Neuroscience and Behavioral Physiology

, Volume 49, Issue 8, pp 1032–1037 | Cite as

Effects of the Interaction of the ANKK1/DRD2 TaqIA and HTR2C Cys23Ser Polymorphisms on Approach Motivation in Schizophrenia Patients and Healthy People

  • M. V. AlfimovaEmail author
  • G. I. Korovaitseva
  • T. V. Lezheiko
  • S. A. Golubev
  • A. A. Snegireva
  • E. A. Sakharova
  • V. E. Golimbet

Objective. To assess the association of the DRD2 gene and its interaction with the HTR2C gene with the characteristics of the hedonistic and activatory aspects of approach motivation in schizophrenia. Materials and methods. Genotypes at the polymorphic loci rs1800497 of DRD2 and rs6318 (Cys23Ser) of HTR2C were identified in a cohort including 174 patients with schizophrenia spectrum disorders and 268 healthy subjects. Subjects completed scales assessing approach motivation (BIS/BAS) and the Temporal Experience of Pleasure Scale (TEPS). Results and conclusions. Analysis taking account of sex and age identified an effect of the interaction between the DRD2 and HTR2C genes and diagnosis (p = 0.033) on assessments on the BAS scales. The effect was significant on the Fun-Seeking and Drive subscales. Among patients, the highest scores on both scales were seen with the combination of the DRD2 TT/CT and HTR2C GG/G genotypes and the lowest in carriers of the diplotypes with the minor alleles at both loci. Differences between these group were nominally significant for both scales, but were not significant after correction for multiple comparisons. Among healthy subjects, the highest levels of motivation were seen in people lacking the minor alleles. They were significantly different from those in carriers of the DRD2 TT/CT and HTR2C GG/G diplotype on the Fun-Seeking subscale (pcorr = 0.008). DRD2 and HTR2C were not found to have any effect on TEPS evaluations. Our results can be interpreted as indicating a role for the interaction of the DRD2 and HTR2C genes in the variation of the activatory aspects of approach motivation in both schizophrenia patients and healthy subjects. However, the absence of highly significant (persisting after the Bonferroni correction) differences between groups with different diplotypes makes it difficult to interpret this effect.


