The interaction effect of ANKK1/DRD2 TaqIA and HTR2C Cys23Ser on approach motivation in schizophrenic patients and normals

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Objective. To evaluate the association of the DRD2 gene and DRD2 x HTR2C interaction with hedonic and activational aspects of approach motivation in schizophrenia. Material and methods. Genotypes at polymorphic loci DRD2 rs1800497 and HTR2C rs6318 (Cys23Ser) were identified in a sample that included 174 patients with schizophrenic spectrum disorders and 268 healthy subjects without a family history of psychoses. The participants completed the BIS/BAS and Temporal Experience of Pleasure Scale (TEPS). Results and conclusion. A MANCOVA with sex and age as covariates revealed the effect of the «DRD2 x HTR2C x diagnosis» interaction on the BAS scores (p=0.033). The effect was significant for the Fun-Seeking and Drive scales. Among patients, the carriers of the DRD2 TT/CT x HTR2C GG/G genotype showed the highest scores on the both scales, and those with the minor alleles in the two loci had the lowest ones. Differences between these groups were nominally significant for both the Fun-Seeking and Drive, but did not survive the correction for multiple comparisons. Among controls, subjects without minor alleles demonstrated the highest scores on these two scales. They differed significantly from the carriers of the DRD2 TT/CT+HTR2C GG/G genotype on the Fun-Seeking (p=0.008). No effects of DRD2 and HTR2C on TEPS scores were found. In general, the results of the study can be interpreted in favor of the hypothesis about the role of the HTR2C and DRD2 genes interaction in the variability of the activational aspects of approach motivation in schizophrenia and healthy subjects. However, the lack of differences survived correction for multiple comparisons makes it difficult to interpret the revealed effects.

Keywords:

psychosis

motivation

pleasure

dopamine

serotonin

genetic polymorphism

gene X gene interaction

Authors:

Alfimova M.V.

Nauchnyĭ tsentr psikhicheskogo zdorov'ia RAMN

Korovaĭtseva G.I.

Nauchnyĭ tsentr psikhicheskogo zdorovia RAMN, Moskva

Lezheĭko T.V.

Nauchnyĭ tsentr psikhicheskogo zdorov'ia RAMN, Moskva

Golubev S.A.

Snegireva A.A.

GKUZ "Moskovskaia gorodskaia klinicheskaia psikhiatricheskaia bol'nitsa #1 im. N.A. Alekseeva", Moskva

Sakharova E.A.

Volgogradskiĭ oblastnoĭ klinicheskiĭ onkologicheskiĭ dispanser #1

Golimbet V.E.

Nauchnyĭ tsentr psikhicheskogo zdorov'ia RAMN, Moskva

List of references:

Fervaha G, Foussias G, Agid O, Remington G. Motivational deficits in early schizophrenia: prevalent, persistent, and key determinants of functional outcome. Schizophrenia Research. 2015;166(1-3):9-16. https://doi.org/10.1016/j.schres.2015.04.040
Soares-Cunha C, Coimbra B, Sousa N, Rodrigues AJ. Reappraising striatal D1- and D2-neurons in reward and aversion. Neuroscience & Biobehavioral Reviews. 2016;68:370-386. https://doi.org/10.1016/j.neubiorev.2016.05.021
Gluskin BS, Mickey BJ. Genetic variation and dopamine D2 receptor availability: a systematic review and meta-analysis of human in vivo molecular imaging studies. Translational Psychiatry. 2016;6:747. https://doi.org/10.1038/tp.2016.22
Kibitov AO. Genetics of substance abuse: the molecular-genetic profile of dopamine neurotransmitter system for alcoholism and opiate addiction. Narkologia. 2011;10(9):25-42. (In Russ.)
Bühler KM, Giné E, Echeverry-Alzate V, Calleja-Conde J, de Fonseca FR, López-Moreno JA. Common single nucleotide variants underlying drug addiction: more than a decade of research. Addiction Biology. 2015;20(5):845-871. https://doi.org/10.1111/adb.12204
Cohen MX, Young J, Baek JM, Kessler C, Ranganath C. Individual differences in extraversion and dopamine genetics predict neural reward responses. Cognitive Brain Research. 2005;25(3):851-861. https://doi.org/10.1016/j.cogbrainres.2005.09.018
Felsted JA, Ren X, Chouinard-Decorte F, Small DM. Genetically determined differences in brain response to a primary food reward. The Journal of neuroscience: the official journal of the Society for Neuroscience. 2010;30(7):2428-2432. https://doi.org/10.1523/JNEUROSCI.5483-09.2010
Nikolova YS, Ferrell RE, Manuck SB, Hariri AR. Multilocus Genetic Profile for Dopamine Signaling Predicts Ventral Striatum Reactivity. Neuropsychopharmacology. 2011;36(9):1940-1947. https://doi.org/10.1038/npp.2011.82
Stice E, Yokum S, Burger K, Epstein H, Smolen A. Multilocus Genetic Composite Reflecting Dopamine Signaling Capacity Predicts Reward Circuitry Responsivity. The Journal of neuroscience: the official journal of the Society for Neuroscience. 2012;32(29):10093-10100. https://doi.org/10.1523/JNEUROSCI.1506-12.2012
Richter A, Barman A, Wüstenberg T, Soch J, Schanze D, Deibele A, Behnisch G, Assmann A, Klein M, Zenker M, Seidenbecher C, Schott BH. Behavioral and Neural Manifestations of Reward Memory in Carriers of Low-Expressing versus High-Expressing Genetic Variants of the Dopamine D2 Receptor. Frontiers in Psychology. 2017;8:654. https://doi.org/10.3389/fpsyg.2017.00654
Reuter M, Schmitz A, Corr P, Hennig J. Molecular genetics support Gray’s personality theory: The interaction of COMT and DRD2 polymorphisms predicts the behavioural approach system. International Journal of Neuropsychopharmacology. 2006;9(2):155-166. https://doi.org/10.1017/S1461145705005419
Lee SH, Ham BJ, Cho YH, Lee SM, Shim SH. Association study of dopamine receptor D2 TaqI A polymorphism and reward-related personality traits in healthy Korean young females. Neuropsychobiology. 2007;56(2-3):146-151. https://doi.org/10.1159/000115781
Davis C, Levitan RD, Kaplan AS, Carter J, Reid C, Curtis C, Patte K, Hwang R, Kennedy JL. Reward sensitivity and the D2 dopamine receptor gene: A case-control study of binge eating disorder. Progress in Neuro-Psychopharmacology & Biological Psychiatry. 2008;32(3):620-628. https://doi.org/10.1016/j.pnpbp.2007.09.024
Montag C, Buckholtz JW, Hartmann P, Merz M, Burk C, Hennig J, Reuter M. COMT genetic variation affects fear processing: psychophysiological evidence. Behavioral Neuroscience. 2008;122(4):901-909. https://doi.org/10.1037/0735-7044.122.4.901
