Acute Hypernatremia Exerts an Inhibitory Oxytocinergic Tone That Is Associated With Anxiolytic Mood in Male Rats

Abstract

Anxiety disorders are the most common psychiatric illnesses and are associated with heightened stress responsiveness. The neuropeptide oxytocin (OT) has garnered significant attention for its potential as a treatment for anxiety disorders; however, the mechanism mediating its effects on stress responses and anxiety is not well understood. Here we used acute hypernatremia, a stimulus that elevates brain levels of OT, to discern the central oxytocinergic pathways mediating stress responsiveness and anxiety-like behavior. Rats were rendered hypernatremic by acute administration of 2.0 M NaCl and had increased plasma sodium concentration, plasma osmolality, and Fos induction in OT-containing neurons relative to 0.15 M NaCl-treated controls. Acute hypernatremia decreased restraint-induced elevations in corticosterone and created an inhibitory oxytocinergic tone on parvocellular neurosecretory neurons within the paraventricular nucleus of the hypothalamus. In contrast, evaluation of Fos immunohistochemistry determined that acute hypernatremia followed by restraint increased neuronal activation in brain regions receiving OT afferents that are also implicated in the expression of anxiety-like behavior. To determine whether these effects were predictive of altered anxiety-like behavior, rats were subjected to acute hypernatremia and then tested in the elevated plus maze. Relative to controls given 0.15 M NaCl, rats given 2.0 M NaCl spent more time in the open arms of the elevated plus maze, suggesting that acute hypernatremia is anxiolytic. Collectively the results suggest that acute elevations in plasma sodium concentration increase central levels of OT, which decreases anxiety by altering neuronal activity in hypothalamic and limbic nuclei.

Acute hypernatremia promotes anxiolysis and attenuates stress-induced activation of the hypothalamic–pituitary–adrenal axis in male mice

“…Relative to isonatremic controls, mice rendered mildly hypernatremic had decreased plasma CORT subsequent to the onset of restraint. These results are in agreement with our previous studies demonstrating that rats subjected to a similar degree of hypernatremia have decreased plasma CORT subsequent to a restraint challenge [8] [9]. Our previous study also determined that acute hypernatremia decreases the secretion of adrenocorticotropic-releasing-hormone (ACTH) into the systemic circulation [8].…”

“…Microcapillary samples were measured for hematocrit, and plasma was extracted and stored at −80° C until pNa + , plasma proteins, and CORT analyses took place. Plasma sodium levels were determined for the blood sample taken at the onset of restraint using an auto flame photometer as previously described [9] (Instrumentation Laboratory, Lexington, Massachusetts). Plasma CORT was determined for each time point a blood sample was taken using an 125 I RIA kit (MP Biomedicals, Santa Ana, California) as previously described [9].…”

“…Plasma sodium levels were determined for the blood sample taken at the onset of restraint using an auto flame photometer as previously described [9] (Instrumentation Laboratory, Lexington, Massachusetts). Plasma CORT was determined for each time point a blood sample was taken using an 125 I RIA kit (MP Biomedicals, Santa Ana, California) as previously described [9]. Plasma proteins and hematocrit were determined for the blood sample taken at the onset of restraint using a handheld refractometer (VET 360, Reichert) and microcapillary reader, respectively.…”

“…As mentioned, the secretion of Ang-II, ALDO, AVP, and OT are heavily influenced by the pNa + , and therefore, it is possible that alterations in body sodium levels affect stress responding and anxiety-like behavior through manipulation of these neuroendocrine signals. In this regard, previous work from our group and others have found that sodium depletion is anxiogenic [7] but acute salt loading is anxiolytic and dampens stress responsiveness in laboratory rats [8] [9]. While the changes in the pNa + are found to influence mood and stress responding in rats, whether these effects generalize to mice, and therefore, allow the use of the genetic manipulations that mouse models afford to investigate central mechanism(s) underlying the stress limiting effects of acute hypernatremia has not been evaluated.…”

Target-based biomarker selection – Mineralocorticoid receptor-related biomarkers and treatment outcome in major depression

“…In contrast, a rapid uptake of extracellular glutamate to avoid activation of extra-synaptic glutamate appears to be beneficial. Animal data demonstrate that an increased dietary Na þ leads to reduced anxiety and depression like behavior (Frazier et al, 2013;Krause et al, 2011), while Na þ depletion leads to the increased anxiety and anhedonia (Morris et al, 2006(Morris et al, , 2010. In both situations these effects appear to be mediated via a change of RAAS activity.…”