Saliva oxytocin measures do not reflect peripheral plasma concentrations after intranasal oxytocin administration in men
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Oxytocin plays an important role in social behavior. Thus, there has been significant research interest for the role of the oxytocin system in several psychiatric disorders, and the potential of intranasal oxytocin administration to treat social dysfunction. Measurement of oxytocin concentrations in saliva are sometimes used to approximate peripheral levels of oxytocin; however, the validity of this approach is unclear. In this study, saliva and plasma oxytocin was assessed after two doses of Exhalation Delivery System delivered intranasal oxytocin (8IU and 24IU), intravenous oxytocin (1IU) and placebo in a double-dummy, within-subjects design with men. We found that intranasal oxytocin (8IU and 24IU) administration increased saliva oxytocin concentrations in comparison to saliva oxytocin concentration levels after intravenous and placebo administration. Additionally, we found that saliva oxytocin concentrations were not significantly associated with plasma oxytocin concentrations after either intranasal or intravenous oxytocin administration. Altogether, we suggest that saliva oxytocin concentrations do not accurately index peripheral oxytocin after intranasal or intravenous oxytocin administration, at least in men. The data indicates that elevated oxytocin saliva levels after nasal delivery primarily reflect exogenous administered oxytocin that is cleared from the nasal cavity to the oropharynx, and is therefore a weak surrogate for peripheral blood measurements.Oxytocin has been suggested to have behavioral effects opposite to those ofvasopressin, and exogenous vasopressin is known to induce ACTH release in man. Thus, we tested the influence of exogenous oxytocin on blood levels of ACTH and cortisol during insulin-induced hypoglycemia and after vasopressin injection. Our results demonstrate an inhibitory effect of exogenous oxytocin on ACTH release and support the hypothesis of a reciprocal, balanced modulation of behavioral and neuroendocrine function by the two closely related neurohormones, vasopressin and oxytocin. (J Clin Endocrinol Metab55: 1035, 1982)
Neurohormones
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Adult male rats of the Brattleboro strain were used to investigate the impact of the congenital absence of vasopressin on plasma adrenocorticotropin, corticosterone, and oxytocin concentrations as well as the release pattern of oxytocin within the hypothalamic paraventricular nucleus (PVN), in response to a 10-min forced swimming session. Measurement of adrenocorticotropin in plasma samples collected via chronically implanted jugular venous catheters revealed virtually identical stress responses for vasopressin-lacking Brattleboro (KO) and intact control animals. In contrast, plasma corticosterone and oxytocin levels were found to be significantly elevated 105 min after onset of the stressor in KO animals only. Microdialysis samples collected from the extracellular fluid of the PVN showed significantly higher levels of oxytocin both under basal conditions and in response to stressor exposure in KO vs. intact control animals accompanied by elevated oxytocin mRNA levels in the PVN of KO rats. These findings suggest that the increased oxytocin levels in the PVN caused by the congenital absence of vasopressin may contribute to normal adrenocorticotropin stress responses in KO animals. However, whereas the stressor-induced elevation of plasma oxytocin in KO rats may be responsible for their maintained corticosterone levels, oxytocin seems unable to fully compensate for the lack of vasopressin. This hypothesis was tested by retrodialyzing synthetic vasopressin into the PVN area concomitantly with blood sampling in KO animals. Indeed, this treatment normalized plasma oxytocin and corticosterone levels 105 min after forced swimming. Thus, endogenous vasopressin released within the PVN is likely to act as a paracrine signal to facilitate the return of plasma oxytocin and corticosterone to basal levels after acute stressor exposure.
Corticosterone
Supraoptic nucleus
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Recent studies suggest that oxytocin inhibits ACTH secretion in normal men, whereas previous animal studies indicate that oxytocin is a weak secretagogue of ACTH. We studied the effect of oxytocin on plasma ACTH and cortisol in normal men under three conditions. Using four different doses of oxytocin (30, 60, 90, and 120 mU/kg), given by iv bolus injection, we found no difference in the effect of oxytocin on morning ACTH and cortisol levels compared with the effect of a placebo. A prolonged infusion of oxytocin (90 mU/kg . h) given from 0300-0600 h did not suppress basal ACTH or cortisol levels or delay or blunt their normal circadian rise. In addition, pretreatment with oxytocin (50 mU/kg, iv bolus dose, followed by an infusion of 50 mU/kg . h) did not alter the ACTH and cortisol responses to vasopressin. We conclude that oxytocin is not a major regulator of pituitary-adrenal activity in normal men.
