Effects of Intranasal Neuropeptide Y and HS014 in Preventing Anxiety and Depressive‐like Behavior Elicited by Single Prolonged Stress Animal Model of PTSD: Comparative Study

Abstract

Stress triggered neuropsychiatric disorders are a serious societal problem. Prophylactic treatment or early intervention has great potential in increasing resilience to traumatic stress and reducing its harmful impact. Previously, we demonstrated proof of concept that intranasal administration of NPY or the MC4 receptor antagonist, HS014, prior to single prolonged stress (SPS) rodent PTSD model, can prevent or attenuate many PTSD associated impairments. Here, we compare effects of NPY and HS014 given 30 min before or immediately after SPS stressors on development of anxiety, depressive‐like behavior and associated biochemical abnormalities. SPS triggered anxiety on EPM was reduced by intranasal pre‐administration of 100 µg NPY and to even greater extent HS014 (3.5 ng or 100 µg). The SPS‐elicited depressive‐like behavior on FST was prevented with 100 µg NPY or the high dose HS014. Combined administration of low HS014 and NPY, ineffective by themselves, prevented development of depressive‐like behavior. Reductions in stress triggered activation of LC/noradrenergic system and HPA axis were observed with both HS014 and NPY. In contrast to NPY, early intervention with HS014 immediately after SPS did not prevent the development of anxiogenic behavior on EPM. However, HS014 given after SPS stressors, even at very low dose, prevented development of depressive‐like behavior. Thus, both MC4R antagonist and NPY, alone or combined, have potential for prophylactic treatment against traumatic stress triggered anxiety or depressive‐like behaviors, while NPY has more widespread potential for early intervention. (Supported by US Amy grant DM102281)