Juvenile stress reduces hypothalamic prepro-orexin, increases hippocampal OX1R in rats; antagonists cut depressive behaviors.

Current treatments for major depressive disorder (MDD) often have limited efficacy or side effects, necessitating novel therapeutic targets. The orexin system (also known as hypocretin) plays crucial roles in sleep, feeding, and autonomic function, with orexin receptor antagonists already approved as hypnotics. Emerging evidence suggests a significant role for orexins in mood regulation, making them a potential target for antidepressant therapies. However, the specific changes in the orexin system and its interaction with the hypothalamic-pituitary-adrenal (HPA) axis in stress-induced depression models, particularly following juvenile stress, remain underexplored.

Researchers investigated the orexin system using a juvenile-stressed rat model of depression, inducing stress via 3-week foot shock (3wFS). They measured prepro-orexin mRNA and orexin A protein in the hypothalamus, and orexin receptor type 1 (OX1R) mRNA and protein in the dorsal hippocampus. To assess therapeutic potential, they microinjected SB334867 (a selective OX1R antagonist) and TCS OX2 29 (a selective OX2R antagonist) into the dorsal hippocampus of naïve rats. Primary endpoints included depressive-like behaviors, HPA axis activity, and circadian rhythm parameters like body temperature and behavioral activity.

Juvenile-stressed rats (3wFS) exhibited significant alterations in the orexin system. Hypothalamic prepro-orexin mRNA was significantly reduced in 3wFS rats, though orexin A protein and orexin A-like immunoreactive cells remained unchanged. In contrast, orexin receptor type 1 (OX1R) mRNA and its protein were significantly increased in the dorsal hippocampus of stressed animals, suggesting abnormal orexin neurotransmission in this region.

Microinjection of SB334867 (OX1R antagonist) and TCS OX2 29 (OX2R antagonist) into the dorsal hippocampus of naïve rats reduced depressive-like behaviors, highlighting the hippocampus as a key target for antidepressant effects. Furthermore, 3wFS rats showed a slight enhancement of the hypothalamus-pituitary-adrenal (HPA) axis, a decrease in daily variations in body temperature, and increased behavioral activity, indicating broader physiological dysregulation.