Association of Serotonin Receptors with Attention Deficit Hyperactivity Disorder: A Systematic Review and Meta-analysis

Abstract

Attention deficit hyperactivity disorder (ADHD) is one of the most common mental disorders in childhood, with a high heritability about 60% to 90%. Serotonin is a monoamine neurotransmitter. Numerous studies have reported the association between the serotonin receptor family (5-HTR) gene polymorphisms and ADHD, but the results are still controversial. In this study, we conducted a meta-analysis of the association between 5-HTR1B, 5-HTR2A, and 5-HTR2C genetic variants and ADHD. The results showed that the 861G allele of 5-HTR1B SNP rs6296 could significantly increase the risk of ADHD (C)R=1.09, 95% CI: 1.01-1.18); the 5-HTR2C gene rs518147 (OR=1.69, 95% CI: 1.38-2.07) and rs3813929 (OR = 1.57, 95% CI: 1.25-1.97) were all associated with the risk of ADHD. In addition, we also carried on a casecontrol study to explore the relevance between potential candidate genes 5-HTR1A, 5-HTR1E, 5-HTR3A and ADHD. The results indicated that 5-HTR1A rs6295 genotype (CC+CG vs. GG OR=2.00, 95% CI: 1.23-3.27) and allele (OR=1.77, 95% CI: 1.16-2.72) models were statistically significantly different between case group and control group. This study is the first comprehensive exploration and summary of the association between serotonin receptor family genetic variations and ADHD, and it also provides more evidence for the etiology of ADHD.

Keywords

attention deficit hyperactivity disorder / serotonin receptor / genetic variations / meta-analysis / association study

References

[1] KooijSJ, BejerotS, BlackwellA, et al.. European consensus statement on diagnosis and treatment of adult ADHD: The European Network Adult ADHD. BMC Psychiatry, 2010, 10: 67

[2] LangeKW, ReichlS, LangeKM, et al.. The history of attention deficit hyperactivity disorder. Atten Defic Hyperact Disord, 2010, 2(4): 241-255

[3] SroubekA, KellyM, LiX. Inattentiveness in attention-deficit/hyperactivity disorder. Neurosci Bull, 2013, 29(1): 103-110

[4] Clauss-EhlersS. Encyclopedia of Cross-Cultural School Psychology Springer Science & Business Media, 2010

[5] ChildressAC, BerrySA. Pharmacotherapy of attention-deficit hyperactivity disorder in adolescents. Drugs, 2012, 72(3): 309-325

[6] KenemansJL, BekkerEM, LijffijtM, et al.. Attention deficit and impulsivity: selecting, shifting, and stopping. Int J Psychophysiol, 2005, 58(1): 59-70

[7] PolanczykG D, LimaMS, HortaBL, et al.. The worldwide prevalence of ADHD:a systematic review and metaregression analysis. Am J Psychiatry, 2007, 164(6): 942-948

[8] Akutagava-MartinsGC, Salatino-OliveiraA, KielingCC, et al.. Genetics of attention-deficit/hyperactivity disorder: current findings and future directions. Expert Rev Neurother, 2013, 13(4): 435-445

[9] BaumgaertelA, WolraichML, DietrichM. Comparison of diagnostic criteria for attention deficit disorders in a German elementary school sample. J Am Acad Child Adolesc Psychiatry, 1995, 34(5): 629-638

[10] AndersonJC, WilliamsS, McGeeR, et al.. DSM-III disorders in preadolescent children. Prevalence in a large sample from the general population. Arch Gen Psychiatry, 1987, 44(1): 69-76

[11] BiedermanJ, FaraoneSV, MonuteauxMC, et al.. Gender effects on attention-deficit/hyperactivity disorder in adults, revisited. Biol Psychiatry, 2004, 55(7): 692-700

[12] SimonV, CzoborP, BálintS, et al.. Prevalence and correlates of adult attention-deficit hyperactivity disorder: Meta-analysis. Br J Psychiatry, 2009, 194(3): 204-211