psychosis motivation pleasure dopamine serotonin genetic polymorphism intergene interaction 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    G. Fervaha, G. Foussias, O. Agid, and G. Remington, “Motivational deficits in early schizophrenia: prevalent, persistent, and key determinants of functional outcome,” Schizophr. Res., 166, No. 1–3, 9–16 (2015), Scholar
  2. 2.
    C. Soares-Cunha, B. Coimbra, N. Sousa, and A. J. Rodrigues, “Reappraising striatal D1- and D2-neurons in reward and aversion,” Neurosci. Biobehav. Rev., 68, 370–386 (2016), Scholar
  3. 3.
    B. S. Gluskin and B. J. Mickey, “Genetic variation and dopamine D2 receptor availability: a systematic review and meta-analysis of human in vivo molecular imaging studies,” Transl. Psychiatry, 6, 747 (2016), Scholar
  4. 4.
    A. O. Kibitov, “The genetics of addiction diseases: molecular genetic profile of the dopamine neurotransmitter system in alcoholism and opioid addiction,” Narkologiya, 10, No. 9, 25–42 (2011).Google Scholar
  5. 5.
    K. M. Bühler, E. Giné, V. Echeverry-Alzate, et al., “Common single nucleotide variants underlying drug addiction: more than a decade of research,” Addict. Biol., 20, No. 5, 845–871 (2015), Scholar
  6. 6.
    M. X. Cohen, J. Young, J. M. Baek, et al., “Individual differences in extraversion and dopamine genetics predict neural reward responses,” Cogn. Brain Res., 25, No. 3, 851–861 (2005), Scholar
  7. 7.
    J. A. Felsted, X. Ren, F. Chouinard-Decorte, and D. M. Small, “Genetically determined differences in brain response to a primary food reward,” J. Neurosci., 30, No. 7, 2428–2432 (2010), Scholar
  8. 8.
    Y. S. Nikolova, R. E. Ferrell, S. B. Manuck, and A. R. Hariri, “Multilocus genetic profile for dopamine signaling predicts ventral striatum reactivity,” Neuropsychopharmacology, 36, No. 9, 1940–1947 (2011), Scholar
  9. 9.
    E. Stice, S. Yokum, K. Burger, et al., “Multilocus genetic composite reflecting dopamine signaling capacity predicts reward circuitry responsivity,” J. Neurosci., 32, No. 29, 10093–10100 (2012), Scholar
  10. 10.
    A. Richter, A. Barman, T. Wustenberg, et al., “Behavioral and neural manifestations of reward memory in carriers of low-expressing versus high-expressing genetic variants of the dopamine D2 receptor,” Front. Psychol., 8, 654 (2017),
  11. 11.
    M. Reuter, A. Schmitz, P. Corr, and J. Hennig, “Molecular genetics support Gray’s personality theory: The interaction of COMT and DRD2 polymorphisms predicts the behavioural approach system,” Int. J. Neuropsychopharmacol., 9, No. 2, 155–166 (2006), Scholar
  12. 12.
    S. H. Lee, B. J. Ham, Y. H. Cho, et al., “Association study of dopamine receptor D2 TaqIA polymorphism and reward-related personality traits in healthy Korean young females,” Neuropsychobiology, 56, No. 23, 146–151 (2007),
  13. 13.
    C. Davis, R. D. Levitan, A. S. Kaplan, et al., “Reward sensitivity and the D2 dopamine receptor gene: A case-control study of binge eating disorder,” Prog. Neuropsychopharmacol. Biol. Psychiatry, 32, No. 3, 620–628 (2008), Scholar
  14. 14.
    C. Montag, J. W. Buckholtz, P. Hartmann, et al., “COMT genetic variation affects fear processing: psychophysiological evidence,” Behav. Neurosci, 122, No. 4, 901–909 (2008), Scholar
  15. 15.
    S. L. Johnson, C. S. Carver, J. Joormann, and M. L. Cuccaro, “Genetic polymorphisms related to behavioral approach and behavioral inhibition scales,” Personal. Individ. Differ., 88, 251–255 (2016), Scholar
  16. 16.
    Schizophrenia Working Group of the Psychiatric Genomics Consortium, “Biological insights from 108 schizophrenia-Associated geof netic loci,” Nature, 511, No. 7510, 421–427 (2014),\.Google Scholar
  17. 17.
    R. Brisch, A. Saniotis, R. Wolf, et al., “The Role of dopamine in schizophrenia from a neurobiological and evolutionary perspective: old fashioned, but still in vogue,” Front. Psychiatry, 5, 47 (2014),
  18. 18.
    Z. Zahari, L. K. Teh, R. Ismail, and S. M. Razali, “Influence of DRD2 polymorphisms on the clinical outcomes of patients with schizophrenia,” Psychiatr. Genet., 21, No. 4, 183–189 (2011), Scholar
  19. 19.
    S. G. Kang, K. S. Na, H. J. Lee, et al., “DRD2 genotypic and haplotype variation is associated with improvements in negative symptoms after 6 weeks’ amisulpride treatment,” J. Clin. Psychopharmacol., 35, No. 2, 158–162 (2015), Scholar
  20. 20.
    S. A. Eisenstein, R. Bogdan, L. Chen, et al., “Preliminary evidence that negative symptom severity relates to multilocus genetic profile for dopamine signaling capacity and D2 receptor binding in healthy controls and in schizophrenia,” J. Psychiatr. Res., 86, 9–17 (2017), Scholar
  21. 21.
    A. M. Kring and D. M. Barch, “The motivation and pleasure dimension of negative symptoms: Neural substrates and behavioral outputs,” Eur. Neuropsychopharmacol., 24, No. 5, 725–736 (2014), Scholar
  22. 22.
