Changes in the orexin system, hypothalamic-pituitary-adrenal axis and circadian rhythm in juvenile-stressed rats

The orexin system has been demonstrated to play various physiological roles, such as in feeding, sleep, and autonomic neural function. Clinically, orexin receptor antagonists are used as hypnotics, and several clinical trials have suggested their efficacy in major depressive disorder. We investigated the orexin system using juvenile-stressed (3-week foot shock) rats, an animal model of depression. 3-week foot shock rats had significantly reduced prepro-orexin mRNA in the hypothalamus, but not orexin A protein or orexin A -like immunoreactive cells. In contrast, orexin receptor type 1 mRNA and its protein were significantly increased in the dorsal hippocampus, suggesting that some abnormality in orexin neurotransmission in this region due to 3wFS led to changes in orexin receptor type 1. Microinjection of a selective orexin receptor type 1 antagonist, SB33486, and a selective orexin receptor type 2 antagonist, TCS OX2 29, into the dorsal hippocampus in naïve rats reduced depressive-like behaviors, suggesting that the hippocampus is a target brain site for the antidepressant effects of orexin receptor antagonists. Furthermore, 3-week foot shock rats showed a slight enhancement of the hypothalamus-pituitary-adrenal axis, a decrease in daily variations in body temperature, and increased behavioral activity.