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Association of the met66 allele of brain-derived neurotrophic factor (BDNF) with smoking

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Abstract

Rationale

It has been suggested that a susceptibility locus near the gene encoding the brain-derived neurotrophic factor (BDNF) contributes to individual differences in human addiction vulnerability. BDNF modulates several behaviors that are associated with addictive drugs, and upregulation of BDNF was found to be associated with several drugs of abuse such as amphetamine, cocaine, and nicotine. In this study, we addressed the question if a common BDNF missense variation (Val66Met) influences the risk for smoking behavior in otherwise healthy human volunteers.

Materials and methods

In total, 320 healthy unrelated volunteers (155 male, 165 female, mean age: 38.4 ± 14.1 years) consisting of 43.3% never smokers, 20.9% former smokers, and 35.6% current smokers were investigated.

Results

The frequency of both Met/Met genotype and Met allele was significantly increased in current and in former smokers when compared to never smokers (χ 2 = 10.856, df = 2, p = 0.004 and χ 2 = 4.350, df = 1, p = 0.045, respectively).

Conclusions

Our results suggest that humans who carry the Met allele of the BDNF missense polymorphism might be more vulnerable to initiate and also maintain smoking.

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References

  • Beuten J, Ma JZ, Payne TJ, Dupont RT, Quezada P, Huang W, Crews KM, Li MD (2005) Significant association of BDNF haplotypes in European-American male smokers but not in European-American female of African-American smokers. Am J Med Genet B 139B:73–80

    Article  Google Scholar 

  • Butovsky E, Juknat A, Goncharov I, Elbaz J, Eilam R, Zangen A, Vogel Z (2005) In vivo upregulation of brain derived neurotrophic factor in specific brain areas by chronic exposure to Δ9-tetrahydrocannabinol. J Neurochem 93:802–811

    Article  PubMed  CAS  Google Scholar 

  • Cargill M, Altshuler D, Ireland J, Sklar P, Ardlie K, Patil N et al (1999) Characterization of single-nucleotide polymorphisms in coding regions of human genes. Nat Genet 22:231–238

    Article  PubMed  CAS  Google Scholar 

  • Cloninger CR (1987) A systematic method for clinical description and classification of personality variants. A proposal. Arch Gen Psychiatry 44:573–588

    PubMed  CAS  Google Scholar 

  • De Luca V, Wong AH, Muller DJ, Wong GW, Tyndale RF, Kennedy JL (2004) Evidence of association between smoking and alpha7 nicotinic receptor subunit gene in schizophrenia patients. Neuropsychopharmacology 29:1522–1526

    Article  PubMed  Google Scholar 

  • Dluzen DE, Story GM, Xu K, Kucera J, Walro JM (1999) Alterations in nigrostriatal dopaminergic function within BDNF mutant mice. Exp Neurol 160:500–507

    Article  PubMed  CAS  Google Scholar 

  • Egan MF, Kojima M, Callicott JH, Goldberg TE, Kolachana BS, Bertolino A, Zaitsev E, Gold B, Goldman D, Dean M, Lu B, Weinberger DR (2003) The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell 112:257–269

    Article  PubMed  CAS  Google Scholar 

  • Gallinat J, Mulert C, Bajbouj M, Herrmann WM, Schunter J, Senkowski D et al (2002) Frontal and temporal dysfunction of auditory stimulus processing in schizophrenia. Neuroimage 17:110–127

    Article  PubMed  Google Scholar 

  • Gallinat J, Senkowski D, Wernicke C, Juckel G, Becker I, Sander T, Smolka M, Hegerl U, Rommelspacher H, Winterer G, Herrmann WM (2003) Allelic variants of the functional promoter polymorphism of the human serotonin transporter gene is associated with auditory cortical stimulus processing. Neuropsychopharmacology 28:530–532