[13] ShenYC, WangYF, YangXL. An epidemiological investigation of minimal brain dysfunction in six elementary schools in Beijing. J Child Psychol Psychiatry, 1985, 26(5): 777-787

[14] GaoQ, LiuL, QianQ, et al.. Advances in molecular genetic studies of attention deficit hyperactivity disorder in China. Shanghai Arch Psychiatry, 2014, 26(4): 194-206

[15] MannuzzaS, KleinRG, BesslerA, et al.. Adult outcome of hyperactive boys. Educational achievement, occupational rank, and psychiatric status. Arch Gen Psychiatry, 1993, 50(7): 565-576

[16] SwansonJM, SergeantJA, TaylorE, et al.. Attentiondeficit hyperactivity disorder and hyperkinetic disorder. Lancet, 1998, 351(9100): 429-433

[17] WoodwardL, TaylorE, DowdneyL. The parenting and family functioning of children with hyperactivity. J Child Psychol Psychiatry, 1998, 39(2): 161-169

[18] GreydanusDE, PrattHD, PatelDR. Attention deficit hyperactivity disorder across the lifespan: the child, adolescent, and adult. Dis Mon, 2007, 53(2): 70-131

[19] BarkleyRA. Attention-Deficit Hyperactivity Disorder: A Handbook for Diagnosis and Treatment, 2014

[20] BiedermanJ, NewcornJ, SprichS. Comorbidity of attention deficit hyperactivity disorder with conduct, depressive, anxiety, and other disorders. Am J Psychiatry, 1991, 148(5): 564-577

[21] BihlarMB, JokinenJ, BolteS, et al.. Attention deficit/hyperactivity disorders with co-existing substance use disorder is characterized by early antisocial behaviour and poor cognitive skills. BMC Psychiatry, 2013, 13: 336

[22] LoeberR, DishionT. Early predictors of male delinquency: a review. Psychol Bull, 1983, 94(1): 68-99

[23] BiedermanJ, FaraoneSV. Attention-deficit hyperactivity disorder. Lancet, 2005, 366(9481): 237-248

[24] Akutagava-MartinsGC, RohdeLA, HutzMH. Genetics of attention-deficit/hyperactivity disorder: an update. Expert Rev Neurother, 2016, 16(2): 145-156

[25] FaraoneSV, MickE. Molecular Genetics of Attention Deficit Hyperactivity Disorder. Psychiatr Clin North Am, 2010, 33(1): 159-180

[26] ThaparA, CooperM, EyreO, et al.. What have we learnt about the causes of ADHD. J Child Psychol Psychiatry, 2013, 54(1): 3-16

[27] FrankeB, FaraoneSV, AshersonP, et al.. The genetics of attention deficit/hyperactivity disorder in adults, a review. Mol Psychiatr, 2011, 17(10): 960-987

[28] LiZ, ChangS, ZhangL, et al.. Molecular genetic studies of ADHD and its candidate genes: A review. Psychiat Res, 2014, 219(1): 10-24

[29] CifarielloA, PompiliA, GasbarriA. 5-HT(7) receptors in the modulation of cognitive processes. Behav Brain Res, 2008, 195(1): 171-179

[30] LuckiI. The spectrum of behaviors influenced by serotonin. Biol Psychiatry, 1998, 44(3): 151-162

[31] BarnesNM, SharpT. A review of central 5-HT receptors and their function. Neuropharmacology, 1999, 38(8): 1083-1152

[32] HoyerD, HannonJP, MartinGR. Molecular, pharmacological and functional diversity of 5-HT receptors. Pharmacol Biochem Behav, 2002, 71(4): 533-554

[33] NicholsDE, NicholsCD. Serotonin receptors. Chem Rev, 2008, 108(5): 1614-1641

[34] FilipM, BaderM. Overview on 5-HT receptors and their role in physiology and pathology of the central nervous system. Pharmacol Rep, 2009, 61(5): 761-777

[35] Advances in Serotonin Receptor Research: Molecular Biology, Signal Transduction, and Therapeutics. Conference proceedings. San Francisco, California, USA. October 8–10, 1997. Ann N Y Acad Sci, 1998,861:1-297

