฀terms฀of฀environmental฀factors,฀with฀the฀result฀that฀ biological฀pharmacological฀factors,฀psychiatric฀disorders,฀neuroadaptation฀and฀genetic฀ effects฀ [97,฀98] ฀are฀implicated,฀as฀is฀evident฀from฀research฀in฀twins. Recent฀ studies฀ from฀ molecular฀ genetics฀ have฀ suggested฀ an฀ association฀ between฀ the฀ tryptophan฀hydroxylase฀1฀TPH1฀gene฀and฀nicotine฀addiction,฀indicating฀a฀dysfunction฀of฀ the฀serotonergic฀5-HT฀system฀in฀smoking฀behaviour.฀Reuter฀and฀Hennig฀published฀in฀ 2004฀that฀in฀a฀sample฀of฀252฀healthy฀subjects,฀a฀signiicant฀association฀between฀variations฀ observed฀in฀nicotine฀dependence฀and฀the฀heterozygous฀AC-genotype฀of฀the฀TPH฀A779C฀ polymorphism฀could฀be฀demonstrated.฀Moreover,฀the฀heterozygous฀genotype฀was฀signii- cantly฀associated฀with฀a฀personality฀trait฀of฀neurotic฀aggression฀indirect฀hostility,฀negativ- ism,฀as฀measured฀by฀the฀Buss-Durkee-Hostility-Inventory฀BDHI.฀The฀positive฀heterosis฀ effects฀with฀respect฀to฀nicotine฀addiction฀and฀personality฀support฀the฀idea฀that฀the฀TPH1฀ gene฀exerts฀pleiotropic฀effects฀ [99] . Dopamine฀is฀a฀key฀neurotransmitter฀of฀the฀mesolimbic฀reward฀pathway฀in฀the฀human฀ brain,฀and฀tyrosine฀hydroxylase฀TH฀is฀the฀rate-limiting฀enzyme฀in฀dopamine฀biosynthe- sis.฀Consequently,฀Anney฀et฀al.฀postulated฀in฀2004฀that฀the฀gene฀encoding฀TH฀is฀a฀strong฀ candidate฀for฀involvement฀in฀the฀genetic฀component฀of฀addiction.฀The฀importance฀of฀this฀ gene฀in฀nicotine฀dependence฀is฀supported฀by฀many฀studies฀showing฀a฀link฀between฀nicotine฀ administration฀ and฀ TH฀ expression.฀ A฀ functional฀ tetranucleotide฀ repeat฀ polymorphism฀ within฀intron฀1฀of฀the฀TH฀gene฀HUMTH01-VNTR฀has฀been฀shown฀to฀modify฀tobacco฀use฀ in฀two฀independent฀Caucasian฀samples฀from฀the฀USA฀and฀Australia.฀Using฀information฀ drawn฀from฀an฀eight-wave฀Australian฀population-based฀longitudinal฀study฀of฀adolescent฀ health,฀Anney฀et฀al.฀tested฀the฀effect฀of฀the฀HUMTH01-VNTR฀on฀nicotine฀dependence฀ [100] .฀ Comparisons฀were฀made฀between฀dependent฀smokers฀and฀non-dependent฀smokers.฀The฀ results฀provided฀further฀support฀for฀a฀protective฀association฀between฀the฀K4฀allele฀and฀ dependent฀smoking฀odds฀ratio฀0.54,฀95฀conidence฀interval฀0.28–1.0.฀No฀associations฀ were฀ observed฀ at฀ any฀ of฀ three฀ other฀ common฀ TH฀ polymorphisms฀ rs6356,฀ rs6357฀ and฀ HUMTH01-PstI.