Lateral characteristics of oxytocin distribution in the mouse brain following intranasal peptide administration

Abstract

BACKGROUND: Intranasal administration of oxytocin is an effective method for delivering the hormone to the central nervous system, bypassing the blood-brain barrier. This approach holds significant promise for psychiatric clinical applications. Previous studies have demonstrated that simultaneous oxytocin administration in both nostrils induces lateralized changes in monoamine metabolism in the mouse brain.

AIM: To investigate the lateral characteristics of oxytocin penetration in the brain following intranasal administration.

MATERIALS AND METHODS: Experiments were conducted on 12 male outbred white mice. The experimental group received intranasal oxytocin (5 IU/1 mL, 10 μL per nostril), while the control group received an equivalent volume of saline. Oxytocin levels were measured 15 minutes post-instillation in the hypothalamus, olfactory bulbs, striatum, and hippocampus on both sides of the brain using an enzyme-linked immunosorbent assay (ELISA).

RESULTS: In the control group, oxytocin distribution was symmetric in the olfactory bulb and striatum. However, in the hippocampus, control mice exhibited asymmetry with a higher oxytocin concentration on the right side (p = 0.0192). In the experimental group, oxytocin levels significantly increased in the left hippocampus (p = 0.0223) and hypothalamus (p = 0.0036), with a trend observed in the left olfactory bulb (p = 0.0572).

CONCLUSION: Intranasal oxytocin administration enhances oxytocin penetration into the left side of the brain, primarily through the left olfactory bulb and hippocampus, ultimately reaching the hypothalamus.

Keywords

oxytocin / intranasal administration / hippocampus / brain asymmetry

References

[1] Yao S, Kendrick KM. Effects of intranasal administration of oxytocin and vasopressin on social cognition and potential routes and mechanisms of action. Pharmaceutics. 2022;14(2):323. doi: 10.3390/pharmaceutics14020323

[2] Yao S., Kendrick K.M. Effects of intranasal administration of oxytocin and vasopressin on social cognition and potential routes and mechanisms of action // Pharmaceutics. 2022. Vol. 14, N 2. P. 323. doi: 10.3390/pharmaceutics14020323

[3] 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

[4] 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, N 8. P. 1544–1564. doi: 10.1111/bph.15481

[5] Litvinova MV, Tissen IYu, Lebedev AA, et al. Influence of oxytocin on the central nervous system by different routes of administration. Psychopharmacology and biological narcology. 2023;14(2):139–147. (In Russ.) EDN: ANORKE doi: 10.17816/phbn501752

[6] Литвинова М.В., Тиссен И.Ю., Лебедев А.А., и др. Анализ действия окситоцина на центральную нервную систему при различных путях введения // Психофармакология и биологическая наркология. 2023. Т. 14, № 2. С. 139–147. EDN: ANORKE doi: 10.17816/phbn501752

[7] Karpova IV, Mikheev VV, Marysheva VV, et al. Oxytocin-induced changes in monoamine level in symmetric brain structures of isolated aggressive C57Bl/6 Mice. Bulletin of Experimental Biology and Medicine. 2016;160(5):605–609. EDN: WVWDND doi: 10.1007/s10517-016-3228-2

[8] Karpova I.V., Mikheev V.V., Marysheva V.V., et al. Oxytocin-induced changes in monoamine level in symmetric brain structures of isolated aggressive C57Bl/6 Mice // Bulletin of Experimental Biology and Medicine. 2016. Vol. 160, N 5. P. 605–609. (In Russ.) EDN: WVWDND doi: 10.1007/s10517-016-3228-2

[9] Karpova IV, Bychkov ER, Marysheva VV, et al. Effects of oxytocin on the levels and metabolism of monoamines in the brain of white outbred mice during long-term social isolation. Bulletin of Experimental Biology and Medicine. 2017;163(6):714–717. EDN: XPAABR doi: 10.1007/s10517-017-3887-7

[10] Karpova I.V., Bychkov E.R., Marysheva V.V., et al. Effects of oxytocin on the levels and metabolism of monoamines in the brain of white outbred mice during long-term social isolation // Bulletin of Experimental Biology and Medicine. 2017. Vol. 163, N 6. P. 714–717. EDN: XPAABR doi: 10.1007/s10517-017-3887-7

[11] 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. EDN: ZCJIRN doi: 10.17816/RCF15223-30

[12] 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. EDN: ZCJIRN doi: 10.17816/RCF15223-30

[13] Karpova IV. Asymmetry of monoaminergic systems of the brain. [dissertation abstract]. Saint Petersburg; 2021. 46 p. (In Russ.)

[14] Карпова И.В. Асимметрия моноаминергических систем мозга. Автореф. дис. … д-ра биол. наук. Санкт-Петербург, 2021. 46 с.

