Genetic Aspects Nicotine Dependence

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฀ A1฀ allele฀ appears฀ to฀ occur฀ in฀ severe฀ forms฀ of฀ alcoholism฀ [114,฀ 115] .฀ This฀ form฀ of฀ ฀genetically-induced฀ dependence฀ also฀ appears฀ to฀ apply฀ in฀ smokers฀ [69–71,฀ 109] ฀ in฀ whom฀ prevalence฀ was฀ increased฀ 48.7฀ compared฀ with฀ the฀ “normal”฀ population฀ 25.9฀ [109,฀115] .฀People฀carrying฀this฀A1฀allele฀start฀to฀smoke฀earlier฀and฀are฀also฀ able฀to฀remain฀abstinent฀for฀short฀periods฀only฀ [109] .฀It฀is฀thought฀that฀the฀A1฀allele฀is฀ associated฀with฀reduced฀D2฀receptor฀activity฀due฀to฀lower฀receptor฀density,฀but฀not฀to฀ altered฀structure฀or฀function฀ [115] . 4.฀ The฀SLC6A3฀gene฀regulates฀synaptic฀dopamine฀by฀coding฀for฀a฀reuptake฀protein฀known฀ as฀the฀DAT฀ [116] .฀This฀gene฀has฀also฀been฀implicated฀in฀Parkinson’s฀disease฀ [117] ,฀ attention฀deicit฀disorder฀ [118] ฀and฀Tourette฀syndrome฀ [119] .฀The฀SLC6A3฀gene฀may฀ display฀several฀single฀nucleotide฀polymorphisms฀SNIPs฀ [120] ,฀with฀the฀9-repeat฀allele฀ being฀associated฀with฀cocaine-induced฀psychosis,฀a฀state฀attributed฀to฀diminished฀dop- amine฀reuptake฀and฀greater฀availability฀of฀synaptic฀dopamine฀ [121] .฀According฀to฀one฀ study฀in฀twins,฀an฀altered฀dopamine฀transporter฀SLC6A3฀occurs฀in฀conjunction฀with฀ the฀D2฀dopamine฀receptor฀DRD2฀located฀on฀chromosome฀11;฀it฀was฀found฀that฀indi- viduals฀with฀the฀SLC6A3-9฀genotype฀in฀conjunction฀with฀the฀DRD2-A2฀genotype฀were฀ less฀likely฀to฀be฀smokers฀ [122] .฀Individuals฀with฀the฀SLC6A3฀gene฀are฀more฀likely฀to฀be฀ smokers฀and฀nicotine-dependent.฀In฀addition,฀an฀association฀has฀been฀reported฀between฀ alcoholics฀and฀the฀presence฀of฀a฀D4฀receptor฀ [123] . 5.฀ Alcohol฀dependence฀and฀nicotine฀dependence฀share฀a฀considerable฀number฀of฀features฀in฀ common,฀with฀heritability฀being฀60.3฀for฀nicotine฀dependence฀and฀55.1฀for฀alcohol฀ dependence.฀A฀common฀genetic฀correlation฀has฀been฀demonstrated฀for฀the฀two฀depen- dence฀types฀ [124] .฀Recent฀research฀indicates฀that฀fetal฀alcohol฀exposure฀may฀produce฀ increased฀risk฀for฀later฀dependence฀on฀nicotine,฀alcohol฀and฀a฀variety฀of฀drugs฀ [125] . Very฀rarely฀0.01฀of฀cases,฀dependence฀may฀also฀develop฀during฀the฀course฀of฀smoking฀ cessation฀therapy฀with฀nicotine฀preparations;฀in฀these฀circumstances,฀ex-smokers฀become฀ ixated฀with฀nicotine฀preparations฀for฀the฀most฀part฀nasal฀spray฀฀chewing฀gum฀and฀then฀ frequently฀use฀these฀products฀over฀a฀period฀of฀months.

