Influence of oxytocin on the central nervous system by different routes of administration

Abstract

BACKGROUND: One of the unresolved problems in improving the pharmacotherapy of central nervous system diseases is the development and creation of technologies that allow drugs to cross the blood–brain barrier. One way to bypass the blood–brain barrier is the intranasal route of administration. Drug delivery is influenced by the peculiarities of the mechanism of transport of substances.

AIM: To examine the effect of intranasal administration of oxytocin on the behavior of mice and its content in various brain structures.

MATERIALS AND METHODS: The study used 60 outbred mice divided into six groups. Group 1 were healthy and did not receive oxytocin or physiological solution, groups 2 and 3 received single injection of 20 and 300 µL of oxytocin 5 IU intraperitoneally, respectively, group 4 was injected intranasally with 20 µL of oxytocin 5 IU, group 5 received 20 µL of saline intranasally, and group 6 received 300 µL of saline intraperitoneally. Behavioral effects were recorded in the elevated plus maze for 5 min, and the duration of stay in the open arm, number of transitions between the arms, and number of hangings from the arms were assessed. The concentration of oxytocin was measured in the following structures: olfactory bulb, striatum, hypothalamus, and hippocampus using an enzyme immunoassay.

RESULTS: Intranasal administration of oxytocin causes changes in behavior in mice, particularly a decrease in the degree of anxiety (anxiolytic effect). When timing the open arms in the plus maze test, mice administered intranasal oxytocin spent more time in the arms (32.44 ± 4.28 versus the control group with 5.66 ± 1.96 s), the number of transitions between the sleeves increased (1.90 ± 0.10 s versus 1.10 ± 0.10 s in the control group), and number of hangings from the sleeves increased (8.44 ± 1.37 versus 3.77 ± 0.98 in the control group). An increase was noted in one of the indicators — number of hangings from the sleeve after intraperitoneal injection of 300 µL of oxytocin, which may indicate the anxiolytic effect of oxytocin. The remaining groups receiving intranasal saline injection, intraperitoneal saline injection, and intraperitoneal injection of 20 µL of oxytocin did not show significant changes in behavior compared with the control group. In addition, after intranasal administration of oxytocin, its content increased in certain brain structures, i.e., the hypothalamus and hippocampus.

CONCLUSION: The results of this study indicate the potential efficacy of intranasal administration of oxytocin in the treatment of diseases affecting the central nervous system.

Keywords

oxytocin / intranasal administration / blood–brain barrier / central nervous system drug delivery strategies / elevated plus maze

References

[1] Pardridge WM. A historical review of brain drug delivery. Pharmaceutics. 2022;14(6):1283. DOI: 10.3390/pharmaceutics14061283

[2] Pardridge W.M. A historical review of brain drug delivery // Pharmaceutics. 2022. Vol. 14, No. 6. ID 1283. DOI: 10.3390/pharmaceutics14061283

[3] Crowe TP, Hsu WH. Evaluation of Recent intranasal drug delivery systems to the central nervous system. Pharmaceutics. 2022;14(3):629. DOI: 10.3390/pharmaceutics14030629

[4] Crowe T.P., Hsu W.H. Evaluation of Recent intranasal drug delivery systems to the central nervous system // Pharmaceutics. 2022. Vol. 14, No. 3. ID629. DOI: 10.3390/pharmaceutics14030629

[5] Litvinova MV, Trofimov AN, Shabanov PD, et al. Molecular mechanisms of transport of substances across the blood-brain barrie as targets for pharmacological action. Part 2. Modern methods of delivery of pharmacological agents to the central nervous system. Pharmacy Formulas. 2022;4(3):82–96. (In Russ.) DOI: 10.17816/phf120109

[6] Литвинова М.В., Трофимов А.Н., Шабанов П.Д., и др. Молекулярные механизмы транспорта веществ через гематоэнцефалический барьер как мишени для фармакологического воздействия. Часть 2. Современные способы доставки фармакологических агентов в центральную нервную систему // Формулы Фармации. 2022. Т. 4, № 3. C. 82–96. DOI: 10.17816/phf120109