    Article  PubMed  CAS  Google Scholar 

  • Gallinat J, Kunz D, Lang UE, Kalus P, Juckel G, Eggers J, Mahlberg R, Staedtgen M, Wernicke C, Rommelspacher H, Smolka MN (2005a) Serotonergic effects of smoking are independent from the human serotonin transporter gene promoter polymorphism: evidence from auditory cortical stimulus processing. Pharmacopsychiatry 38:158–160

    Article  PubMed  CAS  Google Scholar 

  • Gallinat J, Hellweg R, Lang UE (2005b) Indicators of central serotonergic activity: How “specific” is neurotransmission? Neuropsychopharmacology 30:1586–1587

    Article  CAS  Google Scholar 

  • Gallinat J, Lang UE, Jacobsen LL, Bajbouj M, Kalus P, von Haebler D, Seifert F, Schubert F (2006) Abnormal hippocampal neurochemistry in smokers: Evidence from proton magnetic resonance spectroscopy at 3 tesla. J Clin Psychopharmacol (in press)

  • Garcia C, Chen MJ, Garza AA, Cotman CW, Russo-Neustadt A (2003) The influence of specific noradrenergic and serotonergic lesions on the expression of hippocampal brain-derived neurotrophic factor transcripts following voluntary physical activity. Neuroscience 119:721–732

    Article  PubMed  CAS  Google Scholar 

  • Gelernter J, Kranzler H, Cubells JF (1997) Serotonin transporter protein (SLC6A4) allele and haplotype frequencies and linkage disequilibria in African and European American and Japanese populations and in alcohol-dependent subjects. Hum Genet 101:243–246

    Article  PubMed  CAS  Google Scholar 

  • Gilbert DG, Gilbert BO (1995) Personality, psychopathology, and nicotine response as mediators of the genetics of smoking. Behav Genet 25:133–147

    Article  PubMed  CAS  Google Scholar 

  • Goldstein RZ, Volkow ND (2002) Drug addiction and its underlying neurobiological basis: neuroimaging evidence for the involvement of the frontal cortex. Am J Psychiatry 159:1642–1652

    Article  PubMed  Google Scholar 

  • Goodman LJ, Valverde J, Lim F, Geschwind MD, Federoff HJ, Geller AI, Hefti F (1996) Regulated release and polarized localization of brain-derived neurotrophic factor in hippocampal neurons. Mol Cell Neurosci 7:222–238

    Article  PubMed  CAS  Google Scholar 

  • Grimm JW, Lu L, Hayashi T, Hope B, Su TP, Shaham Y (2003) Time dependent increases in brain derived neurotrophic factor protein levels within the mesolimbic dopamine system after withdrawal from cocaine: implications for incubation of cocaine craving. J Neurosci 23:742–747

    PubMed  CAS  Google Scholar 

  • Guillin O, Diaz J, Carroll P, Griffon N, Schwartz JC, Sokoloff P (2001) BDNF controls dopamine D3 receptor expression and triggers behavioural sensitization. Nature 411:86–89

    Article  PubMed  CAS  Google Scholar 

  • Hall FS, Drgonova J, Goeb M, Uhl GR (2003) Reduced behavioural effects of cocaine in heterozygous brain-derived neurotrophic factor (BDNF) knock out mice. Neuropsychopharmacology 28:1485–1490

    Article  PubMed  CAS  Google Scholar 

  • Hensler JG, Ladenheim EE, Lyons WE (2003) Ethanol consumption and serotonin-1A (5-HT1A) receptor function in herterozygous BDNF (±) mice. J Neurochem 85:1139–1147

    Article  PubMed  CAS  Google Scholar 

  • Horger BA, Iyasere CA, Berhow MT, Messer CJ, Nestler EJ, Taylor JR (1999) Enhancement of locomotor activity and conditioned reward to cocaine by brain-derived neurotrophic factor. J Neurosci 19:4110–4122

    PubMed  CAS  Google Scholar 

  • Ivy AS, Rodriguez FG, Garcia C, Chen MJ, Russo-Neustadt AA (2003) Noradrenergic and serotonergic blockade inhibits BDNF mRNA activation following exercise and antidepressant. Pharmacol Biochem Behav 75:81–88

