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Cited by 33Neurotransmitter Receptor Influence on BehaviorPsychopathy, Forensic Psychiatry, Sexual OffendingNeuroendocrine regulation and behavior

Gene-environment interactions in antisocial behavior are mediated by early-life 5-HT2A receptor activation

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Godar, Sean C., Mosher, Laura J., Scheggi, Simona, Devoto, Paola, Moench, Kelly M., Strathman, Hunter J., Jones, Cori M., Frau, Roberto +9 more·2019·Neuropharmacology
DOI 10.1016/j.neuropharm.2019.01.028PMC PMC7578912
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Abstract

The ontogeny of antisocial behavior (ASB) is rooted in complex gene-environment (G×E) interactions. The best-characterized of these interplays occurs between: a) low-activity alleles of the gene encoding monoamine oxidase A (MAOA), the main serotonin-degrading enzyme; and b) child maltreatment. The purpose of this study was to develop the first animal model of this G×E interaction, to help understand the neurobiological mechanisms of ASB and identify novel targets for its therapy. Maoa hypomorphic transgenic mice were exposed to an early-life stress regimen consisting of maternal separation and daily intraperitoneal saline injections and were then compared with their wild-type and non-stressed controls for ASB-related neurobehavioral phenotypes. Maoa hypomorphic mice subjected to stress from postnatal day (PND) 1 through 7 - but not during the second postnatal week - developed overt aggression, social deficits and abnormal stress responses from the fourth week onwards. On PND 8, these mice exhibited low resting heart rate - a well-established premorbid sign of ASB - and a significant and selective up-regulation of serotonin 5-HT 2A receptors in the prefrontal cortex. Notably, both aggression and neonatal bradycardia were rescued by the 5-HT 2 receptor antagonist ketanserin (1-3 mg kg-1, IP), as well as the selective 5-HT 2A receptor blocker MDL-100,907 (volinanserin, 0.1-0.3 mg kg-1, IP) throughout the first postnatal week. These findings provide the first evidence of a molecular basis of G×E interactions in ASB and point to early-life 5-HT 2A receptor activation as a key mechanism for the ontogeny of this condition. This article is part of the Special Issue entitled 'The neuropharmacology of social behavior: from bench to bedside'.

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  • Low-activity MAOA mice show a robust increase in aggressive behaviors relative to wild type only when exposed to an early-life stress paradigm.

    “Studies using low-activity MAOA mice demonstrate a robust increase in aggressive behaviors relative to wild type, only when exposed to an early-life stress paradigm (Godar et al. 2019).”

    From Decoding the bidirectional links between alcohol misuse and aggression: toward a unified translational framework (2026) · cites this paper as Godar et al. 2019

  • In gene-by-environment studies, saline injections in combination with maternal separation increased aggression in MAOA hypomorphic, but not wild-type, mice when performed over the first week of life.

    “In gene-by-environment studies, saline injections in combination with maternal separation increased aggression in monoamine oxidase A (MAOA) hypomorphic, but not wild-type, mice when performed over the first week of life (Frau et al. 2019; Godar et al. 2019).”

    From Decoding the bidirectional links between alcohol misuse and aggression: toward a unified translational framework (2026) · cites this paper as Godar et al. 2019