[7] Rae M, Lemos Duarte M, Gomes I, et al. Oxytocin and vasopressin: Signalling, behavioural modulation and potential therapeutic effects. Br J Pharmacol. 2022;179(8):1544–1564. DOI: 10.1111/bph.15481

[8] Rae M., Lemos Duarte M., Gomes I., et al. Oxytocin and vasopressin: Signalling, behavioural modulation and potential therapeutic effects // Br J Pharmacol. 2022. Vol. 179, No. 8. P. 1544–1564. DOI: 10.1111/bph.15481

[9] Kendrick KM, Guastella AJ, Becker B. Overview of human oxytocin research. Hurlemann R, Grinevich V, editors. Behavioral pharmacology of neuropeptides: Oxytocin. current topics in behavioral neurosciences. Vol 35. Springer, Cham. 2017. P. 321–348. DOI: 10.1007/7854_2017_19

[10] Kendrick K.M., Guastella A.J., Becker B. Overview of human oxytocin research. Behavioral pharmacology of neuropeptides: Oxytocin. Current topics in behavioral neurosciences. Vol 35 / R. Hurlemann, V. Grinevich, editors. Springer, Cham. 2017. P. 321–348. DOI: 10.1007/7854_2017_19

[11] Jiang X, Ma X, Geng Y, et al. Intrinsic, dynamic and effective connectivity among large-scale brain networks modulated by oxytocin. Neuroimage. 2021;227:117668. DOI: 10.1016/j.neuroimage.2020.117668

[12] Jiang X., Ma X., Geng Y., et al. Intrinsic, dynamic and effective connectivity among large-scale brain networks modulated by oxytocin // Neuroimage. 2021. Vol. 227. ID 117668. DOI: 10.1016/j.neuroimage.2020.117668

[13] Le J, Kou J, Zhao W, et al. Oxytocin biases eye-gaze to dynamic and static social images and the eyes of fearful faces: associations with trait autism. Transl Psychiatry. 2020;10(1):142. DOI: 10.1038/s41398-020-0830-x

[14] Le J., Kou J., Zhao W., et al. Oxytocin biases eye-gaze to dynamic and static social images and the eyes of fearful faces: associations with trait autism // Transl Psychiatry. 2020. Vol. 10, No. 1. ID 142. DOI: 10.1038/s41398-020-0830-x

[15] Kruppa JA, Gossen A, Oberwelland Weiß E, et al. Neural modulation of social reinforcement learning by intranasal oxytocin in male adults with high-functioning autism spectrum disorder: a randomized trial. Neuropsychopharmacology. 2019;44(4):749–756. DOI: 10.1038/s41386-018-0258-7

[16] Kruppa J.A., Gossen A., Oberwelland Weiß E., et al. Neural modulation of social reinforcement learning by intranasal oxytocin in male adults with high-functioning autism spectrum disorder: a randomized trial // Neuropsychopharmacology. 2019. Vol. 44, No. 4. P. 749–756. DOI: 10.1038/s41386-018-0258-7

[17] Le J, Zhang L, Zhao W, et al. Infrequent intranasal oxytocin followed by positive social interaction improves symptoms in autistic children: A pilot randomized clinical trial. Psychother Psychosom. 2022;91(5):335–347. DOI: 10.1159/000524543

[18] Le J., Zhang L., Zhao W., et al. Infrequent intranasal oxytocin followed by positive social interaction improves symptoms in autistic children: A pilot randomized clinical trial // Psychother Psychosom. 2022. Vol. 91, No. 5. P. 335–347. DOI: 10.1159/000524543

[19] MacDonald E, Dadds MR, Brennan JL, et al. A review of safety, side-effects and subjective reactions to intranasal oxytocin in human research. Psychoneuroendocrinology. 2011;36(8):1114–1126. DOI: 10.1016/j.psyneuen.2011.02.015

[20] MacDonald E., Dadds M.R., Brennan J.L., et al. A review of safety, side-effects and subjective reactions to intranasal oxytocin in human research // Psychoneuroendocrinology. 2011. Vol. 36, No. 8. P. 1114–1126. DOI: 10.1016/j.psyneuen.2011.02.015