[15] Erdő F, Bors LA, Farkas D, et al. Evaluation of intranasal delivery route of drug administration for brain targeting. Brain Res Bull. 2018;143:155–170. doi: 10.1016/j.brainresbull.2018.10.009

[16] Erdő F., Bors L.A., Farkas D., et al. Evaluation of intranasal delivery route of drug administration for brain targeting // Brain Res Bull. 2018. Vol. 143. P. 155–170. doi: 10.1016/j.brainresbull.2018.10.009

[17] Quintana DS, Lischke A, Grace S, et al. Advances in the field of intranasal oxytocin research: lessons learned and future directions for clinical research. Mol Psychiatry. 2021;26(1):80–91. doi: 10.1038/s41380-020-00864-7

[18] Quintana D.S., Lischke A., Grace S., et al. Advances in the field of intranasal oxytocin research: lessons learned and future directions for clinical research // Mol Psychiatry. 2021. Vol. 26, N 1. P. 80–91. doi: 10.1038/s41380-020-00864-7

[19] 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

[20] 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, N 58. P. 8120–8123. doi: 10.1039/c8cc01400k

[21] Neumann ID, Maloumby R, Beiderbeck DI, et al. Increased brain and plasma oxytocin after nasal and peripheral administration in rats and mice. Psychoneuroendocrinology. 2013;38(10):1985–1993. doi: 10.1016/j.psyneuen.2013.03.003

[22] Neumann I.D., Maloumby R., Beiderbeck D.I., et al. Increased brain and plasma oxytocin after nasal and peripheral administration in rats and mice // Psychoneuroendocrinology. 2013. Vol. 38, N 10. P. 1985–1993. doi: 10.1016/j.psyneuen.2013.03.003

[23] Smith AS, Korgan AC, Young WS. Oxytocin delivered nasally or intraperitoneally reaches the brain and plasma of normal and oxytocin knockout mice. Pharmacol Res. 2019;146:104324. doi: 10.1016/j.phrs.2019.104324

[24] Smith A.S., Korgan A.C., Young W.S. Oxytocin delivered nasally or intraperitoneally reaches the brain and plasma of normal and oxytocin knockout mice // Pharmacol Res. 2019. Vol. 146. P. 104324. doi: 10.1016/j.phrs.2019.104324

[25] Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976;72(1-2):248–254. doi: 10.1016/0003-2697(76)90527-3

[26] Bradford M.M. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding // Anal Biochem. 1976. Vol. 72, N. 1-2. P. 248–254. doi: 10.1016/0003-2697(76)90527-3

[27] 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

[28] Galbusera A., De Felice A., Girardi S., et al. Intranasal oxytocin and vasopressin modulate divergent brainwide functional substrates // Neuropsychopharmacology. 2017. Vol. 42, N 7. P. 1420–1434. doi: 10.1038/npp.2016.283

[29] Martins DA, Mazibuko N, Zelaya F, et al. Effects of route of administration on oxytocin-induced changes in regional cerebral blood flow in humans. Nat Commun. 2020;11(1):1160. doi: 10.1038/s41467-020-14845-5

[30] Martins D.A., Mazibuko N., Zelaya F., et al. Effects of route of administration on oxytocin-induced changes in regional cerebral blood flow in humans // Nat Commun. 2020. Vol. 11, N 1. P. 1160. doi: 10.1038/s41467-020-14845-5

[31] Paloyelis Y, Doyle OM, Zelaya FO, et al. A spatiotemporal profile of in vivo cerebral blood flow changes following intranasal oxytocin in humans. Biol Psychiatry. 2016;79(8):693–705. doi: 10.1016/j.biopsych.2014.10.005

[32] Paloyelis Y., Doyle O.M., Zelaya F.O., et al. A spatiotemporal profile of in vivo cerebral blood flow changes following intranasal oxytocin in humans // Biol Psychiatry. 2016. Vol. 79, N 8. P. 693–705. doi: 10.1016/j.biopsych.2014.10.005

[33] Lee MR, Shnitko TA, Blue SW, et al. Labeled oxytocin administered via the intranasal route reaches the brain in rhesus macaques. Nat Commun. 2020;11:2783. doi: 10.1038/s41467-020-15942-1

[34] Lee M.R., Shnitko T.A., Blue S.W., et al. Labeled oxytocin administered via the intranasal route reaches the brain in rhesus macaques // Nat Commun. 2020. Vol. 11, N 1. P. 2783. doi: 10.1038/s41467-020-15942-1

Funding

Ministry of Science and Higher Education of the Russian FederationМинистерство науки и высшего образования Российской Федерации

RIGHTS & PERMISSIONS

Eco-Vector