[36] MillanMJ, MarinP, BockaertJ, et al.. Signaling at G-protein-coupled serotonin receptors: recent advances and future research directions. Trends Pharmacol Sci, 2008, 29(9): 454-464

[37] HannonJ, HoyerD. Molecular biology of 5-HT receptors. Behav Brain Res, 2008, 195(1): 198-213

[38] LanfumeyL, HamonM. 5-HT1 receptors. Curr Drug Targets CNS Neurol Disord, 2004, 3(1): 1-10

[39] DerksEM, HudziakJJ, DolanCV, et al.. Genetic and environmental influences on the relation between attention problems and attention deficit hyperactivity disorder. Behav Genet, 2008, 38(1): 11-23

[40] LiJ, WangY, ZhouR, et al.. Serotonin 5-HT IB receptor gene and attention deficit hyperactivity disorder in Chinese Han subjects. Am J Med Genet B Neuropsychiatr Genet, 2005, 132B(1): 59-63

[41] SchmidtLA, FoxNA, HamerDH. Evidence for a gene-gene interaction in predicting children's behavior problems: association of serotonin transporter short and dopamine receptor D4 long genotypes with internalizing and externalizing behaviors in typically developing 7-year-olds. Dev Psychopathol, 2007, 19(4): 1105-1116

[42] StadlerC, SchmeckK, NowratyI, et al.. Platelet 5-HT uptake in boys with conduct disorder.. Neuropsychobiology, 2004, 50(3): 244-251

[43] Van GoozenSH, FairchildG. Neuroendocrine and neurotransmitter correlates in children with antisocial behavior. Horm Behav, 2006, 50(4): 647-654

[44] WalstabJ, RappoldG, NieslerB. 5-HT(3) receptors: role in disease and target of drugs. Pharmacol Ther, 2010, 128(1): 146-169

[45] WalstabJ, HammerC, LasitschkaF, et al.. RIC-3 exclusively enhances the surface expression of human homomeric 5-hydroxytryptamine type 3A (5-HT3A) receptors despite direct interactions with 5-HT3A, -C, -D, and -E subunits. J Biol Chem, 2010, 285(35): 26956-26965

[46] GizerIR, FicksC, WaldmanID. Candidate gene studies of ADHD: a meta-analytic review. Hum Genet, 2009, 126(1): 51-90

[47] HoyerD, ClarkeDE, FozardJR, et al.. VII International Union of Pharmacology Classification of Receptors for 5-Hydroxytryptamine (Serotonin), 1994

[48] PuigMV, CeladaP, ArtigasF. Serotonergic control of prefrontal cortex. Rev Neurol (Spanish), 2004, 39(6): 539-547

[49] CryanJF, LeonardBE. 5-HT1A and beyond: the role of serotonin and its receptors in depression and the antidepressant response. Hum Psychopharmacol, 2000, 15(2): 113-135

[50] EvendenJL. The pharmacology of impulsive behaviour in rats VII: the effects of serotonergic agonists and antagonists on responding under a discrimination task using unreliable visual stimuli.. Psychopharmacology, 1999, 146(4): 422-431

[51] de BoerSF, KoolhaasJM. 5-HT1A and 5-HT1B receptor agonists and aggression: a pharmacological challenge of the serotonin deficiency hypothesis.. Eur J Pharmacol, 2005, 526(1-3): 125-139

[52] HughesZA, StarrKR, ScottCM, et al.. Simultaneous blockade of 5-HT1A/B receptors and 5-HT transporters results in acute increases in extracellular 5-HT in both rats and guinea pigs: in vivo characterization of the novel 5-HT1A/B receptor antagonist/5-HT transport inhibitor SB-649915-B. Psychopharmacology (Berl), 2007, 192(1): 121-133

[53] TsuchidaR, KuboM, ShintaniN, et al.. Inhibitory effects of osemozotan, a serotonin lA-receptor agonist, on methamphetamine-induced c-Fos expression in prefrontal cortical neurons.. Biol Pharm Bull, 2009, 32(4): 728-731