Johnson SL, Carver CS, Joormann J, Cuccaro ML. Genetic polymorphisms related to behavioral approach and behavioral inhibition scales. Personality and Individual Differences. 2016;88:251-255. https://doi.org/10.1016/j.paid.2015.09.024
Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological Insights From 108 Schizophrenia-Associated Genetic Loci. Nature. 2014;511(7510):421-427. https://doi.org/10.1038/nature13595
Brisch R, Saniotis A, Wolf R, Bielau H, Bernstein H, Steiner J, Bogerts B, Braun K, Jankowski Z, Kumaratilake J, Henneberg M, Gos T. The Role of Dopamine in Schizophrenia from a Neurobiological and Evolutionary Perspective: Old Fashioned, but Still in Vogue. Frontiers in Psychiatry. 2014;5:47. https://doi.org/10.3389/fpsyt.2014.00047
Zahari Z, Teh LK, Ismail R, Razali SM. Influence of DRD2 polymorphisms on the clinical outcomes of patients with schizophrenia. Psychiatric Genetics. 2011;21(4):183-189. https://doi.org/10.1097/YPG.0b013e3283437250
Kang SG, Na KS, Lee HJ, Chee IS, Lee K, Lee J. DRD2 genotypic and haplotype variation is associated with improvements in negative symptoms after 6 weeks’ amisulpride treatment. Journal of Clinical Psychopharmacology. 2015;35(2):158-162. https://doi.org/10.1097/JCP.0000000000000294
Eisenstein SA, Bogdan R, Chen L, Moerlein SM, Black KJ, Perlmutter JS, Hershey T, Barch DM. 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. Journal of Psychiatric Research. 2017;86:9-17. https://doi.org/10.1016/j.jpsychires.2016.11.007
Kring AM, Barch DM. The motivation and pleasure dimension of negative symptoms: Neural substrates and behavioral outputs. European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology. 2014;24(5):725-736. https://doi.org/10.1016/j.euroneuro.2013.06.007
Salamone JD, Yohn SE, López-Cruz L, San Miguel N, Correa M. Activational and effort-related aspects of motivation: neural mechanisms and implications for psychopathology. Brain. 2016;139:1325-1347. https://doi.org/10.1093/brain/aww050
Der-Avakian A, Markou A. The Neurobiology of Anhedonia and Other Reward-Related Deficits. Trends in Neurosciences. 2012;35(1):68-77. https://doi.org/10.1016/j.tins.2011.11.005
Pogorelov VM, Rodriguiz RM, Cheng J, Huang M, Schmerberg CM, Meltzer HY, Roth BL, Kozikowski AP, Wetsel WC. 5-HT2C Agonists Modulate Schizophrenia-Like Behaviors in Mice. Neuropsychopharmacology. 2017;42(11):2163-2177. https://doi.org/10.1038/npp.2017.52
Howell LL, Cunningham KA. Serotonin 5-HT2 Receptor Interactions with Dopamine Function: Implications for Therapeutics in Cocaine Use Disorder. Pharmacological Reviews. 2015;67(1):176-197. https://doi.org/10.1124/pr.114.009514
Simpson EH, Kellendonk C, Ward RD, Richards V, Lipatova O, Fairhurst S, Kandel ER, Balsam PD. Pharmacologic Rescue of Motivational Deficit in an Animal Model of the Negative Symptoms of Schizophrenia. Biological psychiatry. 2011;69(10):928-935. https://doi.org/10.1016/j.biopsych.2011.01.012
Simpson EH, Waltz JA, Kellendonk C, Balsam PD. Schizophrenia in Translation: Dissecting Motivation in Schizophrenia and Rodents. Schizophrenia Bulletin. 2012;38(6):1111-1117. https://doi.org/10.1093/schbul/sbs114
Sumiyoshi T, Kunugi H, Nakagome K. Serotonin and dopamine receptors in motivational and cognitive disturbances of schizophrenia. Frontiers in Neuroscience. 2014; 8:395. https://doi.org/10.3389/fnins.2014.00395
Okada M, Northup JK, Ozaki N, Russell JT, Linnoila M, Goldman D. Modification of human 5-HT(2C) receptor function by Cys23Ser, an abundant, naturally occurring amino-acid substitution. Molecular Psychiatry. 2004;9:55-64. https://doi.org/10.1038/sj.mp.4001357