    Article  PubMed  CAS  Google Scholar 

  • Katz LC, Shatz CJ (1996) Synaptic activity and the construction of cortical circuits. Science 274:1133–1138

    Article  PubMed  CAS  Google Scholar 

  • Kernie SG, Liebl DJ, Parada LF (2000) BDNF regulates eating behavior and locomotor activity in mice. EMBO J 19:1290–1300

    Article  PubMed  CAS  Google Scholar 

  • Kesner RP, Lee I, Gilbert P (2004) A behavioral assessment of hippocampal function based on a subregional analysis. Rev Neurosci 15:333–351

    PubMed  Google Scholar 

  • Krebs MO, Guillin O, Bourdell MC, Schwartz JC, Olie JP, Poirier MF, Sokoloff P (2000) Brain derived neurotrophic factor (BDNF) gene variants association with age at onset and therapeutic response in schizophrenia. Mol Psychiatry 5:558–562

    Article  PubMed  CAS  Google Scholar 

  • Lang UE, Hellweg R, Gallinat J (2004) BDNF serum concentrations in healthy volunteers are associated with depression-related personality traits. Neuropsychopharmacology 29:795–798

    Article  PubMed  CAS  Google Scholar 

  • Lang UE, Hellweg R, Gallinat J (2005) Association of BDNF serum concentrations with central serotonergic activity: evidence from auditory signal processing Neuropsychopharmacology 30:1148–1153

    Article  PubMed  CAS  Google Scholar 

  • Le Foll B, Frances H, Diaz J, Schwartz JC, Sokoloff P (2004) Role of the dopamine D3 receptor in reactivity to cocaine-associated cues in mice. Eur J Neurosci 15:2016–2026

    Article  Google Scholar 

  • Le Foll B, Diaz J, Sokoloff P (2005) A single cocaine exposure increases BDNF and D3 receptor expression: implications for drug-conditioning. Neuroreport 16:175–178

    Article  PubMed  Google Scholar 

  • Lerman C, Shields PG, Audrain J, Main D, Cobb B, Boyd NR, Caporaso N (1998) The role of the serotonin transporter gene in cigarette smoking. Cancer Epidemiol Biomarkers Prev 7:253–255

    PubMed  CAS  Google Scholar 

  • Levin ED, Rezvani AH (2002) Nicotinic treatment for cognitive dysfunction. Curr Drug Targets CNS Neurol Disord 1:423–431

    Article  PubMed  CAS  Google Scholar 

  • Livak KJ (1999) Allelic discrimination using fluorogenic probes and the 5’ nuclease assay. Genet Anal 14:143–149

    PubMed  CAS  Google Scholar 

  • Lu L, Dempsey J, Liu SY, Bossert JM, Shaham Y (2004) A single infusion of brain-derived neurotrophic factor into the ventral tegmental area induces long-lasting potentiation of cocaine seeking after withdrawal. J Neurosci 24:1604–1611

    Article  PubMed  CAS  Google Scholar 

  • Lyons WE, Mamounas LA, Ricaurte GA, Coppola V, Reid SW, Bora SH, Wihler C, Koliatsos VE, Tessarollo L (1999) Brain-derived neurotrophic factor-deficient mice develop aggressiveness and hyperphagia in conjunction with brain serotonergic abnormalities. Proc Natl Acad Sci USA 96:15239–15244

    Article  PubMed  CAS  Google Scholar 

  • Martin CA, Kelly TH, Rayens MK, Brogli BR, Brenzel A, Smith WJ, Omar HA (2002) Sensation seeking, puberty, and nicotine, alcohol, and marijuana use in adolescence. J Am Acad Child Adolesc Psych 41:1495–1502