[54] WuS, ComingsDE. A common C-1018G polymorphism in the human 5-HT1A receptor gene.. Psychiat Genet, 1999, 9(2): 105-106

[55] CzesakM, LemondeS, PetersonEA, et al.. Cellspecific repressor or enhancer activities of Deaf-1 at a serotonin 1A receptor gene polymorphism. J Neurosci, 2006, 26(6): 1864-1871

[56] AlbertPR. Transcriptional regulation of the 5-HT1A receptor: implications for mental illness. Philosophical Transactions of the Royal Society B: Biological Sciences, 2012, 367(1601): 2402-2415

[57] DonaldsonZ l, FrancoisB, SantosTL, et al.. The functional serotonin la receptor promoter polymorphism, rs6295, is associated with psychiatric illness and differences in transcription. Transl Psychiat, 2016, 6(3): e746

[58] Le FrancoisB, CzesakM, SteublD, et al.. Transcriptional regulation at a HTR1A polymorphism associated with mental illness. Neuropharmacology, 2008, 55(6): 977-985

[59] ShimS, HwangboY, KwonY, et al.. A case-control association study of serotonin 1A receptor gene and tryptophan hydroxylase 2 gene in attention deficit hyperactivity disorder. Prog Neuro-Psychoph, 2010, 34(6): 974-979

[60] HsuC, TzangR, LiouY, et al.. Family-based association study of tryptophan hydroxylase 2 and serotonin 1A receptor genes in attention deficit hyperactivity disorder. Psychiat Genet, 2013, 23(1): 38

[61] ParkYH, LeeKK, KwonHJ, et al.. Association between HTR1A gene polymorphisms and attention deficit hyperactivity disorder in Korean children. Genet Test Mol Bioma, 2013, 17(3): 178-182

[62] HawiZ, DringM, KirleyA, et al.. Serotonergic system and attention deficit hyperactivity disorder (ADHD): a potential susceptibility locus at the 5-HT(lB) receptor gene in 273 nuclear families from a multicentre sample. Mol Psychiatry, 2002, 7(7): 718-725

[63] QuistJF, KennedyJL. Genetics of childhood disorders: XXIII. ADHD, Part 7: The serotonin systemJ Am Acad Child Psy, 2001, 40(2): 253-256

[64] ClarkMS, NeumaierJF. The 5-HT1B receptor: behavioral implications. Psychopharmacol Bull, 2001, 35(4): 170-185

[65] BrunnerD, BuhotMC, HenR, et al.. Anxiety, motor activation, and maternal-infant interactions in 5HT1B knockout mice. Behav Neurosci, 1999, 113(3): 587-601

[66] RambozS, SaudouF, AmaraDA, et al.. 5-HT1B receptor knock out—behavioral consequences. Behav Brain Res, 1996, 73(l-2): 305-312

[67] SaudouF, AmaraDA, DierichA, et al.. Enhanced aggressive behavior in mice lacking 5-HT1B receptor. Science, 1994, 265(5180): 1875-1878

[68] DulawaSC, HenR, Scearce-LevieK, et al.. SerotoninlB receptor modulation of startle reactivity, habituation, and prepulse inhibition in wild-type and serotoninlB knockout mice. Psychopharmacology (Berl), 1997, 132(2): 125-134

[69] BarotSK, FergusonSM, NeumaierJF. 5-HT(lB) receptors in nucleus accumbens efferents enhance both rewarding and aversive effects of cocaine. Eur J Neurosci, 2007, 25(10): 3125-3131

[70] BoryczJ, ZapataA, QuirozC, et al.. 5-HT1B receptor-mediated serotoninergic modulation of methylphenidate-induced locomotor activation in rats. Neuropsychopharmacol, 2008, 33(3): 619-626

[71] HallFS, SoraI, HenR, et al.. Serotonin/Dopamine Interactions in a Hyperactive Mouse: Reduced Serotonin Receptor IB Activity Reverses Effects of Dopamine Transporter Knockout. PLoS One, 2014, 9(12): e115009