฀Including฀these฀data,฀three฀independent฀studies,฀two฀of฀which฀use฀identi- cal฀phenotypes,฀have฀now฀identiied฀a฀protective฀relationship฀between฀the฀K4฀allele฀of฀the฀ functional฀HUMTH01-VNTR฀polymorphism฀and฀high-level฀smoking฀ [100] . In฀an฀investigation฀of฀personality฀factors฀and฀smoking฀behaviour฀in฀a฀total฀of฀2,680฀ pairs฀of฀twins฀and฀543฀individual฀twins,฀it฀was฀found฀that฀phenotypic฀associations฀were฀ more฀pronounced฀in฀monozygotic฀than฀in฀dizygotic฀twins฀ [98] .฀While฀this฀inding฀under- lines฀the฀genetic฀contribution฀to฀smoking฀behaviour,฀unequivocal฀statements฀on฀this฀issue฀ are฀problematic฀because฀of฀the฀following฀potentially฀involved฀factors: 1.฀ Enzyme฀CYP 2A6 ฀metabolises฀nicotine฀to฀cotinine.฀Smokers฀carrying฀a฀defective฀variant฀of฀ CYP 2A6 ฀metabolise฀nicotine฀more฀slowly฀and฀exhibit฀reduced฀nicotine฀dependence฀ [101] .฀ Conversely,฀ smokers฀ with฀ a฀ normal฀ CYP 2A6 ฀ pattern฀ may฀ respond฀ particularly฀ well฀ to฀ nicotine฀replacement฀therapy.฀A฀defective฀allele฀frequency฀of฀1–3฀has฀been฀observed฀in฀ Finnish,฀Spanish฀and฀Swedish฀populations,฀much฀lower฀than฀previously฀thought฀ [102] . 2.฀ Dopamine฀has฀been฀increasingly฀incriminated฀in฀the฀production฀of฀dependence฀ [103] ,฀and฀ the฀reinforcing฀properties฀of฀nicotine฀have฀been฀linked฀to฀its฀effects฀on฀dopaminergic฀trans- mission฀ [104,฀105] ฀and฀speciically,฀to฀its฀effects฀on฀the฀D2฀receptor฀ [106] .฀Subgroups฀of฀ dopamine฀receptors฀D1฀and฀D2฀exist฀in฀the฀CNS฀and฀genetic฀variations฀have฀been฀identi- ied฀in฀the฀dopamine฀receptor฀DRD2฀gene฀and฀the฀dopamine฀transporter฀[DAT]฀gene฀ SLC6A3.฀The฀DAT฀inluences฀concentrations฀of฀and฀responses฀to฀synaptic฀dopamine฀in฀ these฀ regions.฀ There฀ is฀ experimental฀ and฀ epidemiological฀ evidence฀ to฀ implicate฀ these฀ genes฀in฀a฀variety฀of฀disorders.฀The฀DRD2-A1฀allele฀has฀been฀associated฀with฀a฀reduced฀ density฀of฀dopamine฀receptors฀ [107] .฀In฀comparison฀with฀people฀with฀DRD2-A2฀geno- types,฀those฀with฀DRD2-A1฀genotypes฀A1A1฀or฀A1A2฀were฀found฀to฀be฀more฀likely฀to฀ exhibit฀compulsive฀and฀addictive฀behaviours฀ [108–111] .฀However,฀the฀data฀are฀inconsis- tent฀ [112] .฀Also,฀according฀to฀investigations฀in฀patients฀with฀lung฀cancer,฀variant฀alleles฀in฀ the฀D2฀receptor฀may฀play฀a฀role฀in฀the฀development฀of฀nicotine฀dependence฀ [71] . 3.฀ The฀two฀alleles฀TaqI-A1฀and฀TaqI-A2Im฀are฀located฀in฀the฀genome฀fragment฀lhD2G1.฀ While฀the฀A1฀allele฀is฀found฀in฀about฀20฀of฀the฀population,฀50–60฀of฀alcoholics฀carry฀ this฀allele฀ [113,฀114] .฀The฀children฀of฀alcoholics฀also฀have฀an฀increased฀prevalence฀of฀this฀ A1฀allele.฀One฀meta-analysis฀has฀reported฀an฀increased฀association฀of฀the฀DRD2-A1฀allele฀ with฀alcoholics฀45฀compared฀with฀the฀general฀population฀25.฀By฀contrast,฀the฀rarer฀