Comparative effects of intranasal neuropeptide Y and HS014 in preventing anxiety and depressive-like behavior elicited by single prolonged stress

• Given prior to SPS both HS014 and NPY are anxiolytic and prevent rise in hippocampal GR.
• Given prior to SPS both alter activation of HPA axis and noradrenergic system.
• Low dose NPY and HS014 have a synergistic effect on depressive like behavior.
• Early intervention with HS014 does not have an anxiolytic effect but reduces depressive behavior.

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 neuropeptide Y (NPY) or the melanocortin receptor four (MC4R) antagonist, HS014, prior to single prolonged stress (SPS) rodent post-traumatic stress disorder (PTSD) model, can prevent or attenuate many PTSD associated impairments. Here, we compare effects of NPY or 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 elevated plus maze (EPM) was reduced by intranasal administration of 100 μg NPY and to even greater extent HS014 (3.5 ng or 100 μg). The SPS-elicited depressive-like behavior on forced swim test 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 locus coeruleus/noradrenergic system and HPA axis were observed with both HS014 and NPY. In contrast to NPY which has been showed earlier, infusion of HS014 immediately after SPS did not prevent the development of anxiogenic behavior on EPM. However, HS014 given after SPS stressors effectively 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.