[72] HuangYY, GrailheR, ArangoV, et al.. Relationship of psychopathology to the human serotoninlB genotype and receptor binding kinetics in postmortem brain tissue. Neuropsychopharmacol, 1999, 21(2): 238-246

[73] QuistJF, BarrCL, SchacharR, et al.. The serotonin 5-HT IB receptor gene and attention deficit hyperactivity disorder. Mol Psychiatry, 2003, 8(1): 98-102

[74] HawiZ, SeguradoR, ConroyJ, et al.. Preferential transmission of paternal alleles at risk genes in attention-deficit/hyperactivity disorder. Am J Hum Genet, 2005, 77(6): 958-965

[75] SmollerJW, BiedermanJ, ArbeitmanL, et al.. Association between the 5HT1B receptor gene (HTR1B) and the inattentive subtype of ADHD. Biol Psychiatry, 2006, 59(5): 460-467

[76] GuimaraesAP, SchmitzM, PolanczykGV, et al.. Further evidence for the association between attention deficit/hyperactivity disorder and the serotonin receptor IB gene. J Neural Transm, 2009, 116(12): 1675-1680

[77] BaneijeeE, BaneijeeD, ChatteijeeA, et al.. Selective matemal inheritance of risk alleles and genetic interaction between serotonin receptor-IB (5-HTR1B) and serotonin transporter (SLC6A4) in ADHD. Psychiatry Res, 2012, 200(2-3): 1083-1085

[78] FonsecaDJ, MateusHE, GalvezJM, et al.. Lack of association of polymorphisms in six candidate genes in Colombian adhd patients. Ann Neurosci, 2015, 22(4): 217-221

[79] OadesRD. Dopamine-serotonin interactions in attention-deficit hyperactivity disorder (ADHD). Prog Brain Res, 2008, 172: 543-565

[80] CoteF, FlignyC, BayardE, et al.. Matemal serotonin is crucial for murine embryonic development. P Natl Acad Sei Usa, 2007, 104(1): 329-334

[81] OgdieMN, FisherSE, YangM, et al.. Attention deficit hyperactivity disorder: fine mapping supports linkage to 5p 13, 6ql2,16pl3, and 17pll. Am JHum Genet, 2004, 75(4): 661-668

[82] BrookesK, XuX, ChenW, et al.. The analysis of 51 genes in DSM-IV combined type attention deficit hyperactivity disorder: association signals in DRD4, DAT1 and 16 other genes. Mol Psychiatry, 2006, 11(10): 934-953

[83] Lasky-SuJ, NealeBM, FrankeB, et al.. Genomewide association scan of quantitative traits for attention deficit hyperactivity disorder identifies novel associations and confirms candidate gene associations. Am J Med Genet B Neuropsychiatr Genet, 2008, 147B(8): 1345-1354

[84] OadesRD, Lasky-SuJ, ChristiansenH, et al.. The influence of serotonin-and other genes on impulsive behavioral aggression and cognitive impulsivity in children with attention-deficit/hyperactivity disorder (ADHD): Findings from a family-based association test (FBAT) analysis. Behav Brain Funct, 2008, 4: 48

[85] LeschKP, WaiderJ. Serotonin in the modulation of neural plasticity and networks: implications for neurodevelopmental disorders. Neuron, 2012, 76(1): 175-191

[86] HartigPR, BranchekTA, WeinshankRL. A subfamily of 5-HT1D receptor genes. Trends Pharmacol Sei, 1992, 13(4): 152-159

[87] LiJ, ZhangX, WangY, et al.. The serotonin 5-HT1D receptor gene and attention-deficit hyperactivity disorder in Chinese Han subjects. Am J Med Genet B Neuropsychiatr Genet, 2006, 141B(8): 874-876

[88] SparkesRS, LanN, KlisakI, et al.. Assignment of a serotonin 5HT-2 receptor gene (HTR2) to human chromosome 13ql4-q21 and mouse chromosome 14. Genomics, 1991, 9(3): 461-465

