Mori Tomohisa, Uzawa Naoki, Iwase Yoshiyuki, Masukawa Daiki, Rahmadi Mahardian, Hirayama Shigeto, Hokazono Mayuna, Higashiyama Kimio, Shioda Seiji, Suzuki Tsutomu
Department of Toxicology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo, 142-8501, Japan.
Department of Pharmacology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo, 142-8501, Japan.
Psychopharmacology (Berl). 2016 Jun;233(12):2343-53. doi: 10.1007/s00213-016-4282-1. Epub 2016 Apr 11.
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.
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.
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.
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.
食欲素基因敲除（KO）小鼠表现出与人类发作性睡病相似的表型，并且单胺相关化合物，如精神兴奋剂和5-羟色胺摄取抑制剂，已被用于治疗发作性睡病。然而，关于食欲素基因敲除小鼠的病理生理特征，尤其是其发作性睡病样疾病以及单胺相关化合物如何影响该疾病，目前所知甚少。
本研究旨在调查食欲素基因敲除小鼠神经元变化的本质以及单胺相关化合物对食欲素基因敲除小鼠睡眠障碍的治疗效果。
在黑暗期观察到食欲素基因敲除小鼠的运动活动减少，而精神兴奋剂和5-羟色胺相关化合物，如8-OH-DPAT（5-HT1A受体激动剂）和DOI（5-HT2受体激动剂），可抑制这种运动减少。我们还发现，在黑暗期，食欲素基因敲除小鼠前额叶皮质中5-HT1A受体mRNA水平显著降低，而5-HT2或多巴胺受体的mRNA水平未降低，并且这伴随着5-羟色胺代谢物水平升高的受损。此外，通过黑暗期多导睡眠图分析，食欲素基因敲除小鼠的睡眠障碍被8-OH-DPAT完全纠正。
这些结果表明，5-HT1A受体功能障碍参与了食欲素基因敲除小鼠的发作性睡病样睡眠功能障碍，并且这种功能障碍可能参与了食欲素缺乏诱导的睡眠障碍。此外，使用5-HT1A受体激动剂可能有助于治疗食欲素缺乏情况下的睡眠障碍。
