Modulators of the Brain Serotonin System in Rats with Genetically Determined Aggression Towards Man or Its Absence

Cover Page

Cite item

Full Text

Open Access Open Access
Restricted Access Access granted
Restricted Access Subscription Access

Abstract

The research of mechanisms regulating aggressive behavior is one of the main problems of neurogenetics. Tame and highly aggressive strains of rats (Rattus norvegicus) obtained through long-term selection are a useful model for studying the mechanisms of genetically determined defensive behavior. The neurotransmitter serotonin (5-HT) controls many forms of behavior, including aggression. The activity of the brain's 5-HT system is regulated not only by its own elements, such as 5-HT1A and 5-HT7 receptors, but also by various modulators. Among their many, trace amines occupy a special place, the main receptor of which, TAAR1, is localized on 5-HT neurons pre- and postsynaptically. Among their diversity, trace amines occupy a special place, the main receptor of which, TAAR1, is localized on pre- and postsynaptic 5-HT neurons. NO is also a perspective modulator, the synthesis of which in the brain is activated predominantly by neuronal NO-synthase (NOS1). In the midbrain, hippocampus, hypothalamus and frontal cortex, NOS1 and TAAR1 expression levels was investigated in comparison with the level of 5-HT, its main metabolite (5-HIAA) and mRNA of 5-HT receptors (Htr1a, Htr7), as well as the expression and activity of TPH2 in tame and aggressive rats. In the midbrain and hypothalamus in the aggressive strain compared to tame rats was detected a decrease in the Htr1a mRNA level, while in the frontal cortex there was an increase in the expression level of the Htr7 gene. However, no interstrain differences in the TAAR1 protein level were detected in the investigated brain structures. Moreover, in highly aggressive rats, an increase in the Taar1 mRNA level was detected in the midbrain and hippocampus, while in the hypothalamus and frontal cortex it was not detected, regardless of the aggressiveness degree. The most significant changes in the 5-HT system of aggressive rats were found in the frontal cortex; an increase in the 5-HT metabolism index was revealed due to an increase in the 5-HIAA level. There was an inverse correlation between the 5-HT metabolism index and NOS1 expression. We hypothesized that the NOS1/NO system is an indicator of the 5-HT system functional activity under conditions of genetically determined aggression.

Full Text

Restricted Access

About the authors

P. D. Pravikova

Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences

Author for correspondence.
Email: PollyPravi@yandex.ru
Russian Federation, Novosibirsk