[89] RoselP, ArranzB, UrretavizcayaM, et al.. Different distributions of the 5-HT reuptake complex and the postsynaptic 5-HT(2A) receptors in Brodmann areas and brain hemispheres. Psychiatry Res, 2002, 111(2-3): 105-115

[90] O'NeillMF, Heron-MaxwellCL, ShawG. 5-HT2 receptor antagonism reduces hyperactivity induced by amphetamine, cocaine, and MK-801 but not D1 agonist C-APB. Pharmacol Biochem Behav, 1999, 63(2): 237-243

[91] ChoSC, SonJW, KimBN, et al.. Serotonin 2A Receptor Gene Polymorphism in Korean Children with Attention-Deficit/Hyperactivity Disorder. Psychiatry Investig, 2012, 9(3): 269-277

[92] StahlSM, ShayeganDK. The psychopharmacology of ziprasidone: receptor-binding properties and realworld psychiatric practice. J Clin Psychiatry, 2003, 64(19): 6-12

[93] ErdmannJ, Shimron-AbarbanellD, RietschelM, et al.. Systematic screening for mutations in the human serotonin-2A (5-HT2A) receptor gene: identification of two naturally occurring receptor variants and association analysis in schizophrenia. Hum Genet, 1996, 97(5): 614-619

[94] HazelwoodLA, Sanders-BushE. His452Tyr polymorphism in the human 5-HT2A receptor destabilizes the signaling conformation. Mol Pharmacol, 2004, 66(5): 1293-1300

[95] OzakiN, ManjiH, LubiermanV, et al.. A naturally occurring amino acid substitution of the human serotonin 5-HT2A receptor influences amplitude and timing of intracellular calcium mobilization. J Neurochem, 1997, 68(5): 2186-2193

[96] QuistJF, BarrCL, SchacharR, et al.. Evidence for the serotonin HTR2A receptor gene as a susceptibility factor in attention deficit hyperactivity disorder (ADHD). Mol Psychiatry, 2000, 5(5): 537-541

[97] BobbAJ, AddingtonAM, SidranskyE, et al.. Support for association between ADHD and two candidate genes: NET1 and DRD1. Am J Med Genet B Neuropsychiatr Genet, 2005, 134B(1): 67-72

[98] GuimaraesAP, ZeniC, PolanczykGV, et al.. Serotonin genes and attention deficit/hyperactivity disorder in a Brazilian sample: preferential transmission of the HTR2A 452His allele to affected boys. Am J Med Genet B Neuropsychiatr Genet, 2007, 144B(1): 69-73

[99] HeiserP, DempfleA, FriedelS, et al.. Family-based association study of serotonergic candidate genes and attention-deficit/hyperactivity disorder in a German sample. J Neural Transm, 2007, 114(4): 513-521

[100] EliaJ, CapassoM, ZaheerZ, et al.. Candidate gene analysis in an on-going genome-wide association study of attention-deficit hyperactivity disorder: suggestive association signals in ADRA1 A. Psychiatr Genet, 2009, 19(3): 134-141

[101] TureckiG, BriereR, DewarK, et al.. Prediction of level of serotonin 2A receptor binding by serotonin receptor 2A genetic variation in postmortem brain samples from subjects who did or did not commit suicide. Am J Psychiatry, 1999, 156(9): 1456-1458

[102] BrownGL, LinnoilaMI. CSF serotonin metabolite (5-HIAA) studies in depression, impulsivity, and violence. J Clin Psychiatry, 1990, 51: 42-43

[103] LiJ, WangY, ZhouR, et al.. No association of attention-deficit/hyperactivity disorder with genes of the serotonergic pathway in Han Chinese subjects. Neurosci Lett, 2006, 403(1-2): 172-175

[104] ZorogluSS, ErdalME, ErdalN, et al.. No evidence for an association between the T102C and 1438 G/A polymorphisms of the serotonin 2A receptor gene in attention deficit/hyperactivity disorder in a Turkish population. Neuropsychobiology, 2003, 47(1): 17-20