Fentress HM, Grinde E, Mazurkiewicz JE, Backstrom JR, Herrick-Davis K, Sanders-Bush E. Pharmacological properties of the Cys23Ser single nucleotide polymorphism in human 5-HT2C receptor isoforms. The Pharmacogenomics Journal. 2005;5:244-254. https://doi.org/10.1038/sj.tpj.6500315
Knyazev GG, Slobodskaya HR, Wilson GD. Comparison of construct validity of the Gray—Wilson personality questionnaire and the BIS/BAS scales. Personality and Individual Differences. 2004;37(8):1565-1582. https://doi.org/10.1016/j.paid.2004.02.013
Monakhov M, Golimbet V, Abramova L, Kaleda V, Karpov V. Association study of three polymorphisms in the dopamine D2 receptor gene and schizophrenia in the Russian population. Schizophrenia Research. 2008;100:302-307. https://doi.org/10.1016/j.schres.2008.01.007
Alfimova MV, Golimbet VE, Korovaitseva GI, Abramova LI, Kaleda VG. Association Between Serotonin Receptor 2c Gene Cys23Ser Polymorphism and Social Behavior in Schizophrenia Patients and Healthy Individuals. Russian Journal of Genetics. 2015;51(2):198-203. https://doi.org/10.1134/S1022795415010020.
Beeler JA, Faust RP, Turkson S, Ye H, Zhuang X. Low Dopamine D2 Receptor Increases Vulnerability to Obesty Via Reduced Physical Activity Not Increased Appetitive Motivation. Biological psychiatry. 2016;79(11):887-897. https://doi.org/10.1016/j.biopsych.2015.07.009
Trifilieff P, Martinez D. Imaging addiction: D2 receptors and dopamine signaling in the striatum as biomarkers for impulsivity. Neuropharmacology. 2014;76(00):498-509. https://doi.org/10.1016/j.neuropharm.2013.06.031
Lerer B, Macciardi F, Segman RH, Adolfsson R, Blackwood D, Blairy S, Del Favero J, Dikeos DG, Kaneva R, Lilli R, Massat I, Milanova V, Muir W, Noethen M, Oruc L, Petrova T, Papadimitriou GN, Rietschel M, Serretti A, Souery D, Van Gestel S, Van Broeckhoven C, Mendlewicz J. Variability of 5-HT2C receptor cys23ser polymorphism among European populations and vulnerability to affective disorder. Molecular Psychiatry. 2001;6(5):579-585. https://doi.org/10.1038/sj.mp.4000883
Brummett BH, Babyak MA, Williams RB, Harris KM, Jiang R, Kraus WE, Singh A, Costa PT, Georgiades A, Siegler IC. A putatively functional polymorphism in the HTR2C gene is associated with depressive symptoms in white females reporting significant life stress. PLoS One. 2014;9(12):114451. https://doi.org/10.1371/journal.pone.0114451
Vyalova NM, Pozhidaev IV, Osmanova DZ, Simutkin GG, Ivanova SA, Bokhan NA. Association of polymorphic variants of PIP5K2A and HTR2C genes with response to antidepressant therapy of patients with a current depressive episode. Zhurnal Nevrologii i Psikhiatrii im. S.S. Korsakova. 2017;117(5):58-61. (In Russ.) https://doi.org/10.17116/jnevro20171175158-61
Alfimova MV, Lezheiko TV, Korovaitseva GI, Golimbet VE. Psychological and Molecular-Genetic Mechanism of Machiavellianism Reduction in Schizophrenia. Psihologiya. Zhurnal vysshej shkoly ehkonomiki. 2015;12(2)70-92. (In Russ.)
Katz AC, Sarapas C, Bishop JR, Patel SR, Shankman SA. The Mediating Effect of Prefrontal Asymmetry on the Relationship between the COMT Val158Met SNP and Trait Consummatory Positive Affect. Cognition & Emotion. 2015;29(5):867-881. https://doi.org/10.1080/02699931.2014.951030
Eisenstein SA, Bogdan R, Chen L, Moerlein SM, Black KJ, Perlmutter JS, Hershey T, Barch DM. 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. Journal of Psychiatric Research. 2017;86:9-17. https://doi.org/10.1016/j.jpsychires.2016.11.007

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