Oxytocin gene deletion mice overconsume palatable sucrose solution but not palatable lipid emulsions.

We previously reported that oxytocin knockout (OT KO) mice display markedly enhanced intake of sweet and nonsweet carbohydrate solutions compared with intake by wild-type (WT) mice of the same background strain. The present