[105] LiJ, KangC, WangY, et al.. Contribution of 5-HT2A receptor gene -1438A>G polymorphism to outcome of attention-deficit/hyperactivity disorder in adolescents. Am J Med Genet B Neuropsychiatr Genet, 2006, 141B(5): 473-476

[106] LiJ, WangY, QianQ, et al.. Association of 5-HT(2A) receptor polymorphism and attention deficit hyperactivity disorder in children. Zhonghua Yi Xue Za Zhi (Chinese), 2002, 82(17): 1173-1176

[107] ReuterM, KirschP, HennigJ. Inferring candidate genes for attention deficit hyperactivity disorder (ADHD) assessed by the World Health Organization Adult ADHD Self-Report Scale (ASRS). J Neural Transm, 2006, 113(7): 929-938

[108] ArranzMJ, MunroJ, OwenMJ, et al.. Evidence for association between polymorphisms in the promoter and coding regions of the 5-HT2A receptor gene and response to clozapine. Mol Psychiatry, 1998, 3(1): 61-66

[109] ArranzMJ, CollierDA, MunroJ, et al.. Analysis of a structural polymorphism in the 5-HT2A receptor and clinical response to clozapine. Neurosci Lett, 1996, 217(2-3): 177-178

[110] PazvantogluO, GunesS, KarabekirogluK, et al.. The relationship between the presence of ADHD and certain candidate gene polymorphisms in a Turkish sample. Gene, 2013, 528(2): 320-327

[111] BaneijeeE, NandagopalK. Does serotonin deficit mediate susceptibility to ADHD?. Neurochem Int, 2015, 82: 52-68

[112] BergKA, ClarkeWP, CunninghamKA, et al.. Fine-tuning serotonin2c receptor function in the brain: molecular and functional implications. Neuropharmacology, 2008, 55(6): 969-976

[113] LeysenJE. 5-HT2 receptors. Curr Drug Targets CNS Neurol Disord, 2004, 3(1): 11-26

[114] BaxterG, KennettG, BlaneyF, et al.. 5-HT2 receptor subtypes: a family re-united?. Trends Pharmacol Sci, 1995, 16(3): 105-110

[115] MilatovichA, HsiehCL, BonaminioG, et al.. Serotonin receptor 1 c gene assigned to X chromosome in human (band q24) and mouse (bands D-F4). Hum Mol Genet, 1992, 1(9): 681-684

[116] SerratsJ, MengodG, CortesR. Expression of serotonin 5-HT2C receptors in GABAergic cells of the anterior raphe nuclei. J Chem Neuroanat, 2005, 29(2): 83-91

[117] OadesRD. Function and dysfunction of monoamine interactions in children and adolescents with AD/HD. EXS, 2006, 98: 207-244

[118] LucasG, SpampinatoU. Role of striatal serotonin2A and serotonin2C receptor subtypes in the control of in vivo dopamine outflow in the rat striatum. J Neurochem, 2000, 74(2): 693-701

[119] StiedlO, MisaneI, KochM, et al.. Activation of the brain 5-HT2C receptors causes hypolocomotion without anxiogenic-like cardiovascular adjustments in mice. Neuropharmacology, 2007, 52(3): 949-957

[120] RobinsonES, DalleyJW, TheobaldDE, et al.. Opposing roles for 5-HT2A and 5-HT2C receptors in the nucleus accumbens on inhibitory response control in the 5-choice serial reaction time task. Neuropsychopharmacol, 2008, 33(10): 2398-2406

[121] PennanenL v d, HartM, YuL, et al.. Impact of serotonin (5-HT)2C receptors on executive control processes. Neuropsychopharmacol, 2013, 38(6): 957-967

[122] GrottickAJ, CorrigallWA, HigginsGA. Activation of 5-HT(2C) receptors reduces the locomotor and rewarding effects of nicotine. Psychopharmacology (Berl), 2001, 157(3): 292-298

