Skip to main content
SpringerLink
Log in

Serotonin transporter promoter polymorphism and dopaminergic sensitivity in alcoholics

  • Biological Psychiatry - Original Article
  • Published:
Journal of Neural Transmission Aims and scope Submit manuscript

Abstract

The central serotonin (5-HT) system plays an important role in the rewarding and addictive properties of alcohol by a direct activation of the mesolimbic dopamine (DA) system. An insertion/deletion (L/S) promoter polymorphism (5-HTTLPR) of the 5-HT transporter (5-HHT) gene (SLC6A4) has been shown to influence transcriptional activity. It is predicted that reduced transynaptic 5-HT neurotransmission in alcoholics with the L/L genotype of 5-HTTLPR would result in a change in DA function compared to the S/S genotype. Thus the present study has tested whether dopaminergic sensitivity is influenced by the 5-HTTLPR genotype. Dopaminergic sensitivity, 5-HTTLPR genotype and smoking status were assessed in 121 alcoholics. Dopaminergic sensitivity as an indicator of the functional state of the dopaminergic system was measured by the amount of growth hormone (GH) secretion after subcutaneous administration of apomorphine (APO, 0.01 mg/kg). 5-HTTLPR genotype was significantly associated with dopaminergic sensitivity (P = 0.004) explaining 9.2% of the variance of GH response. Subjects homozygous for the L allele (with high 5-HTT expression) showed the lowest GH response, whereas those homozygous for the S allele (with low 5-HTT expression) showed the highest GH response (this was intermediate in heterozygous participants). Furthermore smoking was associated with a significantly reduced GH response (P = 0.006). Our findings indicate that the postsynaptic dopaminergic sensitivity is influenced by the 5-HTTLPR genotype. It is hypothesized that the reduction of sensitivity of the central DA receptors in alcoholics with the L/L genotype might be due to their higher vulnerability to the neurotoxic effects of chronic alcohol consumption than the S carriers.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  • Alex KD, Pehek EA (2007) Pharmacologic mechanisms of serotonergic regulation of dopamine neurotransmission. Pharmacol Ther 113:296–320

    Article  CAS  PubMed  Google Scholar 

  • Aymard G, Berlin I, de Brettes B, Diquet B (2003) Pharmacokinetic–pharmacodynamic study of apomorphine’s effect on growth hormone secretion in healthy subjects. Fundam Clin Pharmacol 17:473–481

    Article  CAS  PubMed  Google Scholar 

  • Blomqvist O, Ericson M, Engel JA, Soderpalm B (1997) Accumbal dopamine overflow after ethanol: localization of the antagonizing effect of mecamylamine. Eur J Pharmacol 334:149–156

    Article  CAS  PubMed  Google Scholar 

  • Boileau I, Assaad JM, Pihl RO, Benkelfat C, Leyton M, Diksic M, Tremblay RE, Dagher A (2003) Alcohol promotes dopamine release in the human nucleus accumbens. Synapse 49:226–231

    Article  CAS  PubMed  Google Scholar 

  • Budde H, Zimmermann US, Steffin B, Rommelspacher H, Schmidt LG, Smolka MN (2007) Apomorphine-induced growth hormone response is attenuated by ethanol but not dextromethorphan. Alcohol Clin Exp Res 31:100–103

    Article  CAS  PubMed  Google Scholar 

  • Dagher A, Bleicher C, Aston JA, Gunn RN, Clarke PB, Cumming P (2001) Reduced dopamine D1 receptor binding in the ventral striatum of cigarette smokers. Synapse 42:48–53

    Article  CAS  PubMed  Google Scholar 

  • Dettling M, Heinz A, Dufeu P, Rommelspacher H, Graf KJ, Schmidt LG (1995) Dopaminergic responsivity in alcoholism: trait, state, or residual marker? Am J Psychiatry 152:1317–1321

    CAS  PubMed  Google Scholar 

  • Di Chiara G, Imperato A (1988) Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. Proc Natl Acad Sci U S A 85:5274–5278

