Intracerebroventricular injection of neuropeptide Y suppresses luteinizing hormone pulses in mice.

Stress impairs reproduction, at least in part, by inhibition of Kisspeptin/Neurokinin B/Dynorphin (KNDy) cells and suppression of gonadotropin secretion. However, the mechanism for this inhibition is not clear. Neuropeptide Y (NPY) is a pleiotropic molecule that is produced in neurons throughout the brain and mediates several physiological processes including energy homeostasis and stress responses. Centrally administered NPY elicits variable effects on luteinizing hormone (LH) secretion, which vary with species, gonadal status, and the site of infusion. Therefore, our objective was to determine the in vivo action of central NPY administration on LH pulses in mice. Frequent blood samples were collected and assayed for LH concentrations from male and female mice that received a central injection of NPY or saline (control). Additional studies were performed in which NPY or saline treated animals received a kisspeptin challenge to evaluate direct effects on GnRH cells, or tissue collection to evaluate transcripts associated with KNDy cells. Intracerebroventricular injection (ICV) of NPY robustly suppressed LH pulses in ovariectomized (OVX) female and gonadectomized (GDX) male mice. However, the same treatment in gonad-intact males yielded variable responses, and analysis in estradiol-replaced OVX female mice revealed an unexpected suppression of LH following brief isoflurane exposure. In assessment of KNDy neurons, we found a statistically significant increase in the abundance of mRNA encoding dynorphin in micro-punches of the arcuate nucleus 1 h after ICV injection of NPY. In further support of the hypothesis that NPY impairs KNDy cells, we found that animals pretreated with NPY or saline had the same response to exogenous kisspeptin, suggesting gonadotropin-releasing hormone neurons and gonadotrope cells remain fully responsive to stimulation. We conclude that NPY is sufficient to suppress LH secretion in OVX female and GDX male mice and that this suppression is likely mediated by the KNDy cells in the arcuate nucleus.