Types of Dependence Nicotine Dependence

is฀consistent฀with฀nicotine’s฀behaviour-arousing฀and฀behaviour-reinforcing฀properties,฀espe- cially฀since฀the฀identiied฀brain฀regions฀participate฀in฀the฀reinforcing,฀mood-elevating฀and฀ cognitive฀properties฀ [66] . Van฀Den฀Eijnden฀et฀al.฀addressed฀in฀2003฀that฀besides฀nicotine,฀other฀chemicals฀in฀to฀bacco฀ smoke฀such฀as฀norharman฀may฀contribute฀to฀the฀addictive฀properties฀of฀cigarettes฀ [67] .฀ More฀speciically,฀elevated฀blood฀plasma฀levels฀of฀norharman฀may฀reduce฀feelings฀of฀crav- ing฀among฀tobacco-dependent฀individuals.฀To฀test฀this฀hypothesis,฀plasma฀concentrations฀ of฀norharman฀were฀measured฀in฀38฀male฀smokers฀at฀least฀15฀cigarettesday฀at฀three฀time- points฀on฀3฀different฀days฀spread฀over฀a฀4-month฀period.฀The฀irst฀measurement฀T0฀was฀ conducted฀in฀the฀morning฀at฀8.30฀a.m.,฀after฀12฀h฀of฀smoking฀abstinence.฀The฀T1฀and฀T2฀ measurements฀were฀conducted฀at฀13.00฀p.m.฀and฀16.30฀p.m.,฀respectively,฀during฀a฀period฀ of฀ad฀libitum฀smoking฀after฀the฀T0฀measurement,฀participants฀were฀not฀restricted฀in฀their฀ smoking฀behaviour฀ [67] .฀At฀each฀of฀the฀nine฀time-points,฀craving฀was฀assessed฀by฀means฀ of฀a฀shortened฀version฀of฀the฀Questionnaire฀of฀Smoking฀Urges.฀The฀Fagerström฀Test฀of฀ Nicotine฀Dependence฀was฀used฀to฀obtain฀an฀indication฀of฀nicotine฀dependence.฀The฀study฀ showed฀that,฀after฀a฀period฀of฀smoking฀abstinence,฀craving฀was฀stronger฀in฀those฀with฀a฀ high฀tobacco฀dependence฀than฀in฀those฀with฀a฀low฀tobacco฀dependence.฀After฀resumption฀ of฀smoking,฀craving฀declined฀to฀a฀similar฀low฀level฀in฀both฀low฀and฀high฀dependent฀smok- ers.฀The฀authors฀conclude฀that฀measurements฀during฀periods฀of฀ad฀libitum฀smoking฀indi- cate฀that฀plasma฀levels฀of฀norharman฀are฀related฀negatively฀to฀craving฀among฀LN-dependent฀ smokers,฀but฀not฀among฀high฀dependent฀smokers฀ [67] . Approximately฀17฀of฀smokers฀are฀heavily฀dependent฀ [68] ,฀with฀the฀result฀that฀smok- ing฀cessation฀in฀this฀group฀of฀people฀is฀also฀only฀achievable฀with฀great฀dificulty฀and฀gener- ally,฀not฀without฀medical฀help. Different฀dependence฀types฀can฀be฀identiied฀among฀cigarette฀smokers: 1.฀ Those฀who฀smoke฀one฀cigarette฀at฀regular฀intervals฀throughout฀the฀day, 2.฀ Those฀who฀smoke฀by฀preference฀during฀the฀hours฀of฀the฀morning฀or฀evening, 3.฀ Those฀who฀even฀get฀up฀during฀the฀night฀in฀order฀to฀smoke 4.฀ Those฀who฀smoke฀in฀phases,฀e.g.฀at฀weekends,฀while฀on฀holiday฀or฀at฀other฀social฀events. The฀Fagerström฀Test฀for฀Nicotine฀Dependence฀FTDN฀permits฀assessment฀of฀the฀degree฀ of฀dependence฀on฀the฀basis฀of฀six฀questions฀Table฀ 4.5 ฀ [68] .฀This฀can฀be฀estimated฀from฀ the฀scores฀achieved฀maximum฀10,฀with฀scores฀฀7฀being฀associated฀with฀very฀high฀depen- dence฀ [68] .฀According฀to฀the฀Diagnostic฀and฀Statistical฀Manual฀DSM-IV;฀ [69] ฀of฀the฀ American฀Psychiatric฀Association,฀nicotine฀dependence฀is฀assumed฀to฀be฀present฀if฀three฀ or฀more฀of฀the฀following฀six฀assessment฀criteria฀are฀satisied: • ฀ Tolerance • ฀ Withdrawal฀symptoms • ฀ Compulsive฀desire฀to฀consume฀tobacco • ฀ Reduced฀ability฀to฀control฀the฀start,฀end฀and฀quantity฀of฀tobacco฀consumption • ฀ Progressive฀ neglect฀ of฀ other฀ interests฀ or฀ recreational฀ activities฀ due฀ to฀ tobacco฀ consumption • ฀ Smoking฀larger฀amounts฀than฀actually฀intended,฀smoking฀despite฀detailed฀knowledge฀of฀ the฀harmful฀effects฀on฀health. Each฀smoker฀“titrates”฀hisher฀own฀plasma฀nicotine฀level฀in฀terms฀of฀the฀number฀of฀ciga- rettes฀smoked,฀the฀number฀of฀puffs฀and฀the฀depth฀of฀inhalation.฀Smokers,฀thus,฀largely฀ avoid฀the฀signs฀of฀intoxication฀tachycardia,฀perspiration,฀pallor,฀diarrhoea,฀etc..฀Nicotine฀ preparations฀are฀not฀capable฀of฀producing฀this฀“kick”฀because฀the฀delivery฀of฀nicotine฀from฀ all฀formulations฀occurs฀more฀slowly฀than฀from฀a฀cigarette฀see฀Figs.฀ 4.5 ฀and฀ 4.9 .

