Tomohisa Mori1,2, Naoki Uzawa3, Yoshiyuki Iwase3, Daiki Masukawa3, Mahardian Rahmadi3, Shigeto Hirayama3, Mayuna Hokazono3, Kimio Higashiyama4, Seiji Shioda5, Tsutomu Suzuki6,7. 1. Department of Toxicology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo, 142-8501, Japan. t-mori@hoshi.ac.jp. 2. Department of Pharmacology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo, 142-8501, Japan. t-mori@hoshi.ac.jp. 3. Department of Toxicology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo, 142-8501, Japan. 4. Institute of Medicinal Chemistry, Hoshi University School of Pharmacy and Pharmaceutical Sciences, Tokyo, 142-8501, Japan. 5. Peptide Drug Innovation, Global Research Center for Innovative Life Science, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo, 142-8501, Japan. 6. Department of Toxicology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo, 142-8501, Japan. suzuki@hoshi.ac.jp. 7. Institute of Medicinal Chemistry, Hoshi University School of Pharmacy and Pharmaceutical Sciences (K.H.), Tokyo, 142-8501, Japan. suzuki@hoshi.ac.jp.
Abstract
RATIONALE: Orexin knockout (KO) mice exhibit a phenotype that is similar to human narcolepsy, and monoamine-related compounds, such as psychostimulants and 5-HT uptake inhibitors, have been used for the treatment of narcoleptic disorders. However, little information is available regarding the pathophysiological features of orexin KO mice, particularly with respect to their narcoleptic-like disorder and how it is affected by monoamine-related compounds. OBJECTIVES: The present study was designed to investigate both the nature of the neuronal changes in orexin KO mice and the therapeutic effects of monoamine-related compounds on the sleep disorder in orexin KO mice. RESULTS: A decrease in locomotor activity in the dark phase was observed in orexin KO mice, and psychostimulants and 5-HT-related compounds, such as 8-OH-DPAT (5-HT1A receptor agonist) and DOI (5-HT2 receptor agonist), inhibited this hypolocomotion. We also found that 5-HT1A receptor mRNA levels, but not those for 5-HT2 or dopamine receptors, were significantly decreased in the prefrontal cortex of orexin KO mice in the dark period and were accompanied by compromising the increase in 5-HT metabolite levels. In addition, the sleep disorder in orexin KO mice, as analyzed by a polysomnography during the dark period, was completely normalized by 8-OH-DPAT. CONCLUSION: These results suggest that a dysfunction of 5-HT1A receptors is involved in the narcoleptic-like sleep dysfunction in orexin KO mice, and such dysfunction may participate in orexin deficiency-induced sleep disorders. Further, the use of 5-HT1A receptor agonist could be useful for treating the sleep disorder under a deficiency of orexin.
RATIONALE: Orexin knockout (KO) mice exhibit a phenotype that is similar to humannarcolepsy, and monoamine-related compounds, such as psychostimulants and 5-HT uptake inhibitors, have been used for the treatment of narcoleptic disorders. However, little information is available regarding the pathophysiological features of orexin KO mice, particularly with respect to their narcoleptic-like disorder and how it is affected by monoamine-related compounds. OBJECTIVES: The present study was designed to investigate both the nature of the neuronal changes in orexin KO mice and the therapeutic effects of monoamine-related compounds on the sleep disorder in orexin KO mice. RESULTS: A decrease in locomotor activity in the dark phase was observed in orexin KO mice, and psychostimulants and 5-HT-related compounds, such as 8-OH-DPAT (5-HT1A receptor agonist) and DOI (5-HT2 receptor agonist), inhibited this hypolocomotion. We also found that 5-HT1A receptor mRNA levels, but not those for 5-HT2 or dopamine receptors, were significantly decreased in the prefrontal cortex of orexin KO mice in the dark period and were accompanied by compromising the increase in 5-HT metabolite levels. In addition, the sleep disorder in orexin KO mice, as analyzed by a polysomnography during the dark period, was completely normalized by 8-OH-DPAT. CONCLUSION: These results suggest that a dysfunction of 5-HT1A receptors is involved in the narcoleptic-like sleep dysfunction in orexin KO mice, and such dysfunction may participate in orexindeficiency-induced sleep disorders. Further, the use of 5-HT1A receptor agonist could be useful for treating the sleep disorder under a deficiency of orexin.
Authors: J Hara; C T Beuckmann; T Nambu; J T Willie; R M Chemelli; C M Sinton; F Sugiyama; K Yagami; K Goto; M Yanagisawa; T Sakurai Journal: Neuron Date: 2001-05 Impact factor: 17.173
Authors: R M Chemelli; J T Willie; C M Sinton; J K Elmquist; T Scammell; C Lee; J A Richardson; S C Williams; Y Xiong; Y Kisanuki; T E Fitch; M Nakazato; R E Hammer; C B Saper; M Yanagisawa Journal: Cell Date: 1999-08-20 Impact factor: 41.582
Authors: D Hoyer; D E Clarke; J R Fozard; P R Hartig; G R Martin; E J Mylecharane; P R Saxena; P P Humphrey Journal: Pharmacol Rev Date: 1994-06 Impact factor: 25.468