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  1. Anda RF, Felitti VJ, Bremner JD, Walker JD, Whitfield C, Perry BD, Dube SR, Giles WH 2006 The enduring effects of abuse and related adverse experiences in childhood. European archives of psychiatry and clinical neuroscience 256(3), 174– 186. 16311898 PMC3232061
  2. Aznar S, Klein AB 2013 Regulating prefrontal cortex activation: an emerging role for the 5-HT₂A serotonin receptor in the modulation of emotion-based actions? Mol Neurobiol. 48, 841– 53. 23696058
  3. Bagdy G. 1996 Role of the hypothalamic paraventricular nucleus in 5-HT1A, 5-HT2A and 5-HT2C receptor-mediated oxytocin, prolactin and ACTH/corticosterone responses. Behav Brain Res. 73(1–2), 277– 80. 8788518
  4. Barkley RA, Fischer M, Smallish L, Fletcher K. 2004 Young adult follow-up of hyperactive children: antisocial activities and drug use. J Child Psychol Psychiatry. 45, 195– 211. 14982236
  5. Béïque JC, Campbell B, Perring P, Hamblin MW, Walker P, Mladenovic L, Andrade R. 2004 Serotonergic regulation of membrane potential in developing rat prefrontal cortex: coordinated expression of 5-hydroxytryptamine (5-HT)1A, 5-HT2A, and 5-HT7 receptors. J Neurosci. 24, 4807– 4817. 15152041 PMC6729457
  6. Belsky J, Beaver KM 2011 Cumulative-genetic plasticity, parenting and adolescent self-regulation. J Child Psychol Psychiatry 52, 619– 626. 21039487 PMC4357655
  7. Benekareddy M, Goodfellow NM, Lambe EK, Vaidya VA 2010 Enhanced function of prefrontal serotonin 5-HT(2) receptors in a rat model of psychiatric vulnerability. J Neurosci. 30, 12138–12150. PMC4177096 20826676
  8. Benekareddy M, Vadodaria KC, Nair AR, Vaidya VA 2011 Postnatal serotonin type 2 receptor blockade prevents the emergence of anxiety behavior, dysregulated stress-induced immediate early gene responses, and specific transcriptional changes that arise following early life stress. Biol Psychiatry. 70, 1024– 1032. 21959103 PMC3210326
  9. Bortolato M, Chen K, Godar SC, Chen G, Wu W, Rebrin I, Farrell MR, Scott AL, Wellman CL, Shih JC 2011 Social deficits and perseverative behaviors, but not overt aggression, in MAO-A hypomorphic mice. Neuropsychopharmacology 36, 2674– 2688. 21832987 PMC3230491
  10. Bortolato M, Chen K, Shih JC 2008 Monoamine oxidase inactivation: from pathophysiology to therapeutics. Adv Drug Deliv Rev. 60, 1527– 1533. 18652859 PMC2630537
  11. Bortolato M, Floris G, Shih JC 2018 From aggression to autism: new perspectives on the behavioral sequelae of monoamine oxidase deficiency. J Neural Transm. 125, 1589– 1599. 29748850 PMC6215718
  12. Bortolato M, Godar SC, Alzghoul L, Zhang J, Darling RD, Simpson KL, Bini V, Chen K, Wellman CL, Lin RC, Shih JC 2013a Monoamine oxidase A and A/B knockout mice display autistic-like features. Int J Neuropsychopharmacol. 16, 869– 888. 22850464 PMC3517692
  13. Bortolato M, Yardley MM, Khoja S, Godar SC, Asatryan L, Finn DA, Alkana RL, Louie SG, Davies DL 2013b Pharmacological insights into the role of P2X4 receptors in behavioural regulation: lessons from ivermectin. Int J Neuropsychopharmacol. 16(5), 1059– 1070. 23174033 PMC3593990
  14. Bortolozzi A, Díaz-Mataix L, Scorza MC, Celada P, Artigas F. 2005 The activation of 5-HT receptors in prefrontal cortex enhances dopaminergic activity. J Neurochem. 95(6), 1597– 1607. 16277612
  15. Byrd AL, Manuck SB 2014 MAOA, childhood maltreatment, and antisocial behavior: meta-analysis of a gene-environment interaction. Biol Psychiatry 75, 9– 17. 23786983 PMC3858396
  16. Cases O, Seif I, Grimsby J, Gaspar P, Chen K, Pournin S, Müller U, Aquet M, Babinet C, Shih JC, De Maeyer E. 1995 Aggressive behavior and altered amounts of brain serotonin and norepinephrine in mice lacking MAOA. Science 268(5218), 1763– 1766. 7792602 PMC2844866
  17. Caspi A, McClay J, Moffitt TE, Mill J, Martin J, Craig IW, Taylor A, Poulton R. 2002 Role of genotype in the cycle of violence in maltreated children. Science 297, 851– 854. 12161658
  18. Castagné V, Moser P, Roux S, Porsolt RD 2011 Rodent models of depression: forced swim and tail suspension behavioral despair tests in rats and mice. Curr Protoc Neurosci. Chapter 8: Unit 8.10A. 21462162
  19. Chu V, Otero JM, Lopez O, Morgan JP, Amende I, Hampton TG 2001 Method for non-invasively recording electrocardiograms in conscious mice. BMC Physiol. 1, 6. 11476671 PMC35354
  20. Compton WM, Conway KP, Stinson FS, Colliver JD, Grant BF 2005 Prevalence, correlates, and comorbidity of DSM-IV antisocial personality syndromes and alcohol and specific drug use disorders in the United States: results from the national epidemiologic survey on alcohol and related conditions. J Clin Psychiatry 66, 677– 685. 15960559