    Article  Google Scholar 

  • Meredith GE, Callen S, Scheurer DA (2002) Brain derived neurotrophic factor expression is increased in the rat amygdala, piriform cortex and hypothalamus following repeated amphetamine administration. Brain Res 949:218–227

    Article  PubMed  CAS  Google Scholar 

  • Mössner R, Daniel S, Albert D, Heils A, Okladnova O, Schmitt A, Lesch KP (2000) Serotonin transporter function is modulated by brain-derived neurotrophic factor (BDNF) but not nerve growth factor (NGF). Neurochem Int 36:197–202

    Article  PubMed  Google Scholar 

  • Nestler EJ (2001) Molecular basis of long-term plasticity underlying addiction. Nat Rev Neurosci 2:119–128

    Article  PubMed  CAS  Google Scholar 

  • Noble EP, Ozkaragoz TZ, Ritchie TL, Zhang X, Belin TR, Sparkes RS (1998) D2 and D4 dopamine receptor polymorphisms and personality. Am J Med Genet 81:256–257

    Article  Google Scholar 

  • Numan S, Lane-Ladd SB, Zhang L, Lundgren KH, Russell DS, Seroogy KB, Nestler EJ (1998) Differential regulation of neurotrophin and trk receptor mRNAs in catecholaminergic nuclei during chronic opiate treatment and withdrawal. J Neurosci 18:10700–10708

    PubMed  CAS  Google Scholar 

  • Olausson P, Akesson P, Petersson A, Engel JA, Soderpalm B (2001) Behavioral and neurochemical consequences of repeated nicotine treatment in the serotonin-depleted rat. Psychopharmacology 155:348–361

    Article  PubMed  CAS  Google Scholar 

  • Patterson SL, Abel T, Deuel TA, Martin KC, Rose JC, Kandel ER (1996) Recombinant BDNF rescues deficits in basal synaptic transmission and hippocampal LTP in BDNF knockout mice. Neuron 16:1137–1145

    Article  PubMed  CAS  Google Scholar 

  • Patton JH, Stanford MS, Barratt ES (1995) Factor structure of the Barratt Impulsiveness Scale. J Clin Psychol 51:768–774

    PubMed  CAS  Google Scholar 

  • Pierce RC, Bari AA (2001) The role of neurotrophic factors in psychostimulant-induced behavioral and neuronal plasticity. Rev Neurosci 12:95–110

    PubMed  CAS  Google Scholar 

  • Robinson TE, Berridge KC (1993) The neural basis of drug craving: an incentive-sensitization theory of addiction. Brains Res Rev 18:247–291

    Article  CAS  Google Scholar 

  • Seroogy KB, Lundgren KH, Tien TM, Guthrie KM, Isackson PJ, Gall CM (1994) Dopaminergic neurons in rat ventral midbrain express brain-derived neurotrophic factor and neurotrophin-3 mRNAs. J Comp Neurol 342:321–334

    Article  PubMed  CAS  Google Scholar 

  • Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E, Hergueta T, Baker R, Dunbar GC (1998) The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry 59(Suppl 20):22–33

    PubMed  Google Scholar 

  • Sklar P, Gabriel SB, McInnis MG, Bennett P, Lim YM, Tsan G, Schaffner S, Kirov G, Jones I, Owen M, Craddock N, DePaulo JR, Lander ES (2002) Family-based association study of 76 candidate genes in bipolar disorder: BDNF is a potential risk locus. Brain-derived neutrophic factor. Mol Psychiatry 7:579–593

    Article  PubMed  CAS  Google Scholar 

  • Sokoloff P, Guillin O, Diaz J, Carroll P, Griffon N (2002) Brain-derived neurotrophic factor controls dopamine D3 receptor expression: implications for neurodevelopmental psychiatric disorders. Neurotox Res 4:671–678

    Article  PubMed  CAS  Google Scholar 

  • Sora I, Hall FS, Andrews AM, Itokawa M, Li XF, Wei HB, Wichems C, Lesch KP, Murphy DL, Uhl GR (2001) Molecular mechanisms of cocaine reward: combined dopamine and serotonin transporter knockouts eliminate cocaine place preference. Proc Natl Acad Sci USA 98:5300–5305