4.5.2 Molecular Biological Aspects of Dependence

The฀effects฀of฀nicotine฀have฀been฀frequently฀studied฀in฀self-administration฀“self-reward”฀ systems฀in฀rats฀and฀monkeys฀ [70,฀71] .฀Small฀multiple฀doses฀of฀nicotine,฀comparable฀with฀ those฀ delivered฀ during฀ cigarette฀ smoking,฀ have฀ a฀ locomotor฀ stimulant฀ effect฀ similar฀ to฀ amphetamine฀or฀cocaine฀[127].฀The฀locomotor฀stimulant฀and฀“self-rewarding”฀effects฀of฀ nicotine฀are฀produced฀as฀a฀result฀of฀increased฀release฀of฀dopamine฀from฀the฀nucleus฀accum- bens฀in฀the฀posterior฀region฀of฀the฀mesolimbic฀system฀[66,฀ 72] .฀Neuronal฀nicotine฀receptors฀ are฀found฀at฀various฀sites฀in฀the฀CNS,฀both฀at฀the฀terminal฀nerve฀endings฀and฀in฀the฀somato- dentritic฀dopamine-secreting฀neurons฀in฀the฀midbrain฀nucleus฀accumbens฀Fig.฀ 4.10 .฀The฀ increased฀secretion฀of฀dopamine฀occurs฀as฀a฀result฀of฀increased฀impulse฀density฀ [74,฀75] .฀ Parallel฀with฀the฀stimulation฀of฀dopamine฀secretion,฀there฀is฀stimulation฀of฀the฀NMDA฀ receptor,฀which฀is฀responsible฀for฀the฀binding฀of฀glycine฀and฀for฀potentiating฀the฀activity฀of฀ glutamate฀ [34,฀76] .฀The฀increase฀in฀dopamine฀release฀is฀associated฀with฀a฀nicotine-฀preferring฀ behaviour,฀which฀intensiies฀from฀“liking”฀to฀“craving.”฀It฀is,฀therefore,฀highly฀probable฀ Questions Responses Scores 1 How฀soon฀after฀you฀wake฀up฀do฀you฀smoke฀your฀ irst฀cigarette? Within฀5฀min 6–30฀min 31–60฀min After฀60฀min 3 2 1 2 Do฀you฀ind฀it฀dificult฀to฀refrain฀from฀smoking฀in฀ places฀where฀it฀is฀forbidden?฀e.g.฀in฀the฀ cinema,฀at฀meetings฀etc. Yes No 1 3 Which฀cigarette฀would฀you฀hate฀most฀to฀give฀up? The฀irst฀in฀the฀ morning฀ Any฀other 1 4 How฀many฀cigarettesday฀do฀you฀smoke? 10฀or฀less 11–20 21–30 31฀or฀more 1 2 3 5 Do฀you฀smoke฀more฀frequently฀during฀the฀irst฀ hours฀after฀awakening฀than฀during฀the฀rest฀ of฀the฀day? Yes No 1 6 Do฀you฀smoke฀if฀you฀are฀so฀ill฀that฀you฀are฀in฀bed฀ most฀of฀the฀day? Yes No Total฀: 1 [__] Table 4.5 ฀฀฀Fagerström฀test฀for฀nicotine฀dependence฀FTDN฀ [68] 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]