Nasal administration of orexin A partially rescues dizocilpine-induced cognitive impairments in female C57BL/6 J mice.

Sex difference has been reported in several behavioral endophenotypes of neuropsychiatric disorder in both rodents and humans. However, sex difference in cognitive symptoms associated with neuropsychiatric disorders has not been studied in detail. In this study, we induced cognitive impairment using the NMDA receptor antagonist, dizocilpine (MK-801), in male and female C57BL/6 J mice and performed a visual discrimination task in an automated touchscreen system. We found that discrimination performance decreased with increased doses of MK-801 in both sexes. However, female mice showed stronger deficit in discrimination performance than the male mice especially after administration of low (0.01 mg/kg) and high (0.15 mg/kg) doses of MK-801. Furthermore, we tested if administration of orexin A, orexin-1 receptor antagonist SB-334867 or orexin-2 receptor antagonist EMPA rescued MK-801 (0.15 mg/kg) induced cognitive impairment in visual discrimination. We found that nasal administration of orexin A partially rescued the cognitive impairment induced by MK-801 in females but not in males. Taken together, our data show that female C57BL/6 J mice are more sensitive compared to males to some doses of MK-801 in discrimination learning task and that orexin A partially rescues this cognitive impairment in females.