    Article  PubMed  CAS  Google Scholar 

  • Steffens M, Lamina C, Illig T, Bettecken T, Vogler R, Entz P, Suk EK, Toliat MR, Klopp N, Caliebe A, Konig IR, Kohler K, Ludemann J, Lacava AD, Fimmers R, Lichtner P, Ziegler A, Wolf A, Krawczak M, Nurnberg P, Hampe J, Schreiber S, Meitinger T, Wichmann HE, Roeder K, Wienker TF, Baur MP (2006) SNP-Based analysis of genetic substructure in the German population. Hum Hered 62:20–29

    Article  PubMed  CAS  Google Scholar 

  • Sullivan PF, Kendler KS (1999) The genetic epidemiology of smoking. Nicotine Tob Res 1(Suppl 2):69–70

    Google Scholar 

  • Sullivan PF, Fifield WJ, Kennedy MA, Mulder RT, Sellman JD, Joyce PR (1997) Novelty seeking and a dopamine transporter gene polymorphism (DAT1). Biol Psychiatry 42:1070–1072

    Article  PubMed  CAS  Google Scholar 

  • Thoenen H (1995) Neurotrophins and neuronal plasticity. Science 270:593–598

    Article  PubMed  CAS  Google Scholar 

  • Tsai SJ, Cheng CY, Yu YW, Chen TJ, Hong CJ (2003) Association study of a brain-derived neurotrophic-factor genetic polymorphism and major depressive disorders, symptomatology, and antidepressant response. Am J Med Genet 123:19–22

    Article  Google Scholar 

  • Uhl GR, Liu QR, Walther D, Hess J, Naiman D (2001) Polysubstance abuse-vulnerability genes: genome scans for association, using 1,004 subjects and 1,494 single-nucleotide polymorphisms. Am J Hum Genet 69:1290–1300

    Article  PubMed  CAS  Google Scholar 

  • van de Venne J, Bradford K, Martin C, Cox M, Omar HA (2006) Depression, sensation seeking, and maternal smoking as predictors of adolescent cigarette smoking. Scientific World Journal 6:634–652

    Google Scholar 

  • Xu J, Mendrek A, Cohen MS, Monterosso J, Rodriguez P, Simon SL, Brody A, Jarvik M, Domier CP, Olmstead R, Ernst M, London ED (2005) Brain activity in cigarette smokers performing a working memory task: effect of smoking abstinence. Biol Psychiatry 58:143–150

    Article  PubMed  CAS  Google Scholar 

  • Yeom M, Shim I, Lee HJ, Hahm DH (2005) Proteomic analysis of nicotine-associated protein expression in the striatum of repeated nicotine-treated rats. Biochem Biophys Res Commun 326:321–328

    Article  PubMed  CAS  Google Scholar 

  • Zubieta JK, Heitzeg MM, Xu Y, Koeppe RA, Ni L, Guthrie S, Domino EF (2005) Regional cerebral blood flow responses to smoking in tobacco smokers after overnight abstinence. Am J Psychiatry 162:567–577

    Article  PubMed  Google Scholar 

  • Zuckerman M (1986) Sensation seeking and the endogenous deficit theory of drug abuse. NIDA Res Monogr 74:59–70

    PubMed  CAS  Google Scholar 

  • Zuckerman M, Kuhlman DM (2000) Personality and risk-taking: common biosocial factors. J Pers 68:999–1029

    Article  PubMed  CAS  Google Scholar 

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Lang, U.E., Sander, T., Lohoff, F.W. et al. Association of the met66 allele of brain-derived neurotrophic factor (BDNF) with smoking. Psychopharmacology 190, 433–439 (2007). https://doi.org/10.1007/s00213-006-0647-1

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  • DOI: https://doi.org/10.1007/s00213-006-0647-1

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