Narcolepsy-like sleep disturbance in orexin knockout mice are normalized by the 5-HT_1Areceptor agonist 8-OH-DPAT

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-HT_1Areceptor agonist) and DOI (5-HT₂receptor agonist), inhibited this hypolocomotion. We also found that 5-HT_1Areceptor mRNA levels, but not those for 5-HT₂or 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-HT_1Areceptors 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-HT_1Areceptor agonist could be useful for treating the sleep disorder under a deficiency of orexin.