The role of kisspeptin in the regulation of emotional states in modeling acute stress disorder in a vertebrate species

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Abstract

In acute stress disorders, depressive, anxiety-phobic states and sexual dysfunctions are observed, which are poorly amenable to treatment. Neuropeptides of the kisspeptin group have been proposed for the correction of these disorders. We have previously shown the effect of kisspeptin analogs on the activation of sexual behavior in a model of acute stress disorders. The aim of the present work was to determine the role of kisspeptin in the regulation of emotional behavior following the acute stress of predator presentation in a range of vertebrates. The effects of fish presentation of the predator Hypsophrys nicaraguensis to Danio rerio and of tiger python presentation to Wistar rats were investigated. Similarly to the behavior of rodents, fish showed manifestations of negative emotional states: frising on the bottom and decreased motor activity. Administration of phenazepam, paroxetine, or kisspepin 10 ameliorated the effects of predator presentation in Danio rerio: increased movement to the top of the tank; decreased time at the bottom of the tank. Unlike phenazepam, kisspeptin 10 did not reduce anxiety-phobic reactions in the elevated plus maze in modeling of acute stress disorder in rats, while showing disinhibitory and antidepressant effects in the Porsolt test similar to the action of serotonin reuptake inhibitor paroxetine. Data on the unidirectional effects of kisspeptin 10 and paroxetine in Danio rerio and Wistar rats support a role for kisspeptins in modulating serotonin-dependent behavior in a model of acute stress disorder. The data support the hypothesis that kisspeptins are involved in relieving anxiety-phobic states while maintaining emotional aspects of reproductive behavior such as sexual motivation, territorial behavior, and arousal in a range of vertebrates. The work shows promise for the introduction of Danio rerio into preclinical and translational research protocols in the study of acute stress disorders.

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About the authors

V. A. Golts

Institute of Experimental Medicine

Email: aalebedev-iem@rambler.ru
Russian Federation, Saint Petersburg

A. A. Lebedev

Institute of Experimental Medicine

Author for correspondence.
Email: aalebedev-iem@rambler.ru
Russian Federation, Saint Petersburg

S. S. Pyurveev

Institute of Experimental Medicine; Saint Petersburg State Pediatric Medical University

Email: aalebedev-iem@rambler.ru
Russian Federation, Saint Petersburg; Saint Petersburg

A. P. Perova

Institute of Experimental Medicine; Saint Petersburg State University

Email: aalebedev-iem@rambler.ru
Russian Federation, Saint Petersburg; Saint Petersburg

E. R. Bychkov

Institute of Experimental Medicine; Kirov Military Medical Academy

Email: aalebedev-iem@rambler.ru
Russian Federation, Saint Petersburg; Saint Petersburg