  21. Dannlowski U, Ohrmann P, Konrad C, Domschke K, Bauer J, Kugel H, Hohoff C, Schoning S, Kersting A, Baune BT, Mortensen LS, Arolt V, Zwitserlood P, Deckert J, Heindel W, Suslow T. 2009 Reduced amygdala-prefrontal coupling in major depression: association with MAOA genotype and illness severity. Int J Neuropsychopharmacol. 12(1), 11– 22. 18544183
  22. Ellis BJ, Boyce WT, Belsky J, Bakermans-Kranenburg MJ, van Ijzendoorn MH 2011 Differential susceptibility to the environment: an evolutionary--neurodevelopmental theory. Dev Psychopathol. 23, 7– 28. 21262036
  23. Fairchild G, van Goozen SH, Stollery SJ, Brown J, Gardiner J, Herbert J, Goodyer IM 2008 Cortisol diurnal rhythm and stress reactivity in male adolescents with early-onset or adolescence-onset conduct disorder. Biol Psychiatry. 64(7), 599– 606. 18620338 PMC2568813
  24. Fava M. 1997 Psychopharmacologic treatment of pathologic aggression. Psychiatr Clin North Am. 20(2), 427– 451. 9196923
  25. Fergusson DM, Boden JM, Horwood LJ, Miller AL, Kennedy MA 2011 MAOA, abuse exposure and antisocial behavior: 30-year longitudinal study. Br J Psychiatry 198, 457– 463. 21628708 PMC3105117
  26. Fowler SC, Birkestrand BR, Chen R, Moss SJ, Vorontsova E, Wang G, Zarcone TJ 2001 A force-plate actometer for quantitating rodent behaviors: illustrative data on locomotion, rotation, spatial patterning, stereotypies, and tremor. J Neurosci Methods 107, 107– 124. 11389948
  27. Godar SC, Bortolato M, Frau R, Dousti M, Chen K, Shih JC 2011 Maladaptive defensive behaviours in monoamine oxidase A-deficient mice. Int J Neuropsychopharmacol. 14, 1195– 1207. 21156093 PMC3435117
  28. Godar SC, Fite PJ, McFarlin KM, Bortolato M. 2016 The role of monoamine oxidase A in aggression: current translational developments and future directions. Prog Neuropsychopharmacol Biol Psychiatry 269, 90– 100. PMC4865459 26776902
  29. Grappi S, Marchese G, Secci ME, De Montis MG, Gambarana C, Scheggi S. 2011 Morphine sensitization as a model of mania: comparative study of the effects of repeated lithium or carbamazepine administration. Pharmacol Biochem Behav. 99(4), 749– 758. 21741986
  30. Haberstick BC, Lessem JM, Hewitt JK, Smolen A, Hopfer CJ, Halpern CT, Killeya-Jones LA, Boardman JD, Tabor J, Siegler IC, Williams RB, Mullan Harris K. 2014 MAOA genotype, childhood maltreatment, and their interaction in the etiology of adult antisocial behaviors. Biol Psychiatry 75(1), 25– 30. 23726513 PMC3815496
  31. Hedner J, Lundell KH, Breese GR, Mueller RA, Hedner T. 1986 Developmental variations in CSF monoamine metabolites during childhood. Biol Neonate 49(4), 190– 197. 2423144
  32. Heyser CJ. Assessment of developmental milestones in rodents (2003). Curr Protoc Neurosci. Supp 25. 18428605
  33. Hohmann CF, Hamon R, Batshaw ML, Coyle JT 1988 Transient postnatal elevation of serotonin levels in the mouse neocortex. Dev Brain Res. 43, 163– 166. 2464412
  34. Kehne JH, Baron BM, Carr AA, Chaney SF, Elands J, Feldman DJ, Frank RA, van Giersbergen PL, McCloskey TC, Johnson MP, McCarty DR, Poirot M, Senyah Y, Siegel BW, Widmaier C. 1996 Preclinical characterization of the potential of the putative atypical antipsychotic MDL 100,907 as a potent 5-HT2A antagonist with a favorable CNS safety profile. J Pharmacol Exp Ther. 277, 968– 981. 8627580
  35. Khalifa N, Duggan C, Stoffers J, Huband N, Völlm BA, Ferriter M, Lieb K. 2010 Pharmacological interventions for antisocial personality disorder. Cochrane Database Syst Rev. 8: CD007667. PMC4160654 20687091
  36. Kim-Cohen J, Caspi A, Taylor A, Williams B, Newcombe R, Craig IW, Moffitt TE 2006 MAOA, maltreatment, and gene-environment interaction predicting children’s mental health: new evidence and a meta-analysis. Mol Psychiatry 11, 903– 913. 16801953
  37. Latvala A, Kuja-Halkola R, Almqvist C, Larsson H, Lichtenstein P. 2015 A longitudinal study of resting heart rate and violent criminality in more than 700000 men. JAMA Psychiatry 72, 971– 978. 26351735
  38. Leysen JE, Awouters F, Kennis L, Laduron PM, Vandenberk J, Janssen PA 1981 Receptor binding profile of R 41 468, a novel antagonist at 5-HT2 receptors. Life Sci 28, 1015– 1022. 6261070
  39. Li QH, Nakadate K, Tanaka-Nakadate S, Nakatsuka D, Cui Y, Watanabe Y. 2004 Unique expression patterns of 5-HT2A and 5-HT2C receptors in the rat brain during postnatal development: Western blot and immunohistochemical analyses. J Comp Neurol. 469, 128– 140. 14689478
