thatnicotinedependenceunfoldsviathesamedopaminereactionsasamphetamineand cocainedependence
[44] .However,sincenicotinedisplaysprotractedactivityviaseveral
receptors,thesebecomedesensitisedinthecourseoflong-termadministration [6]
. Inaddition,nicotinestimulatesthereleaseofNAfromregionsoftheventralhippocam-
pusthatareinnervatedfromthelocuscoeruleus.Here,too,thenAChRsareisoformsthat aredesensitisedbythepermanentpresenceofnicotine
[77] .
Thecontinuousdeliveryofnicotineleadstoaregionalreductionin5-HTsynthesisand concentrationinthehippocampus
[78] .Post-mortemstudiesinhumanbrainshippocam-
pusfromheavysmokersalsorevealreducedconcentrationsof5-HTanditsmetabolite 5-hydroxyindoleaceticacid;however,thisisnotthecaseinthecerebralandcerebellar
cortexorthemedullaoblongata.Thedensityof5-HT
1A
receptors,butnotof5-HT
2
recep- tors,wasselectivelyincreasedinthehippocampaltissueofsmokers
[77] .Eventhoughthis
situationhasnotbeenfullyelucidated,anxietystimuliinhumansalsoleadtoincreased 5-HTreleaseinthebrainandconversely,anxiolyticagentscansuppressthisrelease
[79] .
Sincenicotinealsolowers5-HTexcessinthehippocampus,thismightexplaintheanxi- olyticeffectsofnicotineinsome
[80,81] ,butnotallexperimentalmodels
[82] .Effective
anxiolyticdrugsactprimarilyonconductionpathwaysinthedorsalraphenucleus,thecon- nectiontothefrontalbrainandtheamygdala
[75] ,whereasnicotineactsonthemedial
Fig. 4.10
Schematicillustrationofthebrainregionsresponsibleforthedevelopmentofdependence reactionsandthesitesofactionofnicotineinthemesolimbicdopaminergicsystem
[73]
raphenucleus,whichradiatesouttothedorsalhippocampusandstimulatestheconduction pathwaysemanatingfromthedorsalraphenucleusintheprocess
[83] .Theincreased5-HT
release from neurons, which innervate the dorsal hippocampus from the medial raphe nucleus,mayberesponsibleforarelativeresistancetoemotionalandotherstressreactions
and may play an important role in the neuropathology of depression [84, 85]
. In fact, depressivepatientssmokemorefrequentlythanhealthyindividuals,suggestinganantide-
pressanteffectinthesepatientsseeSect.7.1.5in Chap.7
[86]
.Theinverseconclusion thatantidepressantssuchasbupropionandnortriptylinemightbeusefulinprinciplefor
smokingcessationtherapyhasbeendemonstratedinstudiesreportedelsewhereinthis booksee
Chap.11 .Itremainstobeseen,however,whethertheseproductswillprove
theirusefulnessinsmokingcessationtherapy. Variousstudiesindicatethatnicotinealsoactsonopioidreceptors.Endogenousopi-
oidsarereleasedinresponsetonicotineabsorption [87]
.Forexample,nicotinepro- ducesananalgesiceffectinthemousethatcanbeantagonisedwithnaloxone
[88] .In
humans,opiateconsumptionandthecravingtosmokearefrequentlyassociated,with eachpotentiatingtheother,andcigaretteconsumptionincreasesduringheroinormetha-
doneself-administration [89,90]
.Todate,however,anumberofstudieshavefailedto establishwhethermorphineantagonistsmightleadtomoreprolongedsmokingcessa-
tion [91]
,aproblemthatawaitsfurtherinvestigationintheyearstocomeseeSect. 11.3.7in
Chap.11 .
Nicotine administration in animal studies leads to the release of GABA from the interneuronsofhippocampalstructures
[92] .VigabatrinadministrationincreasesGABA
levels,whereasextracellularglutamateanddopamineoverlowaredecreased [93,94]
.
4.5.3 Genetic Aspects
Geneticaspectsappeartobelessimportantthanenvironmentalfactorsparents,school groups,education,religiousinvolvement,attitudeofsociety,advertisinginthedevelop-
mentofnicotinedependence [95,96]
.Bycontrast,heavysmokingortheinabilitytostop smokingcannolongerbeexplainedintermsofenvironmentalfactors,withtheresultthat
biologicalpharmacologicalfactors,psychiatricdisorders,neuroadaptationandgenetic effects
[97,98] areimplicated,asisevidentfromresearchintwins.