I. Y. Tissen

Institute of Experimental Medicine

Email: aalebedev-iem@rambler.ru
Russian Federation, Saint Petersburg

S. G. Tsikunov

Institute of Experimental Medicine

Email: aalebedev-iem@rambler.ru
Russian Federation, Saint Petersburg

P. D. Shabanov

Institute of Experimental Medicine

Email: aalebedev-iem@rambler.ru
Russian Federation, Saint Petersburg

References

  1. Meczekalski B, Niwczyk O, Bala G, Szeliga A (2022) Stress, kisspeptin, and functional hypothalamic amenorrhea. Curr Opin Pharmacol 67: 102288. https://doi.org/10.1016/j.coph.2022.102288
  2. Mills EGA, O'Byrne KT, Comninos AN (2019) Kisspeptin as a behavioral hormone. Semin Reprod Med 37(2): 56–63. https://doi.org/10.1055/s-0039-3400239
  3. Mills EGA, Dhillo WS, Comninos AN (2018) Kisspeptin and the control of emotions, mood and reproductive behavior. J Endocrinol 239(1): R1–R12. https://doi.org/10.1530/JOE-18-0269
  4. Гольц ВА, Лебедев АА, Ереско СО, Айрапетов МИ, Пюрвеев СС, Бычков ЕР, Байрамов АА, Лебедев ВА, Шабанов ПД (2024) Влияние кисспептина костистых рыб KISS1 и аналогов кисспептина млекопитающих на коммуникативное поведение Danio rerio, вызванное социальной изоляцией. Обз клин фармакол лек тер 22(2): 191–203. https://doi.org/10.17816/RCF625892
  5. Tsukamura H, Ozawa H, Lehman MN (2024) Kisspeptin and mammalian reproduction. Peptides 181: 171297. https://doi.org/10.1016/j.peptides.2024.171297
  6. Гольц ВА, Лебедев АА, Блаженко АА, Лебедев ВА, Казаков СВ, Байрамов АА, Хохлов ПП, Бычков ЕР, Пюрвеев СС, Шабанов ПД (2023) Анксиолитическое действие аналогов кисспептина у Danio rerio. Обз клин фармакол лек тер 21(2): 159–169. https://doi.org/10.17816/RCF321976
  7. Comninos AN, Wall MB, Demetriou L, Jayasena CN, Colledge WH, Bassett P, Bloom SR, Venkitaraman R, Noreika V, Zeki S, Dhillo WS (2017) Kisspeptin modulates sexual and emotional brain processing in humans. J Clin Invest 127(2): 709–719. https://doi.org/10.1172/JCI89519
  8. Гольц ВА, Лебедев АА, Блаженко АА, Лебедев ВА, Казаков СВ, Байрамов АА, Хохлов ПП, Бычков ЕР, Пюрвеев СС, Шабанов ПД (2023) Сравнение анксиолитического действия кисспептинов млекопитающих и костистых рыб у Danio rerio. Психофармак биол наркол 14(2): 85–96. https://doi.org/10.17816/phbn501442
  9. Somoza GM, Mechaly AS, Trudeau VL (2020) Kisspeptin and GnRH interactions in the reproductive brain of teleosts. Gen Comp Endocrinol 298: 113568. https://doi.org/10.1016/j.ygcen.2020.113568
  10. Nie Z, Zhao N, Zhao H, Fu Z, Ma Z, Wei J (2023) Cloning, expression analysis and SNP screening of the kiss1 gene in male Schizothorax biddulphi. Genes 14(4): 862. https://doi.org/10.3390/genes14040862
  11. Rønnekleiv OK, Qiu J, Kelly MJ (2022) Hypothalamic kisspeptin neurons and the control of homeostasis. Endocrinology 163(2): bqab253. https://doi.org/10.1210/endocr/bqab253
  12. Stincic TL, Qiu J, Connors AM, Kelly MJ, Rønnekleiv OK (2021) Arcuate and preoptic kisspeptin neurons exhibit differential projections to hypothalamic nuclei and exert opposite postsynaptic effects on hypothalamic paraventricular and dorsomedial nuclei in the female mouse. eNeuro 8(4): ENEURO.0093-21.2021. https://doi.org/10.1523/ENEURO.0093-21.2021
  13. Rønnekleiv OK, Qiu J, Kelly MJ (2019) Arcuate kisspeptin neurons coordinate reproductive activities with metabolism. Semin Reprod Med 37(3): 131–140. https://doi.org/10.1055/s-0039-3400251
  14. Пюрвеев СС, Деданишвили НС, Сексте ЭА, Лебедев АА, Бычков ЕР, Шабанов ПД (2024) Влияние стресса ранней материнской депривации на экспрессию OX1R в лимбической системе головного мозга и развитие тревожно-депрессивных симптомов у крыс. Обз клин фармакол лек тер 22(2): 153–162. https://doi.org/10.17816/RCF622940
  15. Ogawa S, Parhar IS, Chau R, von Hertzen LS, Koide T, Soma M, Sawahata H, Yamamoto N, Ito Y, Kubo Y (2014) Habenular kisspeptin modulates fear in the zebrafish. Proc Natl Acad Sci U S A 111(10): 3841–3846. https://doi.org/10.1073/pnas.1314184111
  16. Tanaka M, Csabafi K, Telegdy G (2013) Neurotransmissions of antidepressant-like effects of kisspeptin-13. Regul Pept 180: 1–4. https://doi.org/10.1016/j.regpep.2012.08.017
  17. Csabafi K, Jászberényi M, Bagosi Z, Lipták N, Telegdy G (2013) Effects of kisspeptin-13 on the hypothalamic-pituitary-adrenal axis, thermoregulation, anxiety and locomotor activity in rats. Behav Brain Res 241: 56–61. https://doi.org/10.1016/j.bbr.2012.11.039
  18. Blaser RE, Chadwick L, McGinnis GC (2010) Behavioral measures of anxiety in zebrafish (Danio rerio). Behav Brain Res 208(1): 56–62. https://doi.org/10.1016/j.bbr.2009.11.009
  19. Тиссен ИЮ, Чепик ПА, Лебедев АА (2021) Условная реакция предпочтения места кисспептина-10. Обз клин фармакол лек тер 19(1): 47–53. https://doi.org/10.17816/RCF19147-53
  20. Бочарова ОА, Бочаров ЕВ, Кучеряну ВГ, Карпова РВ (2019) Дофаминергическая система: стресс, депрессия, рак (часть 1). Росс биотер журн 18(3): 6–14. https://doi.org/10.17650/1726-9784-2019-18-3-6-14
  21. Shams S, Amlani S, Buske C (2018) Developmental social isolation affects adult behavior, social interaction, and dopamine metabolite levels in zebrafish. Dev Psychobiol 60(1): 43–56. https://doi.org/10.1002/dev.21581
  22. Бычков ЕР, Карпова ИВ, Цикунов СГ (2021) Действие острого психического стресса на обмен моноаминов в мезокортикальной и нигростриатной системах головного мозга крыс. Педиатр 12(6): 35–42. https://doi.org/10.17816/PED12635-42
  23. Блаженко АА, Хохлов ПП, Лебедев АА. (2022) Содержание грелина в разных отделах головного мозга у Danio rerio после стрессорного воздействия. Психофармакол биол наркол 13(3): 37–42. https://doi.org/10.17816/phbn267375
  24. Перова АП, Гольц ВА, Лебедев АА, Бычков ЕР, Безнин ГВ, Косякова ГП, Шабанов ПД (2024) Кисспептин 10 уменьшает проявление половой дисфункции у крыс в моделях острого психогенного стресса. Патогенез 22(2): 76–80. https://doi.org/10.25557/2310-0435.2024.02.76-80
  25. Тиссен ИЮ, Лебедев АА, Цикунов СГ, Шабанов ПД (2023) Кисспептин уменьшает проявления половой дисфункции у крыс в модели посттравматического стрессового расстройства. Психофармакол биол наркол 14(4): 237–244. https://doi.org/10.17816/phbn623033
  26. Лебедев АА, Пшеничная АГ, Якушина НД, Бычков ЕР, Шабанов ПД (2017) Влияние антагониста рецепторов кортиколиберина астрессина на агрессию и тревожно-фобические состояния у самцов крыс, выращенных в социальной изоляции. Обзоры по клинической фармакологии и лекарственной терапии. 3.
  27. Гольц ВА, Перова АП, Лебедев АА, Лизунов АВ, Надбитова НД, Бычков ЕР, Пюрвеев СС, Шабанов ПД (2024) Действие кисспептина на поведенческие паттерны в ответ на стресс новизны в ряду позвоночных. Эксп клин фармак 87(12): 3–7. https://doi.org/10.30906/0869-2092-2024-87-12-3-7
  28. Вартанян ГА, Петров ЕС (1989) Эмоции и поведение — Ленинград: Наука, Ленинградское отделение 144 с.