[21] Litvinova MV, Bychkov ER, Lebedev AA, et al. Application of the intranasal road of administration for delivery of drugs to the central nervous system. Reviews on Clinical Pharmacology and Drug Therapy. 2022;20(3):281–288. (In Russ.) DOI: 10.17816/RCF203281-288

[22] Литвинова М.В., Бычков Е.Р., Лебедев А.А., и др. Применение интраназального пути введения для доставки лекарственных препаратов в центральную нервную систему // Обзоры по клинической фармакологии и лекарственной терапии. 2022. Т. 20, № 3. С. 281–288. DOI: 10.17816/RCF203281-288

[23] Beard R, Singh N, Grundschober C, et al. High-yielding 18F radiosynthesis of a novel oxytocin receptor tracer, a probe for nose-to-brain oxytocin uptake in vivo. Chem Commun (Camb). 2018;54(58):8120–8123. DOI: 10.1039/c8cc01400k

[24] Beard R., Singh N., Grundschober C., et al. High-yielding 18F radiosynthesis of a novel oxytocin receptor tracer, a probe for nose-to-brain oxytocin uptake in vivo // Chem Commun (Camb). 2018. Vol. 54, No. 58. P. 8120–8123. DOI: 10.1039/c8cc01400k

[25] Galbusera A, De Felice A, Girardi S, et al. Intranasal oxytocin and vasopressin modulate divergent brainwide functional substrates. Neuropsychopharmacology. 2017;42(7):1420–1434. DOI: 10.1038/npp.2016.283

[26] Galbusera A., De Felice A., Girardi S., et al. Intranasal oxytocin and vasopressin modulate divergent brainwide functional substrates // Neuropsychopharmacology. 2017. Vol. 42, No. 7. P. 1420–1434. DOI: 10.1038/npp.2016.283

[27] Karpova IV, Bychkov ER, Marysheva VV, et al. The effect of oxytocin on the level and monoamines turnover in the brain of isolated mice of highand low-aggressive lines. Reviews on Clinical Pharmacology and Drug Therapy. 2017;15(2):23–30. (In Russ.) DOI: 10.17816/RCF15223-30

[28] Карпова И.В., Бычков Е.Р., Марышева В.В., и др. Влияние окситоцина на уровень и обмен моноаминов в мозге изолированных мышей высоко- и низкоагрессивных линий // Обзоры по клинической фармакологии и лекарственной терапии. 2017. Т. 15, № 2. C. 23–30. DOI: 10.17816/RCF15223-30

[29] Kou J, Lan C, Zhang Y, et al. In the nose or on the tongue? Contrasting motivational effects of oral and intranasal oxytocin on arousal and reward during social processing. Transl Psychiatry. 2021;11(1):94. DOI: 10.1038/s41398-021-01241-w

[30] Kou J., Lan C., Zhang Y., et al. In the nose or on the tongue? Contrasting motivational effects of oral and intranasal oxytocin on arousal and reward during social processing // Transl Psychiatry. 2021. Vol. 11, No. 1. ID94. DOI: 10.1038/s41398-021-01241-w

[31] Bharadwaj VN, Tzabazis AZ, Klukinov M, et al. Intranasal administration for pain: oxytocin and other polypeptides. Pharmaceutics. 2021;13(7):1088. DOI: 10.3390/pharmaceutics13071088

[32] Bharadwaj V.N., Tzabazis A.Z., Klukinov M., et al. Intranasal administration for pain: oxytocin and other polypeptides // Pharmaceutics. 2021. Vol. 13, No. 7. ID 1088. DOI: 10.3390/pharmaceutics13071088

[33] Zhu S, Qing Y, Zhang Y, et al. Transcutaneous auricular vagus nerve stimulation increases eye-gaze on salient facial features and oxytocin release. Psychophysiology. 2022;59(11):e14107. DOI: 10.1111/psyp.14107

[34] Zhu S., Qing Y., Zhang Y., et al. Transcutaneous auricular vagus nerve stimulation increases eye-gaze on salient facial features and oxytocin release // Psychophysiology. 2022. Vol. 59, No. 11. ID e14107. DOI: 10.1111/psyp.14107