Secretagogue
Bolus (digestion)
Basal (medicine)
ACTH secretion
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Oxytocin plays an important role in social behavior. Thus, there has been significant research interest for the role of the oxytocin system in several psychiatric disorders, and the potential of intranasal oxytocin administration to treat social dysfunction. Measurement of oxytocin concentrations in saliva are sometimes used to approximate peripheral levels of oxytocin; however, the validity of this approach is unclear. In this study, saliva and plasma oxytocin was assessed after two doses of Exhalation Delivery System delivered intranasal oxytocin (8IU and 24IU), intravenous oxytocin (1IU) and placebo in a double-dummy, within-subjects design with men. We found that intranasal oxytocin (8IU and 24IU) administration increased saliva oxytocin concentrations in comparison to saliva oxytocin concentration levels after intravenous and placebo administration. Additionally, we found that saliva oxytocin concentrations were not significantly associated with plasma oxytocin concentrations after either intranasal or intravenous oxytocin administration. Altogether, we suggest that saliva oxytocin concentrations do not accurately index peripheral oxytocin after intranasal or intravenous oxytocin administration, at least in men. The data indicates that elevated oxytocin saliva levels after nasal delivery primarily reflect exogenous administered oxytocin that is cleared from the nasal cavity to the oropharynx, and is therefore a weak surrogate for peripheral blood measurements.
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In addition to its role in reproduction, oxytocin has central actions modulating behavioural and hypothalamic‐pituitary‐adrenal (HPA) axis responses during late pregnancy and lactation. The hypothesis that ovarian hormones modulate the effects of oxytocin on HPA axis activity was studied in 7‐day ovariectomised rats receiving oestradiol with or without progesterone replacement and intracerebroventricular (i.c.v) minipump infusion of oxytocin (100 ng/h). In an initial experiment, i.c.v. oxytocin had no effect on basal or restraint‐stimulated plasma adrenocorticotrophic hormone (ACTH) and corticosterone concentrations or hypothalamic corticotrophin‐releasing factor (CRF) mRNA expression with low oestradiol replacement alone but it had a stimulatory effect in the presence of low oestradiol and progesterone. To investigate further whether oestradiol modulates central actions of oxytocin, rats received low dioestrous (low), pro‐oestrous (medium) or pregnancy (high) oestradiol replacement levels, yielding plasma concentrations of < 5, 17.3 ± 4.5 and 258 ± 32 pg/ml, respectively, with or without i.c.v. oxytocin. Oestradiol caused dose‐dependent increases in basal plasma ACTH and corticosterone concentrations but decreased the ACTH response to restraint stress. In parallel to the changes in basal plasma ACTH, high oestrogen increased basal CRF hnRNA, CRF mRNA in the paraventricular nucleus and pro‐opiomelanocortin (POMC) mRNA in the pituitary gland, while decreasing restraint stress‐stimulated levels. Intracerebroventricular administration of oxytocin reduced basal and stress‐stimulated plasma ACTH, hypothalamic CRF hnRNA (30 min), CRF mRNA and pituitary POMC mRNA (4 h) levels parallel to the increases induced by elevating plasma oestradiol. The present study demonstrates the converse effects of oestradiol on basal and restraint stress‐stimulated basal HPA axis activity, and that the ability of central oxytocin to inhibit HPA axis activity depends on the levels of circulating oestradiol.
Basal (medicine)
Corticosterone
Hypothalamic–pituitary–adrenal axis
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The contribution of oxytocin to the maintenance of renal Na+ excretion in the Brattleboro rat has been examined in animals infused with hypotonic saline. Brattleboro rats exhibited hypernatraemia and hyperosmolality associated with greatly increased plasma concentrations of oxytocin by comparison with Long-Evans control rats. Neurohypophysectomy to remove the secretion of the remaining posterior pituitary peptide, oxytocin, led to greatly diminished rates of Na+ excretion in the Brattleboro rat. Oxytocin replacement to achieve plasma levels equivalent to those in intact Brattleboro rats produced a substantial and sustained natriuresis in the neurohypophysectomized animal. Oxytocin secretion evoked in response to saline infusion would thus appear to be effective in promoting renal Na+ excretion in the absence of vasopressin in the Brattleboro rat.
Hypertonic saline
Posterior pituitary
Renal physiology
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Basal (medicine)
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We have assessed the response of plasma oxytocin (OT) to intracerebroventricular CRF-41 in both virgin female and lactating rats. In virgin rats CRF-41 resulted in an increase in plasma OT from 5-30 min after administration. In lactating rats, however, there was a complete abolition of the OT response, even at the highest dose of CRF-41. These data demonstrate another feature of the hormone nonresponsiveness apparent during lactation and suggests that one of the reasons for the lack of stress responses could be a down-regulation of the response to endogenously released CRF-41.
Corticotropin-releasing hormone
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