    Article  CAS  PubMed  Google Scholar 

  • Fehr C, Yakushev I, Hohmann N, Buchholz HG, Landvogt C, Deckers H, Eberhardt A, Klager M, Smolka MN, Scheurich A, Dielentheis T, Schmidt LG, Rosch F, Bartenstein P, Grunder G, Schreckenberger M (2008) Association of low striatal dopamine d2 receptor availability with nicotine dependence similar to that seen with other drugs of abuse. Am J Psychiatry 165:507–514

    Article  PubMed  Google Scholar 

  • Greenberg BD, Tolliver TJ, Huang SJ, Li Q, Bengel D, Murphy DL (1999) Genetic variation in the serotonin transporter promoter region affects serotonin uptake in human blood platelets. Am J Med Genet 88:83–87

    Article  CAS  PubMed  Google Scholar 

  • Heils A, Teufel A, Petri S, Stober G, Riederer P, Bengel D, Lesch KP (1996) Allelic variation of human serotonin transporter gene expression. J Neurochem 66:2621–2624

    Article  CAS  PubMed  Google Scholar 

  • Heinz A, Goldman D (2000) Genotype effects on neurodegeneration and neuroadaptation in monoaminergic neurotransmitter systems. Neurochem Int 37:425–432

    Article  CAS  PubMed  Google Scholar 

  • Heinz A, Dettling M, Kuhn S, Dufeu P, Graf KJ, Kurten I, Rommelspacher H, Schmidt IG (1995) Blunted growth hormone response is associated with early relapse in alcohol-dependent patients. Alcohol Clin Exp Res 19:62–65

    CAS  PubMed  Google Scholar 

  • Heinz A, Jones DW, Mazzanti C, Goldman D, Ragan P, Hommer D, Linnoila M, Weinberger DR (2000) A relationship between serotonin transporter genotype and in vivo protein expression and alcohol neurotoxicity. Biol Psychiatry 47:643–649

    Article  CAS  PubMed  Google Scholar 

  • Heinz A, Siessmeier T, Wrase J, Buchholz HG, Grunder G, Kumakura Y, Cumming P, Schreckenberger M, Smolka MN, Rosch F, Mann K, Bartenstein P (2005) Correlation of alcohol craving with striatal dopamine synthesis capacity and D2/3 receptor availability: a combined [18F]DOPA and [18F]DMFP PET study in detoxified alcoholic patients. Am J Psychiatry 162:1515–1520

    Article  PubMed  Google Scholar 

  • Javors MA, Seneviratne C, Roache JD, Ait-Daoud N, Bergeson SE, Walss-Bass MC, Akhtar FZ, Johnson BA (2005) Platelet serotonin uptake and paroxetine binding among allelic genotypes of the serotonin transporter in alcoholics. Prog Neuropsychopharmacol Biol Psychiatry 29:7–13

    Article  CAS  PubMed  Google Scholar 

  • Johnson BA (2004) Role of the serotonergic system in the neurobiology of alcoholism: implications for treatment. CNS Drugs 18:1105–1118

    Article  CAS  PubMed  Google Scholar 

  • Koob G (2000) Drug addiction. Neurobiol Dis 7:543–545

    Article  CAS  PubMed  Google Scholar 

  • LeMarquand D, Pihl RO, Benkelfat C (1994) Serotonin and alcohol intake, abuse, and dependence: clinical evidence. Biol Psychiatry 36:326–337

    Article  CAS  PubMed  Google Scholar 

  • Lesch KP, Bengel D, Heils A, Sabol SZ, Greenberg BD, Petri S, Benjamin J, Muller CR, Hamer DH, Murphy DL (1996) Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science 274:1527–1531

    Article  CAS  PubMed  Google Scholar 

  • Little KY, McLaughlin DP, Zhang L, Livermore CS, Dalack GW, McFinton PR, DelProposto ZS, Hill E, Cassin BJ, Watson SJ, Cook EH (1998) Cocaine, ethanol, and genotype effects on human midbrain serotonin transporter binding sites and mRNA levels. Am J Psychiatry 155:207–213

    CAS  PubMed  Google Scholar 

  • Miller SA, Dykes DD, Polesky HF (1988) A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 16:1215

    Article  CAS  PubMed  Google Scholar 

  • Reimold M, Smolka MN, Schumann G, Zimmer A, Wrase J, Mann K, Hu XZ, Goldman D, Reischl G, Solbach C, Machulla HJ, Bares R, Heinz A (2007) Midbrain serotonin transporter binding potential measured with [11C]DASB is affected by serotonin transporter genotype. J Neural Transm 114:635–639