[35] Everett NA, Turner AJ, Costa PA, et al. The vagus nerve mediates the suppressing effects of peripherally administered oxytocin on methamphetamine self-administration and seeking in rats. Neuropsychopharmacology. 2021;46(2):297–304. DOI: 10.1038/s41386-020-0719-7

[36] Everett N.A., Turner A.J., Costa P.A., et al. The vagus nerve mediates the suppressing effects of peripherally administered oxytocin on methamphetamine self-administration and seeking in rats // Neuropsychopharmacology. 2021. Vol. 46, No. 2. P. 297–304. DOI: 10.1038/s41386-020-0719-7

[37] 19-Martins D, Davies C, De Micheli A, et al. Intranasal oxytocin increases heart-rate variability in men at clinical high risk for psychosis: a proof-of-concept study. Transl Psychiatry. 2020;10(1):227. DOI: 10.1038/s41398-020-00890-7

[38] 19-Martins D., Davies C., De Micheli A., et al. Intranasal oxytocin increases heart-rate variability in men at clinical high risk for psychosis: a proof-of-concept study // Transl Psychiatry. 2020. Vol. 10, No. 1. ID227. DOI: 10.1038/s41398-020-00890-7

[39] Sakamoto T, Sugimoto S, Uekita T. Effects of intraperitoneal and intracerebroventricular injections of oxytocin on social and emotional behaviors in pubertal male mice. Physiol Behav. 2019;212:112701. DOI: 10.1016/j.physbeh.2019.112701

[40] Sakamoto T., Sugimoto S., Uekita T. Effects of intraperitoneal and intracerebroventricular injections of oxytocin on social and emotional behaviors in pubertal male mice // Physiol Behav. 2019. Vol. 212. ID112701. DOI: 10.1016/j.physbeh.2019.112701

[41] Zhuang Q, Zheng X, Yao S, et al. Oral administration of oxytocin, like intranasal administration, decreases top-down social attention. Int J Neuropsychopharmacol. 2022;25(11):912–923. DOI: 10.1093/ijnp/pyac059

[42] Zhuang Q., Zheng X., Yao S., et al. Oral administration of oxytocin, like intranasal administration, decreases top-down social attention // Int J Neuropsychopharmacol. 2022. Vol. 25, No. 11. P. 912–923. DOI: 10.1093/ijnp/pyac059

[43] Kou J, Zhang Y, Zhou F, et al. A randomized trial shows dose-frequency and genotype may determine the therapeutic efficacy of intranasal oxytocin. Psychol Med. 2022;52(10):1959–1968. DOI: 10.1017/S0033291720003803

[44] Kou J., Zhang Y., Zhou F., et al. A randomized trial shows dose-frequency and genotype may determine the therapeutic efficacy of intranasal oxytocin // Psychol Med. 2022. Vol. 52, No. 10. P. 1959–1968. DOI: 10.1017/S0033291720003803

[45] Tanaka A, Furubayashi T, Arai M, et al. Delivery of oxytocin to the brain for the treatment of autism spectrum disorder by nasal application. Mol Pharm. 2018;15(3):1105–1111. DOI: 10.1021/acs.molpharmaceut.7b00991

[46] Tanaka A., Furubayashi T., Arai M., et al. Delivery of oxytocin to the brain for the treatment of autism spectrum disorder by nasal application // Mol Pharm. 2018. Vol. 15, No. 3. P. 1105–1111. DOI: 10.1021/acs.molpharmaceut.7b00991

[47] Ring RH, Malberg JE, Potestio L, et al. Anxiolytic-like activity of oxytocin in male mice: behavioral and autonomic evidence, therapeutic implications. Psychopharmacology (Berl). 2006;185(2):218–225. DOI: 10.1007/s00213-005-0293-z

[48] Ring R.H., Malberg J.E., Potestio L., et al. Anxiolytic-like activity of oxytocin in male mice: behavioral and autonomic evidence, therapeutic implications // Psychopharmacology (Berl). 2006. Vol. 185, No. 2. P. 218–225. DOI: 10.1007/s00213-005-0293-z

RIGHTS & PERMISSIONS

Eco-Vector