Blockade of NK3R signaling in the PVN decreases vasopressin and oxytocin release and c-Fos expression in the magnocellular neurons in response to hypotension

Abstract

Tachykinin neurokinin 3 receptor (NK3R) signaling has a broad role in vasopressin (VP) and oxytocin (OT) release. Hydralazine (HDZ)-induced hypotension activates NK3R expressed by magnocellular neurons, increases plasma VP and OT levels, and induces c-Fos expression in VP and OT neurons. Intraventricular pretreatment with the specific NK3R antagonist, SB-222200, eliminates the HDZ-stimulated VP and OT release. NK3R are distributed in the central pathways conveying hypotension information to the magnocellular neurons, and the NK3R antagonist could act anywhere in the pathways. Alternatively, the antagonist could act at the NK3R expressed by the magnocellular neurons. To determine whether blockade of NK3R on magnocellular neurons impairs VP and OT release to HDZ, rats were pretreated with a unilateral PVN injection of 0.15 M NaCl or SB-222200 prior to an intravenous injection of 0.15 M NaCl or HDZ. Blood samples were taken, and brains were processed for VP/c-Fos and OT/c-Fos immunohistochemistry. Intravenous injection of 0.15 M NaCl did not alter plasma hormone levels, and little c-Fos immunoreactivity was present in the PVN. Conversely, intravenous injection of HDZ increased plasma VP and OT levels and c-Fos expression in VP and OT magnocellular neurons. Intra-PVN injection of SB-222200 prior to an intravenous injection of HDZ significantly decreased c-Fos expression in both VP and OT neurons by approximately 70% and attenuated plasma VP and OT levels by 33% and 35%, respectively. Therefore, NK3R signaling in magnocellular neurons has a critical role for the release of VP and OT in response to hypotension.

Forebrain projections of arcuate neurokinin B neurons demonstrated by anterograde tract-tracing and monosodium glutamate lesions in the rat

“…For example, fluid balance and cardiovascular function could be modulated through projections to the paraventricular nucleus (Haley and Flynn, 2008) or periventricluar hypothalamus (Saper and Levisohn, 1983; McKinley et al, 2001). Projections to the paraventricular nucleus could also play a role in feeding, the stress response and autonomic regulation (Simerly, 2004).…”

Neurokinin 3 receptor forms a complex with acetylated histone H3 and H4 in hypothalamic neurons following hyperosmotic challenge

“…The question becomes what specific genes may be affected by NK3R. Acute hyperosmolarity causes the local intra-PVN release of an NK3R ligand (21,22). Ligand binding to the receptor causes the internalization and translocation of NK3R to the nucleus (21,28).…”

“…Although hyperosmolarity alters the expression levels of multiple mRNAs (6,34), local injections of NK3R agonists into the SON activate a very limited set of genes (33). In particular, both acute hyperosmolarity and NK3R agonists activate c-Fos (22,58). The induction of c-fos involves the acetylation of H3 and H4 at the c-fos promoter (10,59).…”

Functional, anatomical, and neurochemical differentiation of medial preoptic area subregions in relation to maternal behavior in the mouse

“…Not only VTA but also other brain areas might respond to these peptides during maternal behavior. The responsiveness of neurotensin is altered in various brain areas during the postpartum period (Gammie et al, 2009(Gammie et al, , 2012Scotti et al, 2011), and vasopressin and oxytocin release from magnocellular neurons in the periventricular nucleus was inhibited by the receptor antagonism of neurokinin B (Haley and Flynn, 2008). The direct role of these peptides in performance of maternal behavior, however, has not been suggested by observations of genetic mutant mice with deletion of these peptides or their receptors (Wynick al., 1998;Dobner et al, 2001;Jacoby et al, 2002;Kung et al, 2004), and the distribution of c-Fos-ir neurons expressing these peptides overlapped with, but is not limited to, the cMPOA (Fig.…”