Recent studies from molecular genetics have suggested an association between the tryptophanhydroxylase1TPH1geneandnicotineaddiction,indicatingadysfunctionof
theserotonergic5-HTsysteminsmokingbehaviour.ReuterandHennigpublishedin 2004thatinasampleof252healthysubjects,asigniicantassociationbetweenvariations
observedinnicotinedependenceandtheheterozygousAC-genotypeoftheTPHA779C polymorphismcouldbedemonstrated.Moreover,theheterozygousgenotypewassignii-
cantlyassociatedwithapersonalitytraitofneuroticaggressionindirecthostility,negativ- ism,asmeasuredbytheBuss-Durkee-Hostility-InventoryBDHI.Thepositiveheterosis
effectswithrespecttonicotineaddictionandpersonalitysupporttheideathattheTPH1 geneexertspleiotropiceffects
[99] .
Dopamineisakeyneurotransmitterofthemesolimbicrewardpathwayinthehuman brain,andtyrosinehydroxylaseTHistherate-limitingenzymeindopaminebiosynthe-
sis.Consequently,Anneyetal.postulatedin2004thatthegeneencodingTHisastrong candidateforinvolvementinthegeneticcomponentofaddiction.Theimportanceofthis
geneinnicotinedependenceissupportedbymanystudiesshowingalinkbetweennicotine administration and TH expression. A functional tetranucleotide repeat polymorphism
withinintron1oftheTHgeneHUMTH01-VNTRhasbeenshowntomodifytobaccouse intwoindependentCaucasiansamplesfromtheUSAandAustralia.Usinginformation
drawnfromaneight-waveAustralianpopulation-basedlongitudinalstudyofadolescent health,Anneyetal.testedtheeffectoftheHUMTH01-VNTRonnicotinedependence
[100] .
Comparisonsweremadebetweendependentsmokersandnon-dependentsmokers.The resultsprovidedfurthersupportforaprotectiveassociationbetweentheK4alleleand
dependentsmokingoddsratio0.54,95conidenceinterval0.28–1.0.Noassociations were observed at any of three other common TH polymorphisms rs6356, rs6357 and
HUMTH01-PstI.Includingthesedata,threeindependentstudies,twoofwhichuseidenti- calphenotypes,havenowidentiiedaprotectiverelationshipbetweentheK4alleleofthe
functionalHUMTH01-VNTRpolymorphismandhigh-levelsmoking [100]
. Inaninvestigationofpersonalityfactorsandsmokingbehaviourinatotalof2,680
pairsoftwinsand543individualtwins,itwasfoundthatphenotypicassociationswere morepronouncedinmonozygoticthanindizygotictwins
[98] .Whilethisindingunder-
linesthegeneticcontributiontosmokingbehaviour,unequivocalstatementsonthisissue areproblematicbecauseofthefollowingpotentiallyinvolvedfactors:
1. EnzymeCYP
2A6
metabolisesnicotinetocotinine.Smokerscarryingadefectivevariantof CYP
2A6
metabolisenicotinemoreslowlyandexhibitreducednicotinedependence [101]
. Conversely, smokers with a normal CYP
2A6
pattern may respond particularly well to nicotinereplacementtherapy.Adefectiveallelefrequencyof1–3hasbeenobservedin
Finnish,SpanishandSwedishpopulations,muchlowerthanpreviouslythought [102]
. 2. Dopaminehasbeenincreasinglyincriminatedintheproductionofdependence
[103] ,and
thereinforcingpropertiesofnicotinehavebeenlinkedtoitseffectsondopaminergictrans- mission
[104,105] andspeciically,toitseffectsontheD2receptor
[106] .Subgroupsof
dopaminereceptorsD1andD2existintheCNSandgeneticvariationshavebeenidenti- iedinthedopaminereceptorDRD2geneandthedopaminetransporter[DAT]gene
SLC6A3.TheDATinluencesconcentrationsofandresponsestosynapticdopaminein these regions. There is experimental and epidemiological evidence to implicate these
genesinavarietyofdisorders.TheDRD2-A1allelehasbeenassociatedwithareduced densityofdopaminereceptors
[107] .IncomparisonwithpeoplewithDRD2-A2geno-
types,thosewithDRD2-A1genotypesA1A1orA1A2werefoundtobemorelikelyto exhibitcompulsiveandaddictivebehaviours
[108–111] .However,thedataareinconsis-
tent [112]
.Also,accordingtoinvestigationsinpatientswithlungcancer,variantallelesin theD2receptormayplayaroleinthedevelopmentofnicotinedependence
[71] .
3. ThetwoallelesTaqI-A1andTaqI-A2ImarelocatedinthegenomefragmentlhD2G1. WhiletheA1alleleisfoundinabout20ofthepopulation,50–60ofalcoholicscarry
thisallele [113,114]
.Thechildrenofalcoholicsalsohaveanincreasedprevalenceofthis A1allele.Onemeta-analysishasreportedanincreasedassociationoftheDRD2-A1allele
withalcoholics45comparedwiththegeneralpopulation25.Bycontrast,therarer