Mechanismen der Nikotinabhängigkeit

Zusammenfassung

In der westlichen Welt rauchen ca. 30 % der Bevölkerung. Die meisten Raucher tun dies, weil sie nikotinabhängig sind. Neben einer intensiven Fortführung der Aufklärung über die gesundheitlichen Folgen des Rauchens und einer Erschwerung des Zigarettenkonsums in der Gesellschaft ist es nötig, die Mechanismen der Nikotinabhängigkeit besser zu verstehen, um effektivere Therapien und Raucherentwöhnungsprogramme zu entwickeln. Diese Übersicht fasst den aktuellen Kenntnisstand über die Mechanismen der Nikotinabhängigkeit zusammen. Im Zentrum stehen zelluläre Effekte von Nikotin sowie die Effekte auf 3 neurophysiologische Funktionssysteme, die bei der Nikotinabhängigkeit eine Rolle spielen: a) Belohnungssystem, b) kognitive Netzwerke und c) Stress-Response-System. Das Belohnungssystem wird durch Nikotin und andere Suchtstoffe aktiviert. Es ist eng mit dem Emotionsregulationssystem verknüpft. Darüber hinaus moduliert Nikotin die kognitiven Netzwerke für Aufmerksamkeit und Lernen/Gedächtnis, wobei die meisten Daten auf kurzfristig günstige Effekte hindeuten. Schließlich beeinflusst Nikotin auch das Stress-Response-System, wobei abhängig vom Stadium der Nikotinabhängigkeit unterschiedliche Effekte resultieren. Die nikotinische Modulation dieser Netzwerke durch Zigarettenrauchen wird wenigstens bei Subpopulationen von Rauchern als Selbstbehandlungsversuch klinischer oder subklinischer Beschwerden in den Bereichen Stimmungsregulation/Depression, Aufmerksamkeit/Gedächtnis und Stress-Bewältigung angesehen.

Abstract

About 30 % of the population in Western societies smoke. Most smokers do so due to nicotine dependence. In concert with ongoing education about the detrimental consequences of tobacco abuse and further restriction of public smoking, further scientific effort is needed to investigate the mechanisms of nicotine dependence, in order to develop more effective treatments and smoking cessation programmes. This review summarises our current knowledge of the mechanisms of nicotine dependence, focussing mainly on the cellular effects of nicotine and the effects on three neurophysiological systems that contribute to nicotine dependence: a) reward system, b) cognition/attentional networks and c) stress response system. The reward system that is connected with the mood regulatory system is activated by nicotine and other addictive substances. Furthermore, nicotine modulates cognitive networks involved in attention and learning/memory. Most data point to positive effects of acute nicotine administration on these networks. Finally nicotine influences the stress response system, however, the effects depend on the stage of nicotine addiction. Nicotinic modulation of these networks by means of smoking may reflect an attempt to self-medicate clinical or subclinical symptoms in the areas of mood regulation/depression, attention and learning/memory and stress coping, at least in a subset of smokers.

Literatur

• 1 Andreas S, Loddenkemper R. Tabakprävention.  Pneumologie. 2007;  61 588-589
• 2 Raupach T, Nowak D, Hering T. et al . Rauchen und pneumologische Erkrankungen, positive Effekte der Tabakentwöhnung.  Pneumologie. 2007;  61 11-14
• 3 Andreas S, Herth F JF, Rittmeyer A. et al . Tabakrauchen, chronisch obstruktive Lungenerkrankung und Lungenkarzinom.  Pneumologie. 2007;  61 590-595
• 4 WHO report on the global tobacco epidemic,. 2008, http://www.who.int/tobacco
• 5 Welte R, König H H, Leidl R. Cost of health damage and productivity losses attributable to cigarette smoking in Germany.  Eur J Publ Health. 2000;  10 31-38
• 6 John U, Hanke M. Tobacco smoking attributable mortality in Germany.  Gesundheitswesen. 2001;  63 363-369