    J. D. Salamone, S. E. Yohn, L. López-Cruz, et al., “Activational and effort-related aspects of motivation: neural mechanisms and implications for psychopathology,” Brain, 139, 1325–1347 (2016), Scholar
  23. 23.
    A. Der-Avakian and A. Markou, “The Neurobiology of Anhedonia and Other Reward-Related Deficits,” Trends Neurosci., 35, No. 1, 68–77 (2012), Scholar
  24. 24.
    V. M. Pogorelov, R. M. Rodriguiz, J. Cheng, et al., “5-HT2C agonists modulate schizophrenia-like behaviors in mice,” Neuropsychopharmacology, 42, No. 11, 2163–2177 (2017), Scholar
  25. 25.
    L. L. Howell and K. A. Cunningham, “Serotonin 5-HT2 receptor interactions with dopamine function: implications for therapeutics in cocaine use disorder,” Pharmacol. Rev., 67, No. 1, 176–197 (2015), Scholar
  26. 26.
    E. H. Simpson, C. Kellendonk, R. D. Ward, et al., “Pharmacologic rescue of motivational deficit in an animal model of the negative symptoms of schizophrenia,” Biol. Psychiatry, 69, No. 10, 928–935 (2011), Scholar
  27. 27.
    E. H. Simpson, J. A. Waltz, C. Kellendonk, and P. D. Balsam, “Schizophrenia in translation: dissecting motivation in schizophrenia and rodents,” Schizophr. Bull., 38, No. 6, 1111–1117 (2012), Scholar
  28. 28.
    T. Sumiyoshi, H. Kunugi, and K. Nakagome, “Serotonin and dopamine receptors in motivational and cognitive disturbances of schizophrenia,” Front. Neurosci., 8, 395 (2014),
  29. 29.
    M. Okada, J. K. Northup, N. Ozaki, et al., “Modification of human 5-HT(2C) receptor function by Cys23Ser, an abundant, naturally occurring amino-acid substitution,” Mol. Psychiatry, 9, 55–64 (2004), Scholar
  30. 30.
    H. M. Fentress, E. Grinde, J. E. Mazurkiewicz, et al., “Pharmacological properties of the Cys23Ser single nucleotide polymorphism in human 5-HT2C receptor isoforms,” Pharmacogenomics J., 5, 244–254 (2005), Scholar
  31. 31.
    G. G. Knyazev, H. R. Slobodskaya, and G. D. Wilson, “Comparison of construct validity of the Gray–Wilson personality questionnaire and the BIS/BAS scales,” Personal. Individ. Differ., 37, No. 8, 1565–1582 (2004), Scholar
  32. 32.
    M. Monakhov, V. Golimbet, L. Abramova, et al., “Association study of three polymorphisms in the dopamine D2 receptor gene and schizophrenia in the Russian population,” Schizophr. Res., 100, 302–307 (2008), Scholar
  33. 33.
    M. V. Alfimova, V. E. Golimbet, G. I. Korovaitseva, et al., “Association of the Cys23Ser polymorphism of the type 2C serotonin receptor gene with social behavior in schizophrenia patients and healthy subjects,” Genetika, 51, No. 2, 242–247 (2015),].CrossRefGoogle Scholar
  34. 34.
    J. A. Beeler, R. P. Faust, S. Turkson, et al., “Low dopamine D2 receptor increases vulnerability to obesity via reduced physical activity not increased appetitive motivation,” Biol. Psychiatry, 79, No. 11, 887–897 (2016), Scholar
  35. 35.
    P. Trifilieff and D. Martinez, “Imaging addiction: D2 receptors and dopamine signaling in the striatum as biomarkers for impulsivity,” Neuropharmacology, 76, No. 00, 498–509 (2014), Scholar
  36. 36.
    B. Lerer, F. Macciardi, R. H. Segman, et al., “Variability of 5-HT2C receptor cys23ser polymorphism among European populations and vulnerability to affective disorder,” Mol. Psychiatry, 6, No. 5, 579–585 (2001), Scholar
  37. 37.
    B. H. Brummett, M. A. Babyak, R. B. Williams, et al., “A putatively functional polymorphism in the HTR2C gene is associated with depressive symptoms in white females reporting signifi cant life stress,” PLoS One, 9, No. 12, 114451 (2014), Scholar
  38. 38.
    N. M. Vyalova, I. V. Pozhidaev, D. Z. Osmanova, et al., “Association of polymorphic variants of the PIP5K2A and HTR2C genes with antidepressant treatment effi cacy in patients with prolonged depressive episode,” Zh. Nevrol. Psikhiat., 117, No. 5, 58–61 (2017), Scholar
  39. 39.
    M. V. Alfimova, T. V. Lezheiko, G. I. Korovaitseva, and V. E. Golimbet, “Psychological and molecular genetic mechanisms of decreases in Machiavellianism in schizophrenia,” Zh. Vyssh. Shkol. Ekonom., 12, No. 2, 70–92 (2015).Google Scholar
  40. 40.
    A. C. Katz, C. Sarapas, J. R. Bishop, et al., “The mediating effect of prefrontal asymmetry on the relationship between the COMT Val158Met SNP and trait consummatory positive affect,” Cogn. Emot., 29, No. 5, 867–881 (2015), Scholar
  41. 41.
    S. A. Eisenstein, R. Bogdan, L. Chen, et al., “Preliminary evidence that negative symptom severity relates to multilocus genetic profile for dopamine signaling capacity and D2 receptor binding in healthy controls and in schizophrenia,” J. Psychiatr. Res., 86, 9–17 (2017), Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • M. V. Alfimova
    • 1
    Email author
  • G. I. Korovaitseva
    • 1
  • T. V. Lezheiko
    • 1
  • S. A. Golubev
    • 1
  • A. A. Snegireva
    • 2
  • E. A. Sakharova
    • 2
  • V. E. Golimbet
    • 1
  1. 1.Scientific Center for Mental HealthMoscowRussia
  2. 2.Alekseev Psychiatric Clinical Hospital No. 1MoscowRussia

Personalised recommendations