Correction of the wake-sleep cycle by intranasal administration of dopamine in modeling of the preclinical stage of Parkinson's disease in rats

Keywords: model of Parkinson's disease, wake-sleep cycle, intranasal administration of dopamine


Sleep disorders, which are among the earliest and most sensitive non-motor manifestations of Parkinson's disease (PD), are not diagnosed in 40–50 % of patients and are not subject to the necessary correction. In this regard, the ineffectiveness of a late start of treatment, when more than 50 % of dopamine-producing neurons are already affected, dictates the need to search for and develop approaches to the prevention and slowdown of neurodegenerative pathology at the preclinical stages of its development using adequate experimental models. Taking into account the low bioavailability of dopamine (DA) and data on the advantages of the intranasal route of administration in comparison with oral and parenteral methods of drug delivery to the CNS, the aim of the work was to study the neurophysiological features of the wake-sleep cycle as early manifestations of nigrostriatal insufficiency and the effect of intranasal administration of DA on the quality of sleep during the formation of the preclinical stage of PD in rats. It was shown that under the conditions of modeling PD, the cyclic organization of sleep with a predominance of incomplete cycles against the background of hyperproduction of slow-wave sleep and REM phases are early manifestations of nigrostriatal insufficiency. Course administration of DA at a dose of 3 mg/kg is accompanied by the normalization of sleep quality in the form of reduction (by 76 %) in the number of incomplete cycles. The preventive orientation of the obtained effects may indicate a certain therapeutic potential of intranasal delivery of DA to the brain, aimed at slowing down the processes of neurodegeneration and possibly delaying its clinical manifestation


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Author Biographies

Valentina Geiko, State Institution “Institute of Neurology, Psychiatry and Narcology of the National Academy of Medical Sciences of Ukraine”

Laboratory of Neurophysiology, Immunology and Biochemistry

Olga Berchenko, State Institution “Institute of Neurology, Psychiatry and Narcology of the National Academy of Medical Sciences of Ukraine”

Laboratory of Neurophysiology, Immunology and Biochemistry


Chaudhuri, K. R., Schapira, A. H. V. (2009). Non-motor symptoms of Park-inson's disease: dopaminergic pathophysiology and treatment. The Lancet Neurology, 8 (5), 464–474. doi:

Kim, S., Kwon, S.-H., Kam, T.-I., Panicker, N., Karuppagounder, S. S., Lee, S. et al. (2019). Transneuronal Propagation of Pathologic α-Synuclein from the Gut to the Brain Models Parkinson’s Disease. Neuron, 103 (4), 627-641.e7. doi:

Paredes-Rodriguez, E., Vegas-Suarez, S., Morera-Herreras, T., De Deurwaerdere, P., Miguelez, C. (2020). The Noradrenergic System in Parkinson’s Disease. Frontiers in Pharmacology, 11. doi:

Braak, H., Ghebremedhin, E., Rüb, U., Bratzke, H., Del Tredici, K. (2004). Stages in the development of Parkinson’s disease-related pathology. Cell and Tissue Research, 318 (1), 121–134. doi:

Martinez-Martin, P., Rodriguez-Blazquez, C., Kurtis, M. M., Chaudhuri, K. R., Group, N. V. (2011). The impact of non-motor symptoms on health-related quality of life of patients with Parkinson’s disease. Movement Disorders, 26, 399–406. doi:

Hermanowicz, N., Jones, S. A., Hauser, R. A. (2019). Impact of non-motor symptoms in Parkinson’s disease: a PMD Alliance survey. Neuropsychiatric Disease and Treatment, 15, 2205–2212. doi:

Zuzuárregui, J. R. P., During, E. H. (2020). Sleep Issues in Parkinson’s Disease and Their Management. Neurotherapeutics, 17 (4), 1480–1494. doi:

Braak, H., Del Tredici, K. (2016). Potential pathways of abnormal Tau and α-synuclein dissemination in sporadic Alzheimer’s and Parkinson’s diseases. Cold Spring Harbor Perspectives in Biology, 8 (11), a023630. doi:

Zhang, H., Gu, Z., An, J., Wang, C., Chan, P. (2014). Non-Motor Symptoms in Treated and Untreated Chinese Patients with Early Parkinson’s Disease. The Tohoku Journal of Experimental Medicine, 232 (2), 129–136. doi:

Albers, J. A., Chand, P., Anch, A. M. (2017). Multifactorial sleep disturbance in Parkinson's disease. Sleep Medicine, 35, 41–48. doi:

Liu, C.-F., Wang, T., Zhan, S.-Q., Geng, D.-Q., Wang, J., Liu, J. et al. (2018). Management Recommendations on Sleep Disturbance of Patients with Park-inson's Disease. Chinese Medical Journal, 131 (24), 2976–2985. doi:

Amosova, N. A., Smolentseva, I. G., Guseynova, P. M., Maslyuk, O. A., Gavrilov, E. L. (2016). Narusheniya sna na ranney stadii bolezni Parkinsona u patsientov, ne prinimayuschikh protivoparkinsonicheskie preparaty. Zhurnal nevrologii i psikhiatrii im. SS Korsakova. Spetsvypuski, 116 (6), 77–81.