  40. Loney BR, Butler MA, Lima EN, Counts CA, Eckel LA 2006 The relation between salivary cortisol, callous-unemotional traits, and conduct problems in an adolescent non-referred sample. J Child Psychol Psychiatry 47(1), 30– 36. 16405638
  41. Magalhaes AC, Holmes KD, Dale LB, Comps-Agrar L, Lee D, Yadav PN, Drysdale L, Poulter MO, Roth BL, Pin JP, Anisman H, Ferguson SS 2010 CRF receptor 1 regulates anxiety behavior via sensitization of 5-HT2 receptor signaling. Nat Neurosci. 13, 622– 629. 20383137 PMC2862362
  42. Mrug S, Madan A, Windle M. 2016 Emotional desensitization to violence contributes to adolescents’ violent behavior. Journal Abnorm Child Psychol. 44, 75– 86. PMC4539292 25684447
  43. Petersen IT, Bates JE, D’Onofrio BM, Coyne CA, Lansford JE, Dodge KA, Pettit GS, Van Hulle CA 2013 Language ability predicts the development of behavior problems in children. J Abnorm Psychol. 122, 542– 557. 23713507 PMC3760166
  44. Portnoy J, Farrington DP 2015 Resting heart rate and antisocial behavior: An updated systematic review and meta-analysis. Aggress Viol Behav. 22, 33– 45.
  45. Raine A, Venables PH, Williams M. 1990 Relationships between central and autonomic measures of arousal at age 15 years and criminality at age 24 years. Arch Gen Psychiatry 47, 1003– 1007. 2241502
  46. Rebello TJ, Yu Q, Goodfellow NM, Caffrey Cagliostro MK, Teissier A, Morelli E, Demireva EY, Chemiakine A, Rosoklija GB, Dwork AJ, Lambe EK, Ginqrich JA, Ansorge MS 2014 Postnatal day 2 to 11 constitutes a 5-HT-sensitive period impacting adult mPFC function. J Neurosci. 34, 12379–12393. PMC4160773 25209278
  47. Romeo RD, Mueller A, Sisti HM, Ogawa S, McEwen BS, Brake WG 2003 Anxiety and fear behaviors in adult male and female C57BL/6 mice are modulated by maternal separations. Horm Behav. 43, 561– 567. 12799173
  48. Roth BL, Hamblin MW, Ciaranello RD 1991 Developmental regulation of 5-HT2 and 5-HT1c mRNA and receptor levels. Brain Res Dev Brain Res. 58, 51– 58 2015654
  49. Ryabinin AE, Wang YM, Finn DA 1999 Different levels of Fos immunoreactivity after repeated handling and injection stress in two inbred strains of mice. Pharmacol Biochem Behav. 63, 143– 151. 10340535
  50. Sabol SZ, Hu S, Hamer D. 1998 A functional polymorphism in the monoamine oxidase A gene promoter. Hum Genet. 103, 273– 279. 9799080
  51. Scheggi S, Crociani A, De Montis MG, Tagliamonte A, Gambarana C. 2009 Dopamine D1 receptor-dependent modifications in the dopamine and camp-regulated phosphoprotein of Mr 32 kDa phosphorylation pattern in striatal areas of morphine-sensitized rats. Neuroscience 163(2), 627– 639 19559764
  52. Semple BD, Blomgren K, Gimlin K, Ferriero DM, Noble-Haeusslein LJ 2013 Brain development in rodents and humans: Identifying benchmarks of maturation and vulnerability to injury across species. Prog Neurobiol. 106–107, 1– 16. PMC3737272 23583307
  53. Shepherd J, Farrington D, Potts J. 2004 Impact of antisocial lifestyle on health. J Public Health 26, 347– 352. 15598851
  54. Sher L, Siever LJ, Goodman M, McNamara M, Hazlett EA, Koenigsberg HW, New AS 2015 Gender differences in the clinical characteristics and psychiatric comorbidity in patients with antisocial personality disorder. Psychiatry Res. 229, 685– 689. 26296756
  55. Shih JC, Ridd MJ, Chen K, Meehan WP, Kung MP, Seif I, De Maeyer E. 1999 Ketanserin and tetrabenazine abolish aggression in mice lacking monoamine oxidase A. Brain Res. 835, 104– 112. 10415365
  56. von Borries AKL, Volman I, de Bruijn ER, Bulten BH, Verkes RJ, Roelofs K. 2012 Psychopaths lack the automatic avoidance of social threat: relation to instrumental aggression. Psychiatry Res. 200, 761– 766. 22819277
  57. Whitehead CME, Stockdale JE, Razzu G “The Economic and Social Costs of Antisocial Behaviour: A Review”. London School of Economics, 2003.
  58. Wilber AA, Southwood CJ, Wellman CL 2009 Brief neonatal maternal separation alters extinction of conditioned fear and corticolimbic glucocorticoid and NMDA receptor expression in adult rats. Dev Neurobiol. 69, 73– 87. 19025931 PMC7590647
  59. Yadav PN, Kroeze WK, Farrell MS, Roth BL 2011 Antagonist functional selectivity: 5-HT2A serotonin receptor antagonists differentially regulate 5-HT2A receptor protein level in vivo. J Pharmacol Exp Ther. 339, 99– 105. 21737536 PMC3186284
  60. Yu Q, Teixeira CM, Mahadevia D, Huang Y, Balsam D, Mann JJ, Gingrich JA, Ansorge MS 2014 Dopamine and serotonin signaling during two sensitive developmental periods differentially impact adult aggressive and affective behaviors in mice. Mol Psychiatry 19, 688– 698. 24589889 PMC4311886

