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

May 22, 2026Journal of pharmacological sciences

Changes in the brain’s wakefulness system, stress response, and body clock in young rats exposed to stress

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Abstract

Juvenile-stressed rats exhibited significantly reduced prepro-orexin mRNA levels in the hypothalamus.

Foot shock stress resulted in no change in orexin A protein or orexin A-like immunoreactive cells.
Increased mRNA and protein levels of orexin receptor type 1 were observed in the dorsal hippocampus of stressed rats.
Microinjection of orexin receptor type 1 and type 2 antagonists in naïve rats led to reduced depressive-like behaviors.
The findings suggest that the hippocampus may be a target for the antidepressant effects of orexin receptor antagonists.
Stressed rats demonstrated slight enhancement of the hypothalamus-pituitary-adrenal axis, decreased daily temperature variations, and increased behavioral activity.

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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, SB334867, 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.

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

Abstract

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