[123] JohannM, BobbeG, PutzhammerA, et al.. Comorbidity of alcohol dependence with attentiondeficit hyperactivity disorder: differences in phenotype with increased severity of the substance disorder, but not in genotype (serotonin transporter and 5-hydroxytryptamine-2c receptor). Alcohol Clin Exp Res, 2003, 27(10): 1527-1534

[124] LiJ, WangYF, ZhouRL, et al.. Association between serotonin 2C gene polymorphisms and attention deficit hyperactivity disorder comorbid or not comorbid with learning disorder. Beijing Da Xue Xue Bao (Chinese), 2004, 36(4): 366-369

[125] LiJ, WangY, ZhouR, et al.. Association between polymorphisms in serotonin 2C receptor gene and attention-deficit/hyperactivity disorder in Han Chinese subjects. Neurosci Lett, 2006, 407(2): 107-111

[126] LiJ, WangYF, ZhouRL, et al.. Association between serotonin 2C gene polymorphisms and attention deficit hyperactivity disorder in children with or without comorbidity of disruptive behavior disorder. Zhonghua Er Ke Za Zhi (Chinese), 2007, 45(5): 374-377

[127] XuX, BrookesK, SunB, et al.. Investigation of the serotonin 2C receptor gene in attention deficit hyperactivity disorder in UK samples. BMC Res Notes, 2009, 2: 71

[128] RibasesM, Ramos-QuirogaJA, HervasA, et al.. Exploration of 19 serotoninergic candidate genes in adults and children with attention-deficit/ hyperactivity disorder identifies association for 5HT2A, DDC and MAOB. Mol Psychiatry, 2009, 14(1): 71-85

[129] NieslerB, KapellerJ, HammerC, et al.. Serotonin type 3 receptor genes: HTR3A, B, C, D, E. Pharmacogenomics, 2008, 9(5): 501-504

[130] EngelM, SmidtM v, HooftJA. The serotonin 5-HT3 receptor: a novel neurodevelopmental target. Front Cell Neurosci, 2013, 7: 76

[131] ThompsonAJ, LummisSC. 5-HT3 receptors. Curr Pharm Des, 2006, 12(28): 3615-3630

[132] BockaertJ, ClaeysenS, CompanV, et al.. 5-HT4 receptors. Curr Drug Targets CNS Neurol Disord, 2004, 3(1): 39-51

[133] MannuzzaS, KleinRG, KonigPH, et al.. Hyperactive boys almost grown up. IV. Criminality and its relationship to psychiatric status. Arch Gen Psychiatry, 1989, 46(12): 1073-1079

[134] BonhommeN D, DeurwaerdereP L, MoalM, et al.. Evidence for 5-HT4 receptor subtype involvement in the enhancement of striatal dopamine release induced by serotonin: a microdialysis study in the halothane-anesthetized rat. Neuropharmacology, 1995, 34(3): 269-279

[135] CompanV, ZhouM, GrailheR, et al.. Attenuated response to stress and novelty and hypersensitivity to seizures in 5-HT4 receptor knock-out mice. J Neurosci, 2004, 24(2): 412-419

[136] LiJ, WangY, ZhouR, et al.. Association of attentiondeficit/ hyperactivity disorder with serotonin 4 receptor gene polymorphisms in Han Chinese subjects. Neurosci Lett, 2006, 401(l-2): 6-9

[137] AdrianiW, LeoD, GrecoD, et al.. Methylphenidate administration to adolescent rats determines plastic changes on reward-related behavior and striatal gene expression. Neuropsychopharmacol, 2006, 31(9): 1946-1956

[138] RuoccoLA, RomanoE, TrenoC, et al.. Emotional and risk seeking behavior after prepuberal subchronic or adult acute stimulation of 5-HT7-Rs in Naples High Excitability rats. Synapse, 2014, 68(4): 159-167

[139] CaneseR, MarcoE D, PasqualeF, et al.. Differential response to specific 5-Ht(7) versus whole-serotonergic drugs in rat forebrains: a phMRI study. Neuroimage, 2011, 58(3): 885-894