5-HT1А рецептор: роль в регуляции различных видов поведения

Нейромедиатор мозга серотонин регулирует различные формы как нормального, так и патологического поведения, действуя на 14 типов серотониновых (5-НТ) рецепторов. Все 5-НТ рецепторы, за исключением 5-НТ3, представляющего ионный канал (ионотропный рецептор), принадлежат к суперсемейству метаботропных рецепторов, сопряженных с G- белками. Каждый из типов и подтипов рецепторов характеризуется уникальным контролирующим геном, спектром сродства к разнообразным агонистам и антагонистам серотонина, специфическим распределением в мозге и рядом регулируемых функций. Среди этого многообразия 5-НТ рецепторов особый интерес вызывает эволюционно наиболее древний 5-НТ1А рецептор, играющий ключевую роль в ауторегуляции серотониновой системы мозга. Эта роль 5-НТ1А рецепторов обусловлена особенностями их локализации (пост- или пресинаптически на 5-НТ нейронах), в зависимости от которой они могут оказывать прямо противоположное действие на функциональную активность 5-НТ системы. Обзор посвящен данным литературы и результатам, полученным авторами, о факторах, регулирующих экспрессию и функциональную активность 5-НТ1А рецепторов, и их влиянии на поведение. Описана структура гена 5-НТ1А рецептора, приведены новейшие данные о посттрансляционной регуляции активности 5-НТ1А рецепторов и взаимодействии 5-НТ рецепторов. Особое внимание уделено роли гетеромеризации 5-НТ1А рецептора при его взаимодействии с 5-НТ7 серотониновым рецептором с образованием гетеродимера и функциональной инактивации 5-НТ1А рецептора. Показано участие 5-НТ1А рецепторов в регуляции агрессивного поведения, каталепсии, тревожности, депрессии и уникальной природной адаптации – зимней спячки. Особое внимание уделено участию этих рецепторов в регуляции 1) вызванной страхом защитно-оборонительной агрессии по отношению к человеку – основы процесса доместикации; 2) межсамцовой (intermale) агрессии по отношению к сопернику (конкуренту), приводящей к установлению отношения доминант – субординант в сообществе животных и лежащей в основе асоциального поведения человека; 3) механизмов депрессии и действия клинически эффективных антидепрессантов группы ингибиторов обратного захвата серотонина. Выдвинута гипотеза о роли 5-НТ1А / 5-НТ7 гетеродимеризации в механизме действия антидепрессантов.

1. Барыкина Н.Н., Чепкасов И.Л., Алехина Т.А., Колпаков В.Г. Селекция крыс Вистар на предрасположенность к каталепсии. Генетика. 1983;19:2014-2021.

2. Беляев Д.К., Бородин П.М. Влияние стресса на наследственную изменчивость и его роль в эволюции. Ленинград: ЛГУ, 1982:35-59.

3. Куликов А.В., Базовкина Д.В. Проверка гипотез о сцеплении в гибридологическом анализе альтернативных поведенческих признаков с неполной пенетрантностью. Генетика. 2003;39(8): 1066-1072.

4. Куликов А.В., Базовкина Д.В., Муазан М., Мормед П. Картирование гена предрасположенности к каталепсии у мышей с помощью микросателлитных маркеров. Докл. Акад. наук. 2003; 393(1):134-137.

5. Науменко В.С., Иванова Е.А., Куликов А.В., Попова Н.К. Влияние генетического нокаута моноаминоксидазы А на экспрессию 5-НТ1А рецепторов. Докл. РАН. 2005;402(2):282-285.

6. Науменко В.С., Кондаурова Е.М., Куликов А.В., Попова Н.К. Влияние селекции на высокую предрасположенность к каталепсии, на функциональную активность 5-НТ1А-рецепторов и экспрессию кодирующего их гена. Докл. РАН. 2006;409:133-135.

7. Никулина Э.М., Бородин П.М., Попова Н.К. Изменение некоторых форм агрессивного поведения и содержания моноаминов в мозге в процессе селекции на приручение диких крыс. Журн. высш. нервн. деят-сти им. И.П. Павлова. 1985a;35:703-709.

8. Никулина Э.М., Трапезов О.В., Попова Н.К. Содержание моноаминов в головном мозге норок, различающихся по реакции на человека. Журн. высш. нервн. деят-сти им. И.П. Павлова. 1985б; 35:1142-1145.

9. Попова Н.К. Серотонин мозга в генетически детерминированном защитном поведении. Журн. высш. нервн. деят-сти им. И.П. Пав-лова. 1997;47:93-97.

10. Попова Н.К. Роль серотонина мозга в экспрессии генетически детерминированного защитно-оборонительного поведения. Генетика. 2004;40(6):770-778.

11. Попова Н.К., Науменко В.С. Полиморфизм серотониновых 5-НТ рецепторов как основа полифункциональности серотонина. Рос. физиол. журн. им. И.М. Сеченова. 2010;96(8):778-786.

12. Попова Н.К., Науменко Е.В., Колпаков В.Г. Серотонин и поведение. Новосибирск, Наука, 1978.

13. Трут Л.Н. Некоторые новые данные по селекции серебристо-черных лисиц (Vulpes fulvus Desm.) по свойствам их оборонительного поведения. Генетика поведения. Ленинград: Наука, 1969.

14. Трут Л.Н. Очерки по генетике поведения. Новосибирск: Наука, 1978.

15. Abe M., Nakai H., Tabata R., Saito K., Egawa M. Effect of 5-[3-[((2S)-1,4-benzodioxan-2-ylmethyl)amino]propoxy]-1,3-benzodioxole HCl (MKC-242), a novel 5-HT1A-receptor agonist, on aggressive behavior and marble burying behavior in mice. Jpn. J. Pharmacol. 1998;76(3):297-304.

16. Aghajanian G. Electrophysiology of serotonin receptor subtypes and signal transduction pathways. Psychopharmacology: The Fourth Generation of Progress. Eds F.R. Bloom, D.J. Kupfer. N.Y.: Raven Press, 1995;1451-1459.

17. Albert P.R., Lemonde S. 5-HT1A receptors, gene repression, and depression: guilt by association. Neuroscientist. 2004;10(6):575-593.

18. Albert P.R., Sajedi N., Lemonde S., Ghahremani M.H. Constitutive G(i2)-dependent activation of adenylyl cyclase type II by the 5-HT1A receptor. Inhibition by anxiolytic partial agonists. J. Biol. Chem. 1999;274(50):35469-35474.

19. Albert P.R., Zhou Q.Y., Van Tol H.H., Bunzow J.R., Civelli O. Cloning, functional expression, and mRNA tissue distribution of the rat 5-hydroxytryptamine1A receptor gene. J. Biol. Chem. 1990;265(10): 5825-5832.

20. Amir S., Brown Z.W., Amit Z., Ornstein K. Body pinch induces long lasting cataleptic like immobility in mice: behavioral characterization and the effect of naloxone. Life Sci. 1981;28(10):1189-1194.

21. Barnes N.M., Sharp T. A review of central 5-HT receptors and their function. Neuropharmacology. 1999;38(8):1083-1152.

22. Belyaev D.K. The Wilhelmine E. Key 1978 invitational lecture. Destabilizing selection as a factor in domestication. J. Hered. 1979;70(5): 301-308.

23. Blanchard D.C., Herbert M., Blanchard R.J. Continuity versus (Political) Correctness: Animal Models and Human Aggression. Animal Models of Human Emotion and Cognition. (Eds M. Haug, R.E. Whalen, D.C. Washington). American Psychological Association, 1999;297-316.

24. Blier P., Ward N.M. Is there a role for 5-HT1A agonists in the treatment of depression? Biol. Psychiatry. 2003;53(3):193-203.

25. Boutrel B., Monaca C., Hen R., Hamon M., Adrien J. Involvement of 5-HT1A receptors in homeostatic and stress-induced adaptive regulations of paradoxical sleep: studies in 5-HT1A knock-out mice. J. Neurosci. 2002;22(11):4686-4692.

26. Broekkamp C.L., Oosterloo S.K., Berendsen H.H., van Delft A.M. Effect of metergoline, fenfluramine, and 8-OHDPAT on catalepsy induced by haloperidol or morphine. Naunyn Schmiedebergs Arch. Pharmacol. 1988;338(2):191-195.

27. Brunner H.G., Nelen M., Breakefield X.O., Ropers H.H., van Oost B.A. Abnormal behavior associated with a point mutation in the structural gene for monoamine oxidase A. Science. 1993;262(5133): 578-580.

28. Cases O., Seif I., Grimsby J., Gaspar P., Chen K., Pournin S., Muller U., Aguet M., Babinet C., Shih J.C. De Maeyer E.. Aggressive behavior and altered amounts of brain serotonin and norepinephrine in mice lacking MAOA. Science. 1995;268(5218):1763-1766.

29. Charest A., Wainer B.H., Albert P.R. Cloning and differentiation-induced expression of a murine serotonin1A receptor in a septal cell line. J. Neurosci. 1993;13(12):5164-5171.

30. Clotfelter E.D., O’Hare E.P., McNitt M.M., Carpenter R.E., Summers C.H. Serotonin decreases aggression via 5-HT1A receptors in the fighting fish Betta splendens. Pharmacol. Biochem. Behav. 2007;87(2):222-231.

31. Creti P., Capasso A., Grasso M., Parisi E. Identification of a 5-HT1A receptor positively coupled to planarian adenylate cyclase. Cell Biol. Int. Rep. 1992;16(5):427-432.

32. D’Eath R.B., Ormandy E., Lawrence A.B., Sumner B.E., Meddle S.L. Resident-intruder trait aggression is associated with differences in lysine vasopressin and serotonin receptor 1A (5-HT1A) mRNA expression in the brain of pre-pubertal female domestic pigs (Sus scrofa). J. Neuroendocrinol. 2005;17(10):679-686.

33. Dacks A.M., Dacks J.B., Christensen T.A., Nighorn A.J. The cloning of one putative octopamine receptor and two putative serotonin receptors from the tobacco hawkmoth, Manduca sexta. Insect Biochem. Mol. Biol. 2006;36(9):741-747.

34. De Boer S.F., Lesourd M., Mocaer E., Koolhaas J.M. 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. 1999;288(3):1125-1133.

35. De Boer S.F., Lesourd M., Mocaer E., Koolhaas J.M. Somatodendritic 5-HT(1A) autoreceptors mediate the anti-aggressive actions of 5-HT(1A) receptor agonists in rats: an ethopharmacological study with S-15535, alnespirone, and WAY-100635. Neuropsychopharmacology. 2000;23(1):20-33.

36. De Vry J. 5-HT1A receptor agonists: recent developments and controversial issues. Psychopharmacology (Berl.). 1995;121(1):1-26.

37. Deng D.R., Djalali S., Holtje M., Grosse G., Stroh T., Voigt I., Kusserow H., Theuring F., Ahnert-Hilger G., Hortnagl H. Embryonic and postnatal development of the serotonergic raphe system and its target regions in 5-HT1A receptor deletion or overexpressing mouse mutants. Neuroscience. 2007;147(2):388-402.

38. Dixon A.K. Ethological strategies for defence in animals and humans: their role in some psychiatric disorders. Br. J. Med. Psychol. 1998;71(Pt 4):417-445.

39. Drevets W.C., Thase M.E., Moses-Kolko E.L., Price J., Frank E., Kupfer D.J., Mathis C. Serotonin-1A receptor imaging in recurrent depression: replication and literature review. Nucl. Med. Biol. 2007;34(7):865-877.

40. Edwards D.H., Kravitz E.A. Serotonin, social status and aggression. Curr. Opin. Neurobiol. 1997;7(6):812-819.

41. Estrada-Camarena E., Fernandez-Guasti A., Lopez-Rubalcava C. Participation of the 5-HT1A receptor in the antidepressant-like effect of estrogens in the forced swimming test. Neuropsychopharmacology. 2006;31(2):247-255.

42. Evrard A., Malagie I., Laporte A.M., Boni C., Hanoun N., Trillat A.C., Seif I., De Maeyer E., Gardier A., Hamon M., Adrien J. Altered regulation of the 5-HT system in the brain of MAO-A knock-out mice. Eur. J. Neurosci. 2002;15(5):841-851.

43. Fargin A., Raymond J.R., Lohse M.J., Kobilka B.K., Caron M.G., Lefkowitz R.J. The genomic clone G-21 which resembles a betaadrenergic receptor sequence encodes the 5-HT1A receptor. Nature. 1988;335(6188):358-360.

44. Fricchione G.L. Neuroleptic catatonia and its relationship to psychogenic catatonia. Biol. Psychiatry. 1985;20(3):304-313.

45. Fuller R.W. Role of serotonin in therapy of depression and related disorders. J. Clin. Psychiatry. 1991;52(Suppl):52-57.

46. Gerhardt C.C., van Heerikhuizen H. Functional characteristics of heterologously expressed 5-HT receptors. Eur. J. Pharmacol. 1997; 334(1):1-23.

47. Goodwin G.M., De Souza R.J., Green A.R., Heal D.J. The pharmacology of the behavioural and hypothermic responses of rats to 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). Psychopharmacology (Berl.). 1987;91(4):506-511.

48. Haleem D.J., Shireen E., Haleem M.A. Somatodendritic and postsynaptic serotonin-1A receptors in the attenuation of haloperidolinduced catalepsy. Progr. Neuropsychopharmacol. Biol. Psychiatry. 2004;28(8):1323-1329.

49. Hammer R.P., Jr., Hori K.M., Blanchard R.J., Blanchard D.C. Domestication alters 5-HT1A receptor binding in rat brain. Pharmacol. Biochem. Behav. 1992;42(1):25-28.

50. Handley S.L. 5-Hydroxytryptamine pathways in anxiety and its treatment. Pharmacol. Ther. 1995;66(1):103-148.

51. Hansenne M., Pitchot W., Pinto E., Reggers J., Scantamburlo G., Fuchs S., Pirard S., Ansseau M. 5-HT1A dysfunction in borderline personality disorder. Psychol. Med. 2002;32(5):935-941.

52. Hassanain M., Bhatt S., Siegel A. Differential modulation of feline defensive rage behavior in the medial hypothalamus by 5-HT1A and 5-HT2 receptors. Brain Res. 2003;981(1-2):201-209.

53. Heisler L.K., Chu H.M., Brennan T.J., Danao J.A., Bajwa P., Parsons L.H., Tecott L.H. Elevated anxiety and antidepressant-like responses in serotonin 5-HT1A receptor mutant mice. Proc. Natl Acad. Sci. USA. 1998;95(25):15049-15054.

54. Hill R.H., Svensson E., Dewael Y., Grillner S. 5-HT inhibits N-type but not L-type Ca(2+) channels via 5-HT1A receptors in lamprey spinal neurons. Eur. J. Neurosci. 2003;18(11):2919-2924.

55. Hirvonen J., Karlsson H., Kajander J., Lepola A., Markkula J., Rasi-Hakala H., Nagren K., Salminen J.K., Hietala J. Decreased brain serotonin 5-HT1A receptor availability in medication-naive patients with major depressive disorder: an in-vivo imaging study using PET and [carbonyl-11C]WAY-100635. Int. J. Neuropsychopharmacology. 2008;11(4):465-476.

56. Hjorth S. Hypothermia in the rat induced by the potent serotoninergic agent 8-OH-DPAT. J. Neural. Transm. 1985;61(1-2):131-135.

57. Hsiung S.C., Adlersberg M., Arango V., Mann J.J., Tamir H., Liu K.P. Attenuated 5-HT1A receptor signaling in brains of suicide victims: involvement of adenylyl cyclase, phosphatidylinositol 3-kinase, Akt and mitogen-activated protein kinase. J. Neurochem. 2003;87(1): 182-194.

58. Humphrey P.P., Barnard E.A. International Union of Pharmacology. XIX. The IUPHAR receptor code: a proposal for an alphanumeric classification system. Pharmacol. Rev. 1998;50(2):271-277.

59. Humphrey P.P., Hartig P., Hoyer D. A proposed new nomenclature for 5-HT receptors. Trends Pharmacol. Sci. 1993;14(6):233-236.

60. Kaufman J., Sullivan G.M., Yang J., Ogden R.T., Miller J.M., Oquendo M.A., Mann J.J., Parsey R.V., DeLorenzo C. Quantification of the serotonin 1A receptor using PET: identification of a potential biomarker of major depression in males. Neuropsychopharmacology. 2015;40(7):1692-1699.

61. Kobe F., Guseva D., Jensen T.P., Wirth A., Renner U., Hess D., Muller M., Medrihan L., Zhang W., Zhang M., Braun K., Westerholz S., Herzog A., Radyushkin K., El-Kordi A., Ehrenreich H., Richter D.W., Rusakov D.A., Ponimaskin E. 5-HT7R/G12 signaling regulates neuronal morphology and function in an age-dependent manner. J. Neurosci. 2012;32(9):2915-2930.

62. Kobilka B.K., Frielle T., Collins S., Yang-Feng T., Kobilka T.S., Francke U., Lefkowitz R.J., Caron M.G. An intronless gene encoding a potential member of the family of receptors coupled to guanine nucleotide regulatory proteins. Nature. 1987;329(6134):75-79.

63. Kondaurova E.M., Bazovkina D.V., Kulikov A.V., Popova N.K. Selective breeding for catalepsy changes the distribution of microsatellite D13Mit76 alleles linked to the 5-HT serotonin receptor gene in mice. Genes Brain Behav. 2006;5(8):596-601.

64. Korte S.M., Meijer O.C., de Kloet E.R., Buwalda B., Keijser J., Sluyter F., van Oortmerssen G., Bohus B. Enhanced 5-HT1A receptor expression in forebrain regions of aggressive house mice. Brain Res. 1996;736(1-2):338-343.

65. Kulikov A.V., Bazovkina D.V., Moisan M-P., Mormede P. The mapping of the gene of susceptibility to catalepsy in mice using polymorphic microsatellite markers. Dokl. Biol. Sci. 2003;393:531-534.

66. Lai M.K., Tsang S.W., Francis P.T., Esiri M.M., Keene J., Hope T., Chen C.P. Reduced serotonin 5-HT1A receptor binding in the temporal cortex correlates with aggressive behavior in Alzheimer disease. Brain Res. 2003;974(1-2):82-87.

67. Lanzenberger R.R., Mitterhauser M., Spindelegger C., Wadsak W., Klein N., Mien L.K., Holik A., Attarbaschi T., Mossaheb N., Sacher J., Geiss-Granadia T., Kletter K., Kasper S., Tauscher J. Reduced serotonin-1A receptor binding in social anxiety disorder. Biol. Psychiatry. 2007;61(9):1081-1089.

68. Lemonde S., Du L., Bakish D., Hrdina P., Albert P.R. Association of the C(-1019)G 5-HT1A functional promoter polymorphism with antidepressant response. Int. J. Neuropsychopharmacol. 2004;7(4): 501-506.

69. Lemonde S., Turecki G., Bakish D., Du L., Hrdina P.D., Bown C.D., Sequeira A., Kushwaha N., Morris S.J., Basak A., Ou X.M., Albert P.R. Impaired repression at a 5-hydroxytryptamine 1A receptor gene polymorphism associated with major depression and suicide. J. Neurosci. 2003;23(25):8788-8799.

70. Lopez J.F., Chalmers D.T., Little K.Y., Watson S.J. A.E. Bennett Research Award. Regulation of serotonin1A, glucocorticoid, and mineralocorticoid receptor in rat and human hippocampus: implications for the neurobiology of depression. Biol. Psychiatry. 1998;43(8): 547-573.

71. Maurel J.L., Autin J.M., Funes P., Newman-Tancredi A., Colpaert F., Vacher B. High-efficacy 5-HT1A agonists for antidepressant treatment: a renewed opportunity. J. Med. Chem. 2007;50(20):5024-5033.

72. Maxson A.C. Aggression: concepts and methods relevant to genetic analyses in mice and humans. Neurobehavioral genetics. Methods and applications. (Eds B.C. Jones, P. Mormede). N.W., Boca Raton, Florida: CRC Press LLC, 1999;293-300.

73. Mendoza D.L., Bravo H.A., Swanson H.H. Antiaggressive and anxiolytic effects of gepirone in mice, and their attenuation by WAY 100635. Pharmacol. Biochem. Behav. 1999;62(3):499-509.

74. Miyata S., Shimoi T., Hirano S., Yamada N., Hata Y., Yoshikawa N., Ohsawa M., Kamei J. Effects of serotonergic anxiolytics on the freezing behavior in the elevated open-platform test in mice. J. Pharmacol. Sci. 2007;105(3):272-278.

75. Monti J.M., Jantos H. Effects of the 5-HT1A receptor ligands flesinoxan and WAY 100635 given systemically or microinjected into the laterodorsal tegmental nucleus on REM sleep in the rat. Behav. Brain Res. 2004;151(1-2):159-166.

76. Moyer K.B. Kinds of aggression and their physiological basis. Commun. Behav. Biol. 1968;2:65-87.

77. Naumenko V.S., Ivanova E.A., Kulikov A.V., Popova N.K. Effect of monoamine oxidase A knockout on the expression of 5-HTlA receptors. Dokl. Biol. Sci. 2005;402:205-207.

78. Naumenko V.S., Kondaurova E.M., Kulikov A.V., Popova N.K. Effect of selection for a high predisposition to catalepsy on the functional activity of 5-HT1A receptors and expression of their gene. Dokl. Biol. Sci. 2006;409:299-301

79. Naumenko V.S., Kondaurova E.M., Popova N.K. Central 5-HT3 receptor-induced hypothermia in mice: interstrain differences and comparison with hypothermia mediated via 5-HT1A receptor. Neurosci. Lett. 2009;465(1):50-54.

80. Naumenko V.S., Kondaurova E.M., Popova N.K. On the role of brain 5-HT7 receptor in the mechanism of hypothermia: comparison with hypothermia mediated via 5-HT1A and 5-HT3 receptor. Neuropharmacology. 2011;61(8):1360-1365.

81. Naumenko V.S., Kozhemyakina R.V., Plyusnina I.F., Kulikov A.V., Popova N.K. Serotonin 5-HT1A receptor in infancy-onset aggression: comparison with genetically defined aggression in adult rats. Behav. Brain. Res. 2013;243:97-101.

82. Naumenko V.S., Popova N.K., Lacivita E., Leopoldo M., Ponimaskin E.G. Interplay between serotonin 5-HT1A and 5-HT7 receptors in depressive disorders. CNS Neurosci. Ther. 2014;20(7):582-590.

83. Naumenko V.S., Tkachev S.E., Kulikov A.V., Semenova T.P., Amerhanov Z.G., Smirnova N.P., Popova N.K. The brain 5-HT1A receptor gene expression in hibernation. Genes. Brain. Behav. 2008;7(3): 300-305.

84. Oakey R.J., Caron M.G., Lefkowitz R.J., Seldin M.F. Genomic organization of adrenergic and serotonin receptors in the mouse: linkage mapping of sequence-related genes provides a method for examining mammalian chromosome evolution. Genomics. 1991;10(2): 338-344.

85. Olivier B., Mos J., van Oorschot R., Hen R. Serotonin receptors and animal models of aggressive behavior. Pharmacopsychiatry. 1995;28(Suppl. 2):80-90.

86. Ou X.M., Jafar-Nejad H., Storring J.M., Meng J.H., Lemonde S., Albert P.R. Novel dual repressor elements for neuronal cell-specific transcription of the rat 5-HT1A receptor gene. J. Biol. Chem. 2000; 275(11):8161-8168.

87. Ou X.M., Storring J.M., Kushwaha N., Albert P.R. Heterodimerization of mineralocorticoid and glucocorticoid receptors at a novel negative response element of the 5-HT1A receptor gene. J. Biol Chem. 2001;276(17):14299-14307.

88. Overstreet D.H., Commissaris R.C., De La Garza R., 2nd, File S.E., Knapp D.J., Seiden L.S. Involvement of 5-HT1A receptors in animal tests of anxiety and depression: evidence from genetic models. Stress. 2003;6(2):101-110.

89. Parks C.L., Robinson P.S., Sibille E., Shenk T., Toth M. Increased anxiety of mice lacking the serotonin1A receptor. Proc. Natl Acad. Sci. USA. 1998;95(18):10734-10739.

90. Peroutka S.J., Howell T.A. The molecular evolution of G protein-coupled receptors: focus on 5-hydroxytryptamine receptors. Neuropharmacology. 1994;33(3-4):319-324.

91. Plyusnina I., Oskina I. Behavioral and adrenocortical responses to open-field test in rats selected for reduced aggressiveness toward humans. Physiol. Behav. 1997;61(3):381-385.

92. Plyusnina I.Z., Oskina I.N., Tibeikina M.A., Popova N.K. Cross-fostering effects on weight, exploratory activity, acoustic startle reflex and corticosterone stress response in Norway gray rats selected for elimination and for enhancement of aggressiveness towards human. Behav. Genet. 2009;39(2):202-212.

93. Popa D., El Yacoubi M., Vaugeois J.M., Hamon M., Adrien J. Homeostatic regulation of sleep in a genetic model of depression in the mouse: effects of muscarinic and 5-HT1A receptor activation. Neuropsychopharmacology. 2006;31(8):1637-1646.

94. Popova N.K. Serotonin in genetically determined types of defensive behavior. Zh. Vyssh. Nerv. Deiat. im. I.P. Pavlova. 1997;47(2): 350-357.

95. Popova N. Brain serotonin in genetically defined defensive behaviour. Complex Brain Functions: Conceptual Advances in Russian Neuroscience. (Eds R. Millar, A. Ivanitsky, P. Balaban). London: Harwood Press, 1999;307-329.

96. Popova N.K., Avgustinovich D.F., Kolpakov V.G., Plyusnina I.Z. Specific [3H]8-OH-DPAT binding in brain regions of rats genetically predisposed to various defense behavior strategies. Pharmacol. Biochem. Behav. 1998;59(4):793-797.

97. Popova N.K., Gilinsky M.A., Amstislavskaya T.G., Morosova E.A., Seif I., De Maeyer E. Regional serotonin metabolism in the brain of transgenic mice lacking monoamine oxidase A. J. Neurosci. Res. 2001;66(3):423-427.

98. Popova N.K., Kulikov A.V., Nikulina E.M., Kozlachkova E.Y., Maslova G.B. Serotonin metabolism and serotonergic receptors in Norway rats selected for low aggressiveness to man. Aggressive Behav. 1991a;17:207-213.

99. Popova N.K., Naumenko V.S. 5-HT1A receptor as a key player in the brain 5-HT system. Rev. Neurosci. 2013;24(2):191-204.

100. Popova N.K., Naumenko V.S., Plyusnina I.Z., Kulikov A.V. 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. 2005;80(2):286-292.

101. Popova N.K., Voitenko N.N., Kulikov A.V., Avgustinovich D.F. Evidence for the involvement of central serotonin in mechanism of domestication of silver foxes. Pharmacol. Biochem. Behav. 1991b; 40(4):751-756.

102. Pruus K., Skrebuhhova-Malmros T., Rudissaar R., Matto V., Allikmets L. 5-HT1A receptor agonists buspirone and gepirone attenuate apomorphine-induced aggressive behaviour in adult male Wistar rats. J. Physiol. Pharmacol. 2000;51(4 Pt 2):833-846.

103. Rakel R.E. Long-term buspirone therapy for chronic anxiety: a multicenter international study to determine safety. South Med. J. 1990; 83(2):194-198.

104. Ramboz S., Oosting R., Amara D.A., Kung H.F., Blier P., Mendelsohn M., Mann J.J., Brunner D., Hen R. Serotonin receptor 1A knockout: an animal model of anxiety-related disorder. Proc. Natl Acad. Sci. USA. 1998;95(24):14476-14481.

105. Raymond J.R. Protein kinase C induces phosphorylation and desensitization of the human 5-HT1A receptor. J. Biol. Chem. 1991;266(22): 14747-14753.

106. Renner U., Zeug A., Woehler A., Niebert M., Dityatev A., Dityateva G., Gorinski N., Guseva D., Abdel-Galil D., Frohlich M., Doring F., Wischmeyer E., Richter D.W., Neher E., Ponimaskin E.G. Heterodimerization of serotonin receptors 5-HT1A and 5-HT7 differentially regulates receptor signalling and trafficking. J. Cell. Sci. 2012;125(Pt 10):2486-2499.

107. Ricci L.A., Rasakham K., Grimes J.M., Melloni R.H., Jr. Serotonin-1A receptor activity and expression modulate adolescent anabolic/androgenic steroid-induced aggression in hamsters. Pharmacol. Biochem. Behav. 2006;85(1):1-11.

108. Robinson D.S., Alms D.R., Shrotriya R.C., Messina M., Wickramaratne P. Serotonergic anxiolytics and treatment of depression. Psychopathology. 1989;22(Suppl. 1):27-36.

109. Sanberg P.R., Bunsey M.D., Giordano M., Norman A.B. The catalepsy test: its ups and downs. Behav. Neurosci. 1988;102(5):748-759.

110. Saudou F., Hen R. 5-Hydroxytryptamine receptor subtypes: molecular and functional diversity. Adv. Pharmacol. 1994;30:327-380.

111. Sawiniec J., Borkowski K., Ginalska G., Lewandowska-Stanek H. Association between 5-hydroxytryptamine 1A receptor gene polymorphism and suicidal behavior. Przegl. Lek. 2007;64(4-5):208-211.

112. Serretti A., Artioli P., De Ronchi D. The 5-HT2C receptor as a target for mood disorders. Expert Opin. Ther. Targets. 2004;8(1):15-23.

113. Shively C.A., Friedman D.P., Gage H.D., Bounds M.C., Brown-Proctor C., Blair J.B., Henderson J.A., Smith M.A., Buchheimer N. Behavioral depression and positron emission tomography-determined serotonin 1A receptor binding potential in cynomolgus monkeys. Arch. Gen. Psychiatry. 2006;63(4):396-403.

114. Sibille E., Arango V., Galfalvy H.C., Pavlidis P., Erraji-Benchekroun L., Ellis S.P., John Mann J. Gene expression profiling of depression and suicide in human prefrontal cortex. Neuropsychopharmacology.2004;29(2):351-361.

115. Singerman B., Raheja R. Malignant catatonia-a continuing reality. Ann. Clin. Psychiatry. 1994;6(4):259-266.

116. Sperry T.S., Thompson C.K., Wingfield J.C. Effects of acute treatment with 8-OH-DPAT and fluoxetine on aggressive behaviour in male song sparrows (Melospiza melodia morphna). J. Neuroendocrinol. 2003;15(2):150-160.

117. Stein D.J., Miczek K.A., Lucion A.B., de Almeida R.M. Aggressionreducing effects of F15599, a novel selective 5-HT1A receptor agonist, after microinjection into the ventral orbital prefrontal cortex, but not in infralimbic cortex in male mice. Psychopharmacology (Berl.). 2013;230(3):375-387.

118. Storring J.M., Charest A., Cheng P., Albert P.R. TATA-driven transcriptional initiation and regulation of the rat serotonin 5-HT1A receptor gene. J. Neurochem. 1999;72(6):2238-2247.

119. Sun Y.N., Wang T., Wang Y., Han L.N., Li L.B., Zhang Y.M., Liu J. Activation of 5-HT1A receptors in the medial subdivision of the central nucleus of the amygdala produces anxiolytic effects in a rat model of Parkinson’s disease. Neuropharmacology. 2015;95:181-191.

120. Turner J.H., Gelasco A.K., Raymond J.R. Calmodulin interacts with the third intracellular loop of the serotonin 5-hydroxytryptamine1A receptor at two distinct sites: putative role in receptor phosphorylation by protein kinase C. J. Biol. Chem. 2004;279(17):17027-17037.

121. van den Berg L., Kwant L., Hestand M.S., van Oost B.A., Leegwater P.A. Structure and variation of three canine genes involved in serotonin binding and transport: the serotonin receptor 1A gene (htr1A), serotonin receptor 2A gene (htr2A), and serotonin transporter gene (slc6A4). J. Hered. 2005;96(7):786-796.

122. Woehler A., Wlodarczyk J., Ponimaskin E.G. Specific oligomerization of the 5-HT1A receptor in the plasma membrane. Glycoconj J. 2009; 26(6):749-756.

123. Wissink S., Meijer O., Pearce D., van Der Burg B., van Der Saag P.T. Regulation of the rat serotonin-1A receptor gene by corticosteroids. J. Biol. Chem. 2000;275(2):1321-1326.

124. Zhang Y., D’Souza D., Raap D.K., Garcia F., Battaglia G., Muma N.A., Van de Kar L.D. Characterization of the functional heterologous desensitization of hypothalamic 5-HT(1A) receptors after 5-HT(2A) receptor activation. J. Neurosci. 2001;21(20):7919-7927.

125. Zhuang X., Gross C., Santarelli L., Compan V., Trillat A.C., Hen R. Altered emotional states in knockout mice lacking 5-HT1A or 5-HT1B receptors. Neuropsychopharmacology. 1999;21(2 Suppl):52S-60S.

126. Zifa E., Fillion G. 5-Hydroxytryptamine receptors. Pharmacol. Rev. 1992;44(3):401-458.