Potential benefits of intranasal neuropeptide Y include sustained extinction of fear memory

Compelling evidence in animals and humans from a variety of approaches demonstrate that neuropeptide Y (NPY) in the brain can provide resilience to development of many stress-elicited symptoms. Preclinical experiments demonstrated that delivery of NPY by intranasal infusion to rats shortly after single exposure to traumatic stress in the single prolonged stress (SPS) rodent model of post-traumatic stress disorder (PTSD) can prevent development of many relevant behavioral alterations weeks later, including heightened anxiety and depressive-like behavior. Here, we examined responses to intranasal NPY in the absence of stress to evaluate the safety profile. Rats were administered intranasal NPY (150 μg/rat) or equal volume of vehicle (distilled water), and 7 days later they were tested on the elevated plus maze (EPM) and forced swim test (FST). There was no significant difference in the number of entries or duration in the open or closed arms, or in their anxiety index. Defecation on the EPM and immobility on the FST, measures of anxiety and depressive-like behavior respectively, were similar in both groups. To further characterize potential benefits of intranasal NPY, its effect on fear memory and extinction, important features of PTSD, were examined. Intranasal administration of NPY at the time of the traumatic stress had a profound effect on fear conditioning a week later. It prevented the SPS-triggered impairment in the retention of extinguished behavior, both contextual and cued. The findings support the translation of non-invasive intranasal NPY delivery to the brain for PTSD-behaviors including impairments in sustained extinction of fear memories.