Chronic orexin-1 receptor blockage attenuates depressive behaviors and provokes PSD-95 expression in a rat model of depression

Depression is a devastating mood disorder affecting more than 300 million people worldwide. Almost 30% of patients still suffer from treatment resistant depression. Although many reports support the involvement of orexin in the pathophysiology of depression, the precise role of orexin is still unclear. In this study, we evaluated the role of the orexin 1 receptor (Orx 1 R) on depressive behaviors and the alterations in postsynaptic density-95 (PSD-95) protein in the chronic mild stress (CMS) model of depression. Fifty-four male Wistar rats were randomly allocated to 6 groups; Control, CMS, acute SB-334867 (SB), CMS+SB, chronic SB (CSB) and CMS+CSB. Rats were exposed to one or two unpredictable stressors each day for three weeks for the induction of CMS. Intracerebroventricular (icv) injection of SB-334867, a selective Orx 1 R antagonist, was performed either 30 minutes before behavioral tests (acute) or once daily for 14 days (chronic). Behavioral despair was assessed by immobility time in the forced swim test (FST), sucrose consumption in sucrose preference test (SPT), and the number of crosses in the open field test (OFT) on days 1, 11, and 22 of the experiment. Finally, rats were decapitated, and brain tissue of the hippocampus (HPC) and prefrontal cortex (PFC) were collected, and the relative expression of PSD-95 was evaluated by western blotting. The CMS model rats showed a significant increase in FST immobility time (P=0.001) and a decrease in locomotion (P=0.04) and sucrose preference (P=0.039). Chronic application of SB decreased immobility time to the control values (P=0.001) and diminished locomotion (P=0.047) and sucrose preference (P=0.042) in comparison to the CMS group. Acute SB reversed just the immobility time (P≤0.006). Chronic SB treatment increased the relative PSD-95 expression in PFC (P=0.001). Hence, chronic antagonism of Orx 1 R alleviates depressive behaviors induced by CMS and improves PSD-95 expression in PFC. • Orexin-1 receptor is crucial for depressive behaviors in rat model of depression • PSD-95 protein is reduced in the hippocampus and prefrontal cortex of depressed rats • Antagonizing orexin-1 receptor prevents the PSD-95 reduction in prefrontal cortex