• 7 Batra A. „Leitlinie Tabakentwöhnung”. AWMF online, Leitlinien der Dt. Ges. f. Suchtforschung und Suchttherapie (DG-Sucht) und der Dt. Ges. f. Psychiatrie, Psychotherapie und Nervenheilkunde (DGPPN) 2004
• 8 Carmelli D, Swan G E, Robinette D. et al . Genetic influence on smoking – a study of male twins.  N Engl J Med. 1992;  327 829-833
• 9 Edwards K L, Austin M A. Evidence for genetic influences on smoking in adult women twins.  Clin Genet. 1995;  47 236-244
• 10 Mineur Y S, Picciotto M R. Genetics of nicotinic acetylcholine receptors: Relevance to nicotine addiction. Biochem Pharmacol 2007
• 11 Heath A C, Cates R, Martin N G. et al . Genetic contribution to risk of smoking initiation: comparison across birth cohorts and across cultures.  J Subst Abuse. 1993;  5 221-246
• 12 Heath A C, Martin N G. Genetic models for the natural history of smoking: evidence for a genetic influence on smoking persistence.  Addict Behav. 1993;  18 19-34
• 13 Hanewinkel R, Sargent J D. Exposure to smoking in internationally distributed Amercian movies and youth smoking in Germany: a cross-cultural cohort study.  Pediatrics. 2008;  121 108-117
• 14 Mansvelder H D, McGee D S. Long-term potentiation of excitatory inputs to brain reward areas by nicotine.  Neuron. 2000;  27 349-357
• 15 Fidler J A, Wardle J, Henning Brodersen N. et al . Vulnerability to smoking after trying a single cigarette can lie dormant for three years and more.  Tobacco Control. 2006;  15 205-209
• 16 Lindstom J M. Nicotinic acetylcholine receptors of muscles and nerves: Comparison of their structures, functional roles and vulnerability to pathology.  Ann NY Acad Sci. 2003;  998 41-42
• 17 Gotti C, Zoli M, Clementi F. Brain nicotinic acetylcholine receptors: native subtypes and their relevance.  Trends Phramacol Sci. 2006;  27 482-491
• 18 Lindstrom J. Nicotinic acetylcholin receptors in health and disease.  Mol Neurobiol. 1997;  15 193-222
• 19 Alkondon M, Pereira E FR, Almeida E LF. et al . Nicotine at concentrations found in cigarette smokers activates and desensitizes nicotinic acetylchloline receptors in CA1 interneurons of rat hippocampus.  Neuropharmacology. 2000;  39 2726-2739
• 20 Wonnacott S, Sidhpura N, Balfour D JK. Nicotine: from molecular mechanisms to behaviour.  Current Opin Pharmacol. 2005;  5 53-59
• 21 Robinson S E, Vann R E, Britton A F. et al . Cellular nicotinic receptor desensitization correlates with nicotine-induced acute behavioural tolerance in rats.  Psychopharmacology. 2007;  192 71-78
• 22 Peng X, Gerzanich V, Anand R. et al . Nicotine-induced increase in neuronal nicotinic receptors results from a decrease in the rate of receptor turnover.  Mol Pharmacol. 1994;  46 523-530
• 23 Salette J, Pons S, Devillers-Thiery A. et al . Nicotine upregulates its own receptors through enhanced intracellular maturation.  Neuron. 2005;  46 595-607
• 24 Dani J A, De Biasi M. Cellular mechanisms of nicotine addiction.  Pharmacology, Biochemistry and Behavior. 2001;  70 439-446
• 25 Staley J K, Krishnan-Sarin S, Kelly P. et al . Human tobacco smokers in early abstinence have higher levels of β₂ nicotinic acetylcholine receptors than nonsmokers.  J Neurosci. 2006;  26 8707-8714
• 26 Ji D, Lape R, Dani J A. Timing and location of nicotinic activity enhances or depresses hippocampal synaptic plasticity.  Neuron. 2001;  31 131-141
• 27 Couey J J, Meredith R M, Spijker S. et al . Distributed network actions by nicotine increase the threshold for spike-timing dependent plasticity in prefrontal cortex.  Neuron. 2007;  54 73-87
• 28 Raymond C R. LTP forms 1, 2 and 3: different mechanism for the “long” in long-term potentiation.  Trends in Neurosci. 2007;  30 167-175