    Article  CAS  PubMed  Google Scholar 

  • Schmidt LG, Smolka M (2001) Relapse prevention in alcoholics by cigarette smoking? Involvement of nicotinic-dopaminergic mechanisms. Alcohol 24:111–115

    Article  CAS  PubMed  Google Scholar 

  • Schmidt LG, Kuhn S, Smolka M, Schmidt K, Rommelspacher H (2002) Lisuride, a dopamine D2 receptor agonist, and anticraving drug expectancy as modifiers of relapse in alcohol dependence. Prog Neuropsychopharmacol Biol Psychiatry 26:209–217

    Article  CAS  PubMed  Google Scholar 

  • Schuckit MA, Mazzanti C, Smith TL, Ahmed U, Radel M, Iwata N, Goldman D (1999) Selective genotyping for the role of 5-HT2A, 5-HT2C, and GABA alpha 6 receptors and the serotonin transporter in the level of response to alcohol: a pilot study. Biol Psychiatry 45:647–651

    Article  CAS  PubMed  Google Scholar 

  • Skowronek MH, Laucht M, Hohm E, Becker K, Schmidt MH (2006) Interaction between the dopamine D4 receptor and the serotonin transporter promoter polymorphisms in alcohol and tobacco use among 15-year-olds. Neurogenetics 7:239–246

    Article  CAS  PubMed  Google Scholar 

  • Smolka MN, Budde H, Karow AC, Schmidt LG (2004) Neuroendocrinological and neuropsychological correlates of dopaminergic function in nicotine dependence. Psychopharmacology (Berl) 175:374–381

    Article  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  CAS  PubMed  Google Scholar 

  • Volkow ND, Wang GJ, Maynard L, Fowler JS, Jayne B, Telang F, Logan J, Ding YS, Gatley SJ, Hitzemann R, Wong C, Pappas N (2002) Effects of alcohol detoxification on dopamine D2 receptors in alcoholics: a preliminary study. Psychiatry Res 116:163–172

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We would like to thank Nina Alexander (Department of Psychology, Center for Psychobiology and Behavioral Medicine, University of Giessen) for her help in preparing this article. This study was supported by the Deutsche Forschungsgemeinschaft (DFG) grants SM 80/1-1, SM 80/1-2, SM 80/2-2 and SM 80/5-1.

Conflict of interest statement

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Movement and Training Science, Institute of Sport Science, Humboldt University, Philippstraße 13, 10115, Berlin, Germany

    Henning Budde

  2. Cologne Center for Genomics, University of Cologne, Zülpicher Straße 47, 50674, Cologne, Germany

    Thomas Sander

  3. Section of Clinical Neurobiology, Department of Psychiatry and Psychotherapy, Charité University Medicine Berlin, Campus Benjamin Franklin, Eschenallee 3, 14050, Berlin, Germany

    Catrin Wernicke

  4. Department of Psychology, Technische Universität Dresden, Zellescher Weg 19, 01069, Dresden, Germany

    Anett Müller

  5. Department of Psychiatry and Psychotherapy, Charité University Medicine Berlin, Campus Charité Mitte, Berlin, Germany

    Jürgen Gallinat

  6. Department of Psychiatry and Psychotherapy, Universität Mainz, Untere Zahlbacher Str. 8, 55131, Mainz, Germany

    Lutz G. Schmidt

  7. Section of Systems Neuroscience, Department of Psychiatry and Psychotherapy, Technische Universität Dresden, Würzburger Straße 35, 01187, Dresden, Germany

    Michael N. Smolka

Authors
  1. Henning Budde
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Thomas Sander
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Catrin Wernicke
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Anett Müller
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jürgen Gallinat
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Lutz G. Schmidt
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Michael N. Smolka
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michael N. Smolka.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Budde, H., Sander, T., Wernicke, C. et al. Serotonin transporter promoter polymorphism and dopaminergic sensitivity in alcoholics. J Neural Transm 117, 133–138 (2010). https://doi.org/10.1007/s00702-009-0331-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00702-009-0331-9

Keywords

Search

Navigation