Activation of NPY receptor subtype 1 by [D-His26]NPY is sufficient to prevent development of anxiety and depressive like effects in the single prolonged stress rodent model of PTSD

Abstract

The neuropeptide Y (NPY) system plays an important role in mediating resilience to the harmful effect of stress in post-traumatic stress disorder (PTSD). It can mediate its effects via several G-protein coupled receptors: Y1R, Y2R, Y4R and Y5R. To investigate the role of individual NPY receptors in the resilience effects of NPY to traumatic stress, intranasal infusion of either Y1R agonists [D-His²⁶]NPY, [Leu³¹Pro³⁴]NPY, Y2R agonist NPY (3-36) or NPY were administered to male Sprague-Dawley rats immediately following the last stressor of the single prolonged stress (SPS) protocol, a widely used PTSD animal model. After 7 or 14 days, effects of the treatments were measured on the elevated plus maze (EPM) for anxiety, in forced swim test (FST) for development of depressive-like or re-experiencing behavior, in social interaction (SI) test for impaired social behavior, and acoustic startle response (ASR) for hyperarousal. [D-His²⁶]NPY, but not [Leu³¹Pro³⁴]NPY nor NPY (3-36) Y2R, was effective in preventing the SPS-elicited development of anxiety. Y1R, but not Y2R agonists prevented development of depressive- feature on FST, with [D-His²⁶]NPY superior to NPY. The results demonstrate that [D-His²⁶]NPY was sufficient to prevent development of anxiety, social impairment and depressive symptoms, and has promise as an early intervention therapy following traumatic stress.

Keywords: Anxiety; Depressive behavior; Early intervention; Intranasal; NPY receptor agonists; Neuropeptide Y; Single prolonged stress; Social interaction; Y1 receptor; Y2 receptor.