Examine whether intranasal neuropeptide Y (NPY) is able to alter development of several stress-triggered behavioral impairments in females.

Sex is involved in susceptibility to many stress-elicited, neuropsychiatric disorders. However, most of the studies in animal models examining putative therapeutics excludes females. Previous studies in males demonstrated intranasal NPY provided therapeutic relief of stress-elicited behaviors, but not at the same dose in females. Interestingly, the overwhelming majority of studies found that NPY expression is lower in females than in male rodents in many brain areas.

Sprague Dawley female rats were exposed to the Single Prolonged Stress (SPS) animal model and then were immediately infused intranasally with one of several NPY doses starting with 600 µg/rat, which is double the dose effective in males. In a separate cohort of animals, females were infused intranasally with 600µg NPY, a dipeptidyl peptidase IV (DPP4; NPY protease) inhibitor, or both immediately after the SPS stressors. After 14 days they were tested on several behavioral tests.

Intranasal NPY at 600µg prevented the SPS-elicited impairment of social interaction. On the forced swim test (FST), there was a dose-response effect of intranasal NPY, with the 1200µg, but not the 600µg, effectively preventing development of the SPS-elicited increased immobility (depressive-like behavior). However, the DPP4 inhibitor and 600µg NPY combined treatment was sufficient at preventing depressive-like behavior on the FST.

The results indicate that in females SPS elicits behavioral manifestations of stress-related disorders, such as depressive-like behavior and social impairment. This was prevented with early intervention with high doses of NPY, indicating its therapeutic potential also for females, although a higher dose will likely be required. Furthermore, NPY degradation may play a role in the higher dose requirement for females.