V. S. Moskalyuk

Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences

Email: PollyPravi@yandex.ru
Russian Federation, Novosibirsk

D. V. Bazovkina

Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences

Email: PollyPravi@yandex.ru
Russian Federation, Novosibirsk

R. V. Kozhemyakina

Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences

Email: PollyPravi@yandex.ru
Russian Federation, Novosibirsk

V. S. Naumenko

Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences

Email: PollyPravi@yandex.ru
Russian Federation, Novosibirsk

References

  1. Farrell G, Tilley N, Tseloni A (2014) Why the crime drop? Crime Justice 43 (1): 421–490.
  2. Belyaev DK (1979) The Wilhelmine E. Key 1978 invitational lecture. Destabilizing selection as a factor in domestication. J Heredity 70(5): 301–308. https://doi.org/ 10.1093/oxfordjournals.jhered.a109263
  3. Popova NK (2006) From genes to aggressive behavior: The role of serotonergic system. Bioessays 28(5): 495–503. https://doi.org/ 10.1002/bies.20412
  4. Olivier B (2004) Serotonin and aggression. Ann NY Acad Sci 1036: 382–392. https://doi.org/10.1196/annals.1330.022
  5. McCorvy JD, Roth BL (2015) Structure and function of serotonin G protein-coupled receptors. Pharmacol and Therap 150: 129–142. https://doi.org/10.1016/j.pharmthera.2015.01.009
  6. Courtney NA, Ford CP (2016) Mechanisms of 5-HT1A receptor-mediated transmission in dorsal raphe serotonin neurons. J Physiol 594(4): 953–965. https://doi.org/10.1113/JP271716
  7. Hajós M, Hajós-Korcsok E, Sharp T (1999) Role of the medial prefrontal cortex in 5-HT1A receptor-induced inhibition of 5-HT neuronal activity in the rat. Br J Pharmacol 126(8): 1741–1750. https://doi.org/1038/sj.bjp.0702510
  8. Albert PR, Lemonde S (2004) 5-HT1A receptors, gene repression, and depression: Guilt by association. Neuroscientist 10(6): 575–593. https://doi.org/10.1177/1073858404267382
  9. De Boer SF, Lesourd M, Mocaer E, Koolhaas JM (1999) Selective antiaggressive effects of alnespirone in resident-intruder test are mediated via 5-hydroxytryptamine1A receptors: A comparative pharmacological study with 8-hydroxy-2-dipropylaminotetralin, ipsapirone, buspirone, eltoprazine, and WAY-100635. J Pharmacol Exp Ther 288(3): 1125–1133.
  10. Pruus K, Skrebuhhova-Malmros T, Rudissaar R, Matto V, Allikmets L (2000) 5-HT1A receptor agonists buspirone and gepirone attenuate apomorphine-induced aggressive behaviour in adult male Wistar rats. J Physiol Pharmacol 51: 833–846.
  11. Popova NK, Naumenko VS, Plyusnina IZ, Kulikov AV (2005) Reduction in 5-HT1A receptor density, 5-HT1A mRNA expression, and functional correlates for 5-HT1A receptors in genetically defined aggressive rats. J Neurosci Res 80(2): 286–292. https://doi.org/10.1002/jnr.20456
  12. Alcázar-Córcoles MA, Verdejo-García A, Bouso-Saiz JC, Bezos-Saldaña L (2010) Neuropsicología de la agresión impulsiva [Neuropsychology of impulsive aggression]. Rev Neurol 50(5): 291–299.https://doi.org/10.33588/rn.5005.2009316
  13. Ciranna L, Catania MV (2014) 5-HT7 receptors as modulators of neuronal excitability, synaptic transmission and plasticity: physiological role and possible implications in autism spectrum disorders. Front Cell Neurosci 8: 250. https://doi.org/10.3389/fncel.2014.00250
  14. Renner U, Zeug A, Woehler A, Niebert M, Dityatev A, Dityateva G, Gorinski N, Guseva D, Abdel-Galil D, Fröhlich M, Döring F, Wischmeyer E, Richter DW, Neher E, Ponimaskin EG (2012) Heterodimerization of serotonin receptors 5-HT1A and 5-HT7 differentially regulates receptor signalling and trafficking. J Cell Sci 125: 2486–2499. https://doi.org/10.1242/jcs.101337
  15. Popova NK, Kulikov AV (2010) Targeting tryptophan hydroxylase 2 in affective disorder. Expert Opin Ther Targets 14(11): 1259–1271. https://doi.org/10.1517/14728222.2010.524208
  16. Popova NK, Naumenko VS, Cybko AS, Bazovkina DV (2010) Receptor-genes cross-talk: effect of chronic 5-HT(1A) agonist 8-hydroxy-2-(di-n-propylamino) tetralin treatment on the expression of key genes in brain serotonin system and on behavior. Neuroscience 169(1): 229–235. https://doi.org/10.1016/j.neuroscience.2010.04.044
  17. Kulikov AV, Popova NK (1996) Association between intermale aggression and genetically defined tryptophan hydroxylase activity in the brain. Aggr Behav 22: 111–117.
  18. Kulikov AV, Osipova DV, Naumenko VS, Popova NK (2005) Association between Tph2 gene polymorphism, brain tryptophan hydroxylase activity and aggressiveness in mouse strains. Genes Brain Behav 4(8): 482–485. https://doi.org/10.1111/j.1601-183X.2005.00145.x
  19. Smith JC, Whitton PS (2000) Nitric oxide modulates N-methyl-D-aspartate-evoked serotonin release in the raphe nuclei and frontal cortex of the freely moving rat. Neurosci Lett 291(1): 5–8. https://doi.org/10.1016/s0304-3940(00)01378-1
  20. Chiavegatto S, Dawson VL, Mamounas LA, Koliatsos VE, Dawson TM, Nelson RJ (2001) Brain serotonin dysfunction accounts for aggression in male mice lacking neuronal nitric oxide synthase. Proc Natl Acad Sci U S A 98(3): 1277–1281. https://doi.org/10.1073/pnas.98.3.1277
  21. Chiavegatto S, Nelson RJ (2003) Interaction of nitric oxide and serotonin in aggressive behavior. Horm Behav 44(3): 233–241. https://doi.org/10.1016/j.yhbeh.2003.02.002
  22. Gainetdinov RR, Hoener MC, Berry MD (2018) Trace Amines and Their Receptors. Pharmacol Rev 70(3): 549–620. https://doi.org/10.1124/pr.117.015305
  23. Berry MD (2004) Mammalian central nervous system trace amines. Pharmacologic amphetamines, physiologic neuromodulators. J Neurochem 90(2): 257–271. https://doi.org/10.1111/j.1471-4159.2004.02501.x
  24. Lindemann L, Meyer CA, Jeanneau K, Bradaia A, Ozmen L, Bluethmann H, Bettler B, Wettstein JG, Borroni E, Moreau JL, Hoener MC (2008) Trace amine-associated receptor 1 modulates dopaminergic activity. J Pharmacol Exp Ther 324(3): 948–956. https://doi.org/10.1124/jpet.107.132647
  25. Zhukov IS, Karpova IV, Krotova NA, Tissen IY, Demin KA, Shabanov PD, Budygin EA, Kalueff AV, Gainetdinov RR (2022) Enhanced Aggression, Reduced Self-Grooming Behavior and Altered 5-HT Regulation in the Frontal Cortex in Mice Lacking Trace Amine-Associated Receptor 1 (TAAR1). Int J Mol Sci 23(22): 14066. https://doi.org/10.3390/ijms232214066
  26. Naumenko EV, Popova NK, Nikulina EM, Dygalo NN, Shishkina GT, Borodin PM, Markel AL (1989) Behavior, adrenocortical activity, and brain monoamines in Norway rats selected for reduced aggressiveness towards man. Pharmacol Biochem Behav 33(1): 85–91. https://doi.org/10.1016/0091-3057(89)90434-6
  27. Ilchibaeva TV, Tsybko AS, Kondaurova EM, Kovetskaya AI, Kozhemyakina RV, Naumenko VS (2020) Expression Patterns of Serotonin Receptors 1A and 7 in the Brain of Rats with Genetically Determined Fear-Induced Aggressive Behavior or the Lack of Aggression. Neurochem J 14: 180–186. https://doi.org/10.1134/S1819712420020051
  28. Plyusnina I, Oskina I (1997) Behavioral and adrenocortical responses to open-field test in rats selected for reduced aggressiveness toward humans. Physiol Behav 61(3): 381–385. https://doi.org/10.1016/s0031-9384(96)00445-3
  29. Moskaliuk VS, Kozhemyakina RV, Bazovkina DV, Terenina E, Khomenko TM, Volcho KP, Salakhutdinov NF, Kulikov AV, Naumenko VS, Kulikova EA (2022) On an association between fear-induced aggression and striatal-enriched protein tyrosine phosphatase (STEP) in the brain of Norway rats. Biomed Pharmacother 147: 112667. https://doi.org/10.1016/j.biopha.2022.112667
  30. Kulikov AV, Naumenko VS, Voronova IP, Tikhonova MA, Popova NK (2005) Quantitative RT-PCR assay of 5-HT1A and 5-HT2A serotonin receptor mRNAs using genomic DNA as an external standard. J Neurosci Methods 141(1): 97–101. https://doi.org/10.1016/j.jneumeth.2004.06.005
  31. Naumenko VS, Kulikov AV (2006) Quantitative assay of 5-HT(1A) serotonin receptor gene expression in the brain. Mol Biol (Mosk) 40(1): 37–44. https://doi.org/10.1134/s0026893306010079
  32. Naumenko VS, Osipova DV, Kostina EV, Kulikov AV (2008) Utilization of a two-standard system in real-time PCR for quantification of gene expression in the brain. J Neurosci Methods 170: 197–203. https://doi.org/10.1016/j.jneumeth.2008.01.008
  33. Bazovkina D, Naumenko V, Bazhenova E, Kondaurova E (2021) Effect of Central Administration of Brain-Derived Neurotrophic Factor (BDNF) on Behavior and Brain Monoamine Metabolism in New Recombinant Mouse Lines Differing by 5-HT1A Receptor Functionality. Int J Mol Sci 22(21): 11987. https://doi.org/10.3390/ijms222111987
  34. Komleva PD, Alhalabi G, Izyurov AE, Khotskin NV, Kulikov AV (2023) Effects of the Combination of the C1473G Mutation in the Tph2 Gene and Lethal Yellow Mutations in the Raly-Agouti Locus on Behavior, Brain 5-HT and Melanocortin Systems in Mice. Biomolecules 13(6): 963. https://doi.org/10.3390/biom13060963
  35. Van Donkelaar MMJ, Hoogman M, Shumskaya E, Buitelaar JK, Bralten J, Franke B (2020) Monoamine and neuroendocrine gene-sets associate with frustration-based aggression in a gender-specific manner. Eur Neuropsychopharmacol 30: 75–86. https://doi.org/10.1016/j.euroneuro.2017.11.016
  36. Popova NK, Tsybko AS, Naumenko VS (2022) The Implication of 5-HT Receptor Family Members in Aggression, Depression and Suicide: Similarity and Difference. Int J Mol Sci 23(15): 8814. https://doi.org/10.3390/ijms23158814
  37. Popova NK, Kulikov AV, Nikulina EM, Kozlachkova EY, Maslova GB (1991) Serotonin metabolism and serotonergic receptors in Norway rats selected for low aggressiveness to man. Aggr Behav 17: 207–213.
  38. Ara J, Przedborski S, Naini AB, Jackson-Lewis V, Trifiletti RR, Horwitz J, Ischiropoulos H (1998) Inactivation of tyrosine hydroxylase by nitration following exposure to peroxynitrite and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Proc Natl Acad Sci U S A 95(13): 7659–7663. https://doi.org/10.1073/pnas.95.13.7659
  39. Ramaekers VT, Sequeira JM, DiDuca M, Vrancken G, Thomas A, Philippe C, Peters M, Jadot A, Quadros EV (2019) Improving Outcome in Infantile Autism with Folate Receptor Autoimmunity and Nutritional Derangements: A Self-Controlled Trial. Autism Res Treat 2019: 7486431. https://doi.org/10.1155/2019/7486431
  40. Gulevich RG, Shikhevich SG, Konoshenko MY, Kozhemyakina RV, Herbeck YE, Prasolova LA, Oskina IN, Plyusnina IZ (2015) The influence of social environment in early life on the behavior, stress response, and reproductive system of adult male Norway rats selected for different attitudes to humans. Physiol Behav 144: 116–123. https://doi.org/10.1016/j.physbeh.2015.03.018
  41. Zhou QG, Zhu LJ, Chen C, Wu HY, Luo CX, Chang L, Zhu DY (2011) Hippocampal neuronal nitric oxide synthase mediates the stress-related depressive behaviors of glucocorticoids by downregulating glucocorticoid receptor. J Neurosci 31(21): 7579–7590. https://doi.org/10.1523/JNEUROSCI.0004-11.2011
  42. Zhou QG, Zhu XH, Nemes AD, Zhu DY (2018) Neuronal nitric oxide synthase and affective disorders. IBRO Rep 5: 116–132. https://doi.org/10.1016/j.ibror.2018.11.004
  43. Zhang J, Huang XY, Ye ML, Luo CX, Wu HY, Hu Y, Zhou QG, Wu DL, Zhu LJ, Zhu DY (2010) Neuronal nitric oxide synthase alteration accounts for the role of 5-HT1A receptor in modulating anxiety-related behaviors. J Neurosci 30(7): 2433–2441. https://doi.org/10.1523/JNEUROSCI.5880-09.2010
  44. Tateno A, Jorge RE, Robinson RG (2003) Clinical correlates of aggressive behavior after traumatic brain injury. J Neuropsychiatry Clin Neurosci 15(2): 155–160. https://doi.org/10.1176/jnp.15.2.155
  45. Takahashi A, Nagayasu K, Nishitani N, Kaneko S, Koide T (2014) Control of intermale aggression by medial prefrontal cortex activation in the mouse. PloS One 9(4): e94657. https://doi.org/10.1371/journal.pone.0094657
  46. Van Erp AM, Miczek KA (2000) Aggressive behavior, increased accumbal dopamine, and decreased cortical serotonin in rats. J Neurosci 20(24): 9320–9325. https://doi.org/10.1523/JNEUROSCI.20-24-09320.2000
  47. Caramaschi D, de Boer SF, de Vries H, Koolhaas JM (2008) Development of violence in mice through repeated victory along with changes in prefrontal cortex neurochemistry. Behav Brain Res 189(2): 263–272. https://doi.org/10.1016/j.bbr.2008.01.003
  48. Centenaro LA, Vieira K, Zimmermann N, Miczek KA, Lucion AB, de Almeida RM (2008) Social instigation and aggressive behavior in mice: Role of 5-HT1A and 5-HT1B receptors in the prefrontal cortex. Psychopharmacology (Berl) 201(2): 237–248. https://doi.org/10.1007/s00213-008-1269-6
  49. Carreño Gutiérrez H, O'Leary A, Freudenberg F, Fedele G, Wilkinson R, Markham E, van Eeden F, Reif A., Norton WHJ (2020) Nitric oxide interacts with monoamine oxidase to modulate aggression and anxiety-like behaviour. Eur Neuropsychopharmacol 30: 30–43. https://doi.org/10.1016/j.euroneuro.2017.09.004
  50. Arige V, Agarwal A, Khan AA, Kalyani A, Natarajan B, Gupta V, Reddy SS, Barthwal MK, Mahapatra NR (2019) Regulation of Monoamine Oxidase B Gene Expression: Key Roles for Transcription Factors Sp1, Egr1 and CREB, and microRNAs miR-300 and miR-1224. J Mol Biol 431(6): 1127–1147. https://doi.org/10.1016/j.jmb.2019.01.042
  51. Zhu XJ, Hua Y, Jiang J, Zhou QG, Luo CX, Han X, Lu YM, Zhu DY (2006) Neuronal nitric oxide synthase-derived nitric oxide inhibits neurogenesis in the adult dentate gyrus by down-regulating cyclic AMP response element binding protein phosphorylation. Neuroscience 141(2): 827–836. https://doi.org/10.1016/j.neuroscience.2006.04.032
  52. Ilchibaeva TV, Tsybko AS, Kozhemyakina RV, Kondaurova EM, Popova NK, Naumenko VS (2018) Genetically defined fear-induced aggression: Focus on BDNF and its receptors. Behav Brain Res 343: 102–110. https://doi.org/10.1016/j.bbr.2018.01.034
  53. Xie Z, Westmoreland SV, Bahn ME, Chen GL, Yang H, Vallender EJ, Yao WD, Madras BK, Miller GM (2007) Rhesus monkey trace amine-associated receptor 1 signaling: Enhancement by monoamine transporters and attenuation by the D2 autoreceptor in vitro. J Pharmacol Exp Ther 321(1): 116–127. https://doi.org/10.1124/jpet.106.116863
  54. Miller GM (2011) The emerging role of trace amine-associated receptor 1 in the functional regulation of monoamine transporters and dopaminergic activity. J Neurochem 116(2): 164–176. https://doi.org/10.1111/j.1471-4159.2010.07109.x
  55. Jassen AK, Brown JM, Panas HN, Miller GM, Xiao D, Madra BK (2005) Variants of the primate vesicular monoamine transporter-2. Brain Res Mol Brain Res 139(2): 251–257. https://doi.org/10.1016/j.molbrainres.2005.05.028.
  56. Barak LS, Salahpour A, Zhang X, Masri B, Sotnikova TD, Ramsey AJ, Violin JD, Lefkowitz RJ, Caron MG, Gainetdinov RR (2008) Pharmacological characterization of membrane-expressed human trace amine-associated receptor 1 (TAAR1) by a bioluminescence resonance energy transfer cAMP biosensor. Mol Pharmacol 74(3): 585–594. https://doi.org/10.1124/mol.108.048884
  57. Naumenko VS, Popova NK, Lacivita E, Leopoldo M, Ponimaskin EG (2014) Interplay between serotonin 5-HT1A and 5-HT7 receptors in depressive disorders. CNS Neurosci Ther 20(7): 582–590.https://doi.org/10.1111/cns.12247
  58. Bräunig J, Dinter J, Höfig CS, Paisdzior S, Szczepek M, Scheerer P, Rosowski M, Mittag J, Kleinau G, Biebermann H (2018) The Trace Amine-Associated Receptor 1 Agonist 3-Iodothyronamine Induces Biased Signaling at the Serotonin 1b Receptor. Front Pharmacol 9: 222. https://doi.org/10.3389/fphar.2018.00222

Supplementary files

Supplementary Files
Action
1. JATS XML
Download
2. Fig. 1. Levels of Tph2 gene mRNA (a), TPH2 protein (b), and TPH2 activity (c) in brain structures in tame and aggressive rats. Significance of differences: *p < 0.05; **p < 0.01 - comparison of tame and aggressive rats. Here and in Figures 2, 4, 5: gene expression is represented as the number of cDNA copies of the corresponding gene per 100 cDNA copies of Polr2a, n = 8. Here and in Figs. 2, 5: protein levels were estimated in relative chemiluminescence units and normalised to GAPDH protein levels. Immunoblotting membrane designation: I, III, V, VII, manual rats; II, IV, VI, VIII, aggressive rats.

Download (204KB)
Indexing metadata
3. Fig. 2. Nos1 gene (a) and NOS1 protein (b) mRNA levels in brain structures in tame and aggressive rats. Significance of differences: *p < 0.05; **p < 0.01 - comparison of tame and aggressive rats. Immunoblotting membrane designation: I, III, V, VII - manual rats; II, IV, VI, VIII - aggressive rats.

Download (155KB)
Indexing metadata
4. Fig. 3. Levels of 5-HT (a), 5-HIUC (b) and 5-HIUC/5-HT ratio (c) in brain structures in tame and aggressive rats. Significance of differences: *p < 0.05; **p < 0.01 - comparison of tame and aggressive rats.

Download (206KB)
Indexing metadata
5. Fig. 4. The mRNA levels of Htr1a (a), Htr7 (b) genes in brain structures in tame and aggressive rats. Significance of differences: *p < 0.05; **p < 0.01; ***p < 0.001 - comparison of tame and aggressive rats.

Download (152KB)
Indexing metadata
6. Fig. 5. The mRNA levels of Taar1 gene (a) and TAAR1(b) protein in brain structures in tame and aggressive rats. Significance of differences: *p < 0.05; **p < 0.01 - comparison of tame and aggressive rats. Immunoblotting membrane designation: I, III, V, VII - manual rats; II, IV, VI, VIII - aggressive rats.

Download (301KB)
Indexing metadata
7. Fig. 6. Correlation between NOS1 protein levels and 5-HIUC levels (a), and 5-HIUC/5-HT ratio (b) in frontal cortex in tame and aggressive rats. The equation is plotted and the r-Pearson coefficient (r) is indicated.

Download (141KB)
Indexing metadata

Copyright (c) 2024 Russian Academy of Sciences