• 29 Chen L, Bohanick J D, Nishihara M. et al . Dopamin D1/D5 receptor-mediated long-term potentiation of intrinsic excitability in rat prefrontal cortical neurons: Ca⁺⁺-dependent intracellular signalling.  J Neurophysiol. 2007;  97 2448-2464
• 30 Inoue Y, Yao L, Hopf W. et al . Nicotine and ethanol activate protein kinase A synergistically via G_iβ_γ subunits in nucleus acumbens/ventral tegmental cocultures: The role of dopamine D₁/D₂ and adenosine A_2A receptors.  J Pharmacol Exp Ther. 2007;  322 23-29
• 31 Di Chiara G, Bassareo V, Fenu S. et al . Dopamine and drug addiction: the nucleus accumbens shell connection.  Neuropharmacol. 2004;  47 227-241
• 32 Nakayama H, Numakawa T, Ikeuchi T. et al . Nicotine-induced phosphorylation of extracellular signal-regulated protein kinase and CREB in PC12 h cells.  J Neurochem. 2001;  79 489-498
• 33 Ikemoto S. Dopamine reward circuitry: Two projection systems from the ventral midbrain to the nucleus accumbens – olfactory tubercle complex.  Brain Res Rev. 2007;  56 27-78
• 34 Pidoplichko V I, De Biasi M, Williams J T. et al . Nicotine activates and desensitizes midbrain dopamine neurons.  Nature. 1997;  390 401-404
• 35 Ferrari R, Le Novere N, Picciotto M R. et al . Acute and long-term changes in the mesolimbic dopamine pathway after systemic or local single nicotine injections.  Eur J Neurosci. 2002;  15 1810-1818
• 36 Balfour D JK, Wright A E, Benwell M EM. et al . The putative role of extra-synaptic mesolimbic dopamine in the neurobiology of nicotine dependence.  Behav Brain Res. 2000;  113 73-83
• 37 Mansvelder H, Keath J R, McGehee D S. Synaptic mechanisms underlie nicotine-induced excitability of brain reward areas.  Neuron. 2002;  33 905-919
• 38 Di Chiara G, Imperato A. Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats.  PNAS. 1988;  85 5274-5278
• 39 Imperato A, Mulas A, Di Chiara G. Nicotine prefrerentially stimulates dopamine release in the limbic system of freely moving rats.  Eur J Pharmacol. 1986;  132 337-338
• 40 Schilstrom B, Nomikos G G, Nisell M. et al . N-methyl-D-aspartat receptor antagonism in the ventral tegmental area diminishes the systemic nicotine-induced dopamine release in the nucleus accumbens.  Neuroscience. 1998;  85 1005-1009
• 41 Dani J A, Radcliffe K A, Pidoplichko V I. Varations in desensitization of nicotinic acetylcholine receptors from hippocampal and midbrain dopamine areas.  Eur J Pharmacol. 2000;  393 31-38
• 42 Besson M, Granon S, Mameli-Engvall M. et al . Long-term effects of chronic nicotine exposure on brain nicotinic receptors.  PNAS. 2007;  104 8155-8160
• 43 Tsoh J H, Humfleet G L, Munoz R F. et al . Development of major depression after treatment for smoking cessation.  Am J Psychiatry. 2000;  157 368-374
• 44 Glassman A H, Stetner F, Walsh B T. et al . Heavy smokers, smoking cessation, and clonidine. Results of a double-blind, randomized trial.  JAMA. 1988;  259 2863-2866
• 45 Keuthen N J, Niaura R S, Borrelli B. et al . Comorbidity, smoking behavior and treatment outcome.  Psychother Psychosom. 2000;  69 244-250
• 46 Breslau N, Johnson E O. Predicting smoking cessation and major depression in nicotine-dependent smokers.  Am J Public Health. 2000;  90 1122-1127
• 47 Breslau N, Kilbey M M, Andreski P. Nicotine dependence and major depression. New evidence from a prospective investigation.  Arch Gen Psychiatry. 1993;  50 31-35
• 48 Heinz A, Schmidt L G, Reischies F M. Anhedonia in schizophrenic, depressed and alcohol-dependent patients – neurobiological correlates.  Pharmacopsychiatry. 1994;  27 Suppl 1 7-10
• 49 Cardenas L, Tremblay L K, Naranjo C A. et al . Brain reward system activity in major depression and comorbid nicotine dependence.  J Pharmacol Exp Ther. 2002;  302 1265-1271