4.5.4 Withdrawal Symptoms

Withdrawal฀symptoms฀are฀encountered฀in฀heavy฀nicotine฀dependence฀daily฀cigarette฀con- sumption฀30–40฀cigarettes,฀irst฀morning฀cigarette฀smoked฀immediately฀upon฀waking,฀or฀ the฀smoker฀even฀awakes฀during฀the฀night฀and฀then฀smokes฀one฀or฀two฀cigarettes.฀In฀addi- tion,฀cigarette฀smoking฀inluences฀mood฀and฀behaviour฀as฀well฀as฀appetite฀and฀fat฀metabo- lism฀Table฀ 4.4 .฀The฀classic฀symptoms฀of฀withdrawal฀are: • ฀ Mild฀agitation฀and฀restlessness • ฀ Impaired฀ability฀to฀concentrate • ฀ Anxiety฀feelings฀relatively฀pronounced฀ [126] • ฀ Increased฀appetite฀and฀weight฀gain • ฀ Sleep฀disturbances฀and฀drowsiness • ฀ Strong฀craving฀for฀cigarettes There฀are฀considerable฀variations฀in฀the฀degree฀to฀which฀individuals฀experience฀these฀with- drawal฀symptoms,฀which฀may฀last฀for฀several฀weeks฀to฀months.฀Like฀alcoholics,฀many฀ ex-smokers฀are฀severely฀at฀risk฀because฀the฀least฀cause฀going฀to฀a฀restaurant฀and฀having฀ an฀alcoholic฀drink,฀meeting฀up฀with฀smokers฀may฀trigger฀a฀return฀to฀smoking.฀With฀many฀ smokers,฀however,฀it฀is฀“merely”฀the฀absence฀of฀the฀manual฀cues฀associated฀with฀the฀activ- ity฀of฀smoking฀ [120] ,฀which฀leads฀to฀a฀resumption฀of฀the฀habit฀and฀thus,฀undoes฀the฀initial฀ success฀of฀smoking฀cessation฀therapy.

4.6 Concluding Remarks

• ฀ Nicotine฀is฀one฀of฀the฀most฀potent฀toxic฀alkaloids฀with฀a฀dependence-inducing฀effect,฀ comparable฀ to฀ that฀ of฀ cocaine฀ and฀ heroin.฀ Continued฀ administration฀ in฀ the฀ form฀ of฀ tobacco฀smoking฀especially฀of฀cigarettes฀may฀lead฀to฀dependence. • ฀ Nicotine฀unfolds฀its฀effects฀by฀releasing฀CNS฀messenger฀substances,฀among฀which฀dop- amine,฀NA฀and฀5-HT฀are฀particularly฀important. • ฀ Nicotine฀acts฀by฀stimulating฀nicotinic฀acetylcholine฀receptors฀nAChRs:฀these฀are฀ion฀ transporters฀that฀occur฀in฀the฀peripheral฀and฀CNS฀and฀are฀linked฀with฀various฀transmit- ter฀systems.฀The฀structure฀of฀nAChRs฀has฀been฀largely฀elucidated฀and฀the฀various฀sub- units฀a4b2,฀a3b4,฀a7฀etc.฀can฀be฀assigned฀to฀different฀neural฀structures.฀The฀sites฀of฀ action฀of฀agonists฀and฀competitive฀and฀non-competitive฀antagonists฀can฀be฀located฀in฀ the฀receptor฀system. • ฀ Unlike฀the฀absorption฀of฀nicotine฀from฀cigarettes,฀the฀nicotine฀available฀from฀pharma- ceutical฀formulations฀is฀released฀very฀much฀more฀slowly฀and฀in฀smaller฀doses,฀and฀this฀ is฀ultimately฀the฀reason฀for฀the฀products’฀lack฀of฀any฀dependence-inducing฀effect. • ฀ In฀addition฀to฀external฀inluences,฀the฀development฀of฀nicotine฀dependence฀can฀also฀be฀ related฀to฀genetic฀factors.฀In฀this฀context,฀the฀cytochrome฀P450฀subenzyme฀2A6,฀the฀ distribution฀of฀dopamine฀receptors฀DRD1฀vs.฀DRD2฀and฀their฀alleles฀A1฀vs.฀A2,฀as฀ well฀as฀the฀DAT฀gene฀SLC6A3฀inluence฀smoking฀initiation฀and฀nicotine฀dependence. • ฀ The฀nAChR฀macromolecule฀is฀affected฀by฀several฀pathological฀conditions฀congenital฀ myasthenic฀ syndromes,฀ Alzheimer’s฀ and฀ Parkinson’s฀ disease,฀ schizophrenia,฀ some฀ forms฀of฀epilepsies,฀Gilles฀de฀la฀Tourette฀syndrome.฀A฀variety฀of฀strategies฀e.g.,฀syn- thesis฀of฀nAChR฀agonists฀and฀antagonists,฀subtle฀alterations฀to฀nAChR฀function฀or฀par- tial฀occlusion฀of฀the฀nAChR฀channel฀by฀blocking฀drugs฀will฀result฀in฀new฀therapeutic฀ modalities฀in฀the฀near฀future. References ฀ 1.฀Langley฀JN,฀Anderson฀HK฀1892฀The฀actions฀of฀nicotine฀on฀the฀ciliary฀ganglion฀of฀the฀third฀ cranial฀nerve.฀J฀Physiol฀Lond฀13:460–468 ฀ 2.฀Dale฀HH฀1914฀The฀action฀of฀certain฀esters฀and฀ethers฀of฀choline฀and฀their฀relation฀to฀musca- rine.฀J฀Pharmacol฀Exp฀Ther฀6:147–190