Postuma, R. B., Gagnon, J. F., Vendette, M., Fantini, M. L., Massicotte-Marquez, J., Montplaisir, J. (2008). Quantifying the risk of neurodegenerative disease in idiopathic REM sleep behavior disorder. Neurology, 72 (15), 1296–1300. doi:

Cochen De Cock, V. (2015). Objective Measures of the Sleep–Wake Cycle in Parkinson’s Disease. Disorders of Sleep and Circadian Rhythms in Parkinson’s Disease, 51–60. doi:

Nodel, M. R., Ukraintseya, U. V., Yakhno, N. N. (2015). Rapid eye movement sleep behavioral disorder in Parkinson's disease. Nevrologicheskiy zhurnal, 20 (6), 28–34. Available at:

Nodel', M. R., Kovrov, G. V. (2017). Narusheniya sna pri bolezni Parkinsona: podkhody k lecheniyu i profilaktike. Nevrologiya, neyropsikhiatriya, psikhosomatika, 9 (4), 88–94.

Chaudhuri, K. R., Prieto-Jurcynska, C., Naidu, Y., Mitra, T., Frades-Payo, B., Tluk, S. et al. (2010). The nondeclaration of nonmotor symptoms of Parkinson’s disease to health care professionals: an international study using the nonmotor symptoms questionnaire. Movement Disorders, 25 (6), 704–709. doi:

Koval'zon, V. M., Zavalko, I. M. (2013). Neyrokhimiya tsikla bodrstvovanie-son i bolezn' Parkinsona. Neyrokhimiya, 30 (3), 193–206.

Nodel', M. R., Yakhno, N. N., Ukraintseva, Yu. V., Dorokhov, V. B. (2014). Insomniya pri bolezni Parkinsona i ee vliyanie na kachestvo zhizni patsientov. Nevrologicheskiy zhurnal, 4, 19–27.

Hurt, C. S., Rixon, L., Chaudhuri, K. R., Moss-Morris, R., Samuel, M., Brown, R. G. (2019). Barriers to reporting non-motor symptoms to health-care providers in people with Parkinson’s. Parkinsonism & Related Disorders, 64, 220–225. doi:

Amara, A. W., Chahine, L. M., Videnovic, A. (2017). Treatment of Sleep Dysfunction in Parkinson’s Disease. Current Treatment Options in Neurology, 19 (7). doi:

Falup-Pecurariu, C., Diaconu, Ş. (2017). Sleep dysfunction in Parkinson's disease. International Review of Neurobiology, 719–742. doi:

Catalan, M. J., Molina-Arjona, J. A., Mir, P., Cubo, E., Arbelo, J. M., Mar-tinez-Martin, P. (2018). Improvement of impulse control disorders associated with levodopa–carbidopa intestinal gel treatment in advanced Parkinson’s disease. Journal of Neurology, 265 (6), 1279–1287. doi:

Owens-Walton, C., Jakabek, D., Li, X., Wilkes, F. A., Walterfang, M., Ve-lakoulis, D. et al. (2018). Striatal changes in Parkinson disease: An investigation of morphology, functional connectivity and their relationship to clinical symptoms. Psychiatry Research: Neuroimaging, 275, 5–13. doi:

Rodríguez-Nogales, C., Garbayo, E., Carmona-Abellán, M. M., Luquin, M. R., Blanco-Prieto, M. J. (2016). Brain aging and Parkinson’s disease: New therapeutic approaches using drug delivery systems. Maturitas, 84, 25–31. doi:

Salat, D., Tolosa, E. (2013). Levodopa in the treatment of Parkinson’s disease: current status and new developments. Journal of Parkinson's Disease, 3, 255–269. doi:

Krishna, R., Ali, M., Moustafa, A. A. (2014). Effects of combined MAO-B inhibitors and levodopa vs. monotherapy in Parkinson’s disease. Frontiers in Aging Neuroscience, 6. doi:

Erdő, F., Bors, L. A., Farkas, D., Bajza, Á., Gizurarson, S. (2018). Evaluation of intranasal delivery route of drug administration for brain targeting. Brain Research Bulletin, 143, 155–170. doi:

de Souza Silva, M. A., Mattern, C., Decheva, C., Huston, J. P., Sadile, A. G., Beu, M. et al. (2016). Intranasal Dopamine Reduces In Vivo [123I]FP-CIT Binding to Striatal Dopamine Transporter: Correlation with Behavioral Changes and Evidence for Pavlovian Conditioned Dopamine Response. Frontiers in Behavioral Neuroscience, 10. doi:

Graff, C. L., Pollack, G. M. (2005). Nasal Drug Administration: Potential for Targeted Central Nervous System Delivery. Journal of Pharmaceutical Sciences, 94 (6), 1187–1195. doi:

Lawrence, D. (2002). Intranasal delivery could be used to administer drugs directly to the brain. The Lancet, 359 (9318), 1674. doi:

Ross, T. M., Martinez, P. M., Renner, J. C., Thorne, R. G., Hanson, L. R., Frey, W. H. (2004). Intranasal administration of interferon beta bypasses the blood–brain barrier to target the central nervous system and cervical lymph nodes: a non-invasive treatment strategy for multiple sclerosis. Journal of Neuroimmunology, 151 (1-2), 66–77. doi:

Vyas, T., Shahiwala, A., Marathe, S., Misra, A. (2005). Intranasal Drug Delivery for Brain Targeting. Current Drug Delivery, 2 (2), 165–175. doi:

Tang, S., Wang, A., Yan, X., Chu, L., Yang, X., Song, Y. et al. (2019). Brain-targeted intranasal delivery of dopamine with borneol and lactoferrin co-modified nanoparticles for treating Parkinson’s disease. Drug Delivery, 26 (1), 700–707. doi:

Wang, A.-L., Fazari, B., Chao, O. Y., Nikolaus, S., Trossbach, S. V., Korth, C. et al. (2017). Intra-nasal dopamine alleviates cognitive deficits in tgDISC1 rats which overexpress the human DISC1 gene. Neurobiology of Learning and Memory, 146, 12–20. doi:

Gartziandia, O., Egusquiaguirre, S. P., Bianco, J., Pedraz, J. L., Igartua, M., Hernandez, R. M. et al. (2016). Nanoparticle transport across in vitro olfactory cell monolayers. International Journal of Pharmaceutics, 499 (1-2), 81–89. doi:

Singh, K., Ahmad, Z., Shakya, P. et al. (2016). Nano formulation: a novel approach for nose to brain drug delivery. Journal of Chemical and Pharmaceutical Research, 82, 208–215.

Buresh, Ya., Petran', M., Zakhar, I. (1962). Elektrofiziologicheskie metody issledovaniya. Moscow: Izd-vo inostr. lit., 466.

Paxinos, G., Watson, C. (1982). The rat brain in stereotaxic coordinates. Ac-ademic Press.

Berchenko, O. G. (1990). Neyrofiziologicheskaya organizatsiya tsikla bodrstvovanie-son pri alkogolizme krys, sformirovannom v razlichnye fazy emotsional'noy aktivnosti. Fiziologicheskiy zhurnal, 76 (6), 713–719.

De Souza Silva, M. A., Topic, B., Huston, J. P., Mattern, C. (2008). Intranasal dopamine application increases dopaminergic activity in the neostriatum and nucleus accumbens and enhances motor activity in the open field. Synapse, 62 (3), 176–184. doi:

Buddenberg, T. E., Topic, B., Mahlberg, E. D., de Souza Silva, M. A., Huston, J. P., Mattern, C. (2008). Behavioral Actions of Intranasal Application of Dopamine: Effects on Forced Swimming, Elevated Plus-Maze and Open Field Parameters. Neuropsychobiology, 57 (1-2), 70–79. doi:

Makarenko, A. N., Grigor'eva, T. I., Kaluev, A. V. (2006). Morfo-funktsional'nye osobennosti organizatsii obonyatel'nogo analizatora i problema aksonal'nogo transporta veschestv. Neyronauki, 2 (4), 18–28.

Berchenko, O., Usmentseva, Y. (2013). Recovery of nigrostriatal dopaminergic system insufficiency by allotransplantation of embryonic brain tissue. World Journal of Neuroscience, 03 (04), 240–245. doi:

Correction of the wake-sleep cycle by intranasal administration of dopamine in modeling of the preclinical stage of Parkinson's disease in rats

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How to Cite
Geiko, V., & Berchenko, O. (2022). Correction of the wake-sleep cycle by intranasal administration of dopamine in modeling of the preclinical stage of Parkinson’s disease in rats. EUREKA: Life Sciences, (5), 47-57.