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Authors
Godar, S. C., Mosher, L. J., Scheggi, S., Devoto, P., Moench, K. M., Strathman, H. J., Jones, C. M., Frau, R., Melis, M., Gambarana, C., Wilkinson, B., DeMontis, M. G., Fowler, S. C., Coba, M. P., Wellman, C. L., Shih, J. C., & Bortolato, M.
Affiliations
  • University of Kansas (US)
  • University of Siena (IT)
  • Indiana University Bloomington (US)
  • University of Southern California (US)
Corresponding author
Bortolato, Marco
ORCID
Venue
Neuropharmacology
Publisher
Elsevier BV
Published
2019-11
Volume
159
Pages
107513
ISSN
0028-3908 (ISSN-L)
DOI
10.1016/j.neuropharm.2019.01.028
PMC
PMC7578912
OpenAlex
W2912808859
Cited by
33
References
8
Citations by year
2026: 2 · 2025: 3 · 2024: 1 · 2023: 7 · 2022: 10 · 2021: 1 · 2020: 5 · 2019: 4
FWCI
2.39
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Neuropharmacology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • UNICA IRIS Institutional Research Information System (University of Cagliari) (submittedVersion)
  • IUScholarWorks Open (Indiana University) (submittedVersion)
  • Use Siena air (University of Siena) (submittedVersion, cc-by-nc-nd)
Funders
  • National Institute of Mental Health (NIH R01 MH104603, NIH R21 HD070611)
  • University of Kansas Strategic Initiatives Grant
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
  • Social Sciences › Psychology › Clinical Psychology › Psychopathy, Forensic Psychiatry, Sexual Offending
  • Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
Keywords
antisocial behavior, gene-environment interaction, 5-HT2A receptor, serotonin, monoamine oxidase A, early life stress, maternal separation, aggression, social dysfunction, resting heart rate, prefrontal cortex, ketanserin, animal models
MeSH terms
Age Factors, Animals, Animals, Newborn, Antisocial Personality Disorder, Dose-Response Relationship, Drug, Female, Locomotion, Male, Maternal Deprivation, Mice, Transgenic, Stress, Psychological, Prefrontal Cortex, Receptor, Serotonin, 5-HT2A, Mice, Rats, Serotonin 5-HT2 Receptor Antagonists, Gene-Environment Interaction

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