• 50 Levin E D, McClernon F J, Rezvani A H. Nicotinic effects on cognitive function: behavioral characterization, pharmacological specification and anatomical localization.  Psychopharmacol. 2006;  184 523-439
• 51 Mansvelder H D, Aerde K I van, Couey J J. et al . Nicotinic modulation of neuronal networks: from receptors to cognition.  Psychopharmacol. 2006;  184 292-305
• 52 Fujii S, Ji Z, Morita N. et al . Acute and chronic nicotine exposure differentially facilitate the induction of LTP.  Brain Res. 1999;  846 137-143
• 53 Mann E O, Greenfield S A. Novel modulatory mechanisms revealed by the sustained application of nicotine in the guinea-pig hippocampus in vitro.  J Physiol. 2003;  551 539-550
• 54 Ge S, Dani J A. Nicotinic acetylcholine receptors at glutamate synapses facilitate long-term depression or potentiation.  J Neurosci. 2005;  25 6084-6091
• 55 Ohno M, Yamamoto T, Watanabe S. Blockade of hippocampal nicotinic receptors impairs working memory but not reference memory in rats.  Pharmacol Biochem Behav. 1993;  45 89-93
• 56 Edwards J A, Wesnes K, Warburton D M. et al . Evidence of more rapid stimulus evaluation following cigarette smoking.  Addict Behav. 1985;  10 113-126
• 57 Hahn B, Shoaib M, Stolerman I P. Nicotine-induced enhancement of attention in the five-choice serial reaction time task. The influence of task demands.  Psychopharmacology (Berl). 2002;  162 129-137
• 58 Hahn B, Sharples C G, Wonnacott S. et al . Attentional effects of nicotinic agonists in rats.  Neuropharmacology. 2003;  44 1054-1067
• 59 Harris J G, Kongs S, Allensworth D. et al . Effects of nicotine on cognitive deficits in schizophrenia.  Neuropsychopharmacology. 2004;  29 1378-1385
• 60 Houlihan M E, Pritchard W S, Krieble K K. et al . Effects of cigarette smoking on EEG spectral-band power, dimensional complexity, and nonlinearity during reaction time task performance.  Psychophysiology. 1996;  33 740-746
• 61 Houlihan M E, Pritchard W S, Robinson J H. Faster P300 latency after smoking in visual but not auditory oddball tasks.  Psychopharmacology. 1996b ;  123 231-238
• 62 Rezvani A H, Levin E D. Cognitive effects of nicotine.  Biol Psychiatry. 2001;  49 258-167
• 63 Sacco K A, Bannon K L, George T P. Nicotinic receptor mechanisms and cognition in normal states and neuropsychiatric disorders.  J Psychopharmacol. 2004;  18 457-474
• 64 Sherwood N, Kerr J S, Hindmarch I. Psychomotor performance in smokers following single and repeated doses of nicotine gum.  Psychopharmacology (Berlin). 1992;  108 432-436
• 65 Stolerman I P, Mirza N R, Hahn B. et al . Nicotine in an animal model of attention.  Eur J Pharmacol. 2000;  393 147-154
• 66 Wesnes K, Warburton D M. Effects of smoking on rapid information processing performance.  Neuropsychobiology. 1983;  9 223-229
• 67 Thiel C M, Zilles K, Fink G R. Nicotine modulates reorienting of visuospatial attention and neural activity in human parietal cortex.  Neuropsychopharmacology. 2005;  30 810-820
• 68 Lawrence N S, Ross T J, Stein E A. Cognitive mechanisms of nicotine on visual attention.  Neuron. 2002;  36 539-548
• 69 Hahn B, Ross T J, Yang Y. et al . Nicotine enhances visuospatial attention by deactivating areas of the resting brain default network.  J Neurosci. 2007;  27 3477-3489
• 70 Winterer G, Musso F, Beckmann C. et al . Instability of prefrontal signal processing in schizophrenia.  Am J Psychiatry. 2006a;  163 960-1968
• 71 Winterer G, Coppola R, Goldberg T. et al . Prefrontal broadband noise, working memory and genetic risk for schizophrenia.  Am J Psychiatry. 2004;  161 90-500
• 72 Winterer G, Egan M F, Kolachana B S. et al . Prefrontal electrophysiologic “noise” and catechol-O-methyltransferase genotype in schizophrenia.  Biol Psychiatry. 2006b;  60 578-584
• 73 Pomerleau O F, Downey K K, Stelson F W. et al . Cigarette smoking in adult patients diagnosed with attention deficit hyperactivity disorder.  J Subst Abuse. 1995;  7 373-378
• 74 de Leon J, Dadvand M, Canuso C. et al . Schizophrenia and smoking: an epidemiological survey in a state hospital.  Am J Psychiatry. 1995;  152 453-455
• 75 Lasser K, Boyd J W, Woolhandler S. et al . Smoking and mental illness: a population-based prevalence study.  JAMA. 2000;  284 2606-2610
• 76 Levine E D, Conners C K, Sparrow E. et al . Nicotine effects on adults with attention-deficit/hyperactivity disorder.  Psychopharmacology (Berlin). 1996;  123 55-63
• 77 Levine Conners C K, Silva D, Canu W. et al . Effects of chronic nicotine and methylphenidate in adults with ADHD.  Exp Clin Pharmacol. 2001;  9 83-90
• 78 Adler L E, Hoffer L D, Wiser A. et al . Normalization of auditory physiology by cigarette smoking in schizophrenic patients.  Am J Psychiatry. 1993;  150 1856-1861
• 79 Smith R C, Singh A, Infante M. et al . Effects of cigarette smoking and nicotine nasal spray on psychiatric symptoms and cognition in schizophrenia.  Neuropsychopharmacology. 2002;  27 479-497
• 80 Harris J G, Kongs S, Allensworth D. et al . Effects of nicotine on cognitive deficits in schizophrenia.  Neuropsychopharmacology. 2004;  29 1378-1385
• 81 Musso F, Bettermann F, Vucurevic G. et al . Smoking impacts on prefrontal attention network function in young adult brains.  Psychopharmacology. 2007;  191 159-169
• 82 Wessels C, Winterer G. Nikotin und Gehirnentwicklung.  Nervenarzt. 2008;  79 7-16
• 83 Benowitz N L. The role of nicotine in smoking-related cardiovascular disease.  Prev Med. 1997;  26 412-417
• 84 Niedermaier O N, Smith M L, Beightol L A. et al . Influence of cigarette smoking on human autonomic function.  Circulation. 1993;  88 562-571
• 85 Hausberg M, Mark A L, Winniford M D. et al . Sympathetic and vascular effects of short term passive smoke exposure in healthy nonsmokers.  Circulation. 1997;  96 282-287
• 86 Al Abisi M. Hypothalamic-pituitary-adrenocortical responses to psychological stress and risk for smoking relapse.  Int J Psychophysiol. 2006;  59 218-227
• 87 Lovallo W R. Cortisol secretion patterns in addiction and addiction risk.  Int J Psychpharmacol. 2006;  59 195-202
• 88 Rohleder N, Kirschbaum C. The hypothalamic-pituitary-adrenal (HPA) axis in habitual smokers.  Int J Psychphysiol. 2006;  59 236-243
• 89 Fuxe K, Andersson K, Eneroth P. et al . Neuroendocrine actions of nicotine and of exposure to cigarette smoke: medical implications.  Psychoneuroendocrinology. 1989;  14 19-41
• 90 Matta S G, Fu Y, Valentine J D. et al . Response of the hypothalamo-pituitary-adrenalo axis to nicotine.  Psychoneuroendocrinology. 1998;  23 103-113
• 91 Thorndike F P, Wernicke R, Pearlman M Y. et al . Nicotine dependence. PTSD symptoms and depression proneness among male and female smokers.  Addict Behav. 2006;  31 223-231
• 92 Fagen Z M, Mitchum R, Vezina P. et al . Enhanced nicotinic receptor function and drug abuse vulnerability.  J Neurosci. 2007;  27 8771-8778
• 93 Bilkei-Gorzo A, Racz I, Michel K. et al . A common genetic predisposition to stress sensitivity and stress-induced nicotine craving.  Biol Psychiatry. 2007;  im Druck
• 94 Gutkin B S, Dehaene S, Changeux J P. A neurocomputational hypothesis for nicotine addiction.  PNAS. 2006;  103 1106-1111
• 95 Winterer G, Musso F, Konrad A. et al . Association of attentional network function with exon 5 variations of the CHRNA4 gene.  Hum Mol Genet. 2007;  16 2165-2174
• 96 Hutchinson K E, Allen D L, Filbey F M. et al . CHRNA4 and tobacco dependence – from gene regulation to treatment outcome.  Arch Gen Psychiatry. 2007;  64 1078-1086

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