Supplementary files

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2. Fig. 1. The main structural features of kisspeptins formed as a result of post-translational modification of its prohormone [5].

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3. Fig. 2. Schematic model of kisspeptin action in regulating mammalian behavior: POA/Hyp – hypothalamic nuclei; Amyg – amygdala; Hb – frenulum; Hipp – hippocampus; GnRH – gonadotropin-releasing hormone.

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4. Fig. 3. Schematic diagram of the novelty test with a predator.

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5. Fig. 4. Trajectory of fish movement.

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6. Fig. 5. Behavior of Danio rerio fish in the novelty stress test in intact control and after presentation of a predator: (a) — trajectory length; (b) and (c) — time and number of freezings, respectively; (d) — time in the lower part of the aquarium; (e) — number of movements to the upper part of the aquarium. Data are presented as the arithmetic mean ± the error of the mean. Significance of differences from the control group: ** — p <0.001. Student's t-test.

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7. Fig. 6. Behavior of Danio rerio fish in the novelty stress test after presentation of a predator, using phenazepam at a dose of 1 mg per 1000 ml; KS 10 at a dose of 1 mg per 1000 ml; paroxetine at a dose of 1 mg per 1000 ml. (a) - trajectory length; (b) and (c) - time and number of freezing, respectively; (d) - time in the lower part of the aquarium; (e) - number of movements to the upper part of the aquarium. Data are presented as arithmetic mean ± error of the mean. One-way ANOVA and Tukey's test for multiple comparisons of means. * - p < 0.05; ** - p < 0.01; *** - p < 0.001; **** - p < 0.0001 after presentation of the predator.

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8. Fig. 7. Behavior of rats in the Porsolt test (a) and the elevated plus maze test (b) after exposure to the stress of the presentation of a predator and with the use of the studied pharmacological agents.

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9. Table 1. Fig. 1

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10. Table 1. Fig. 2

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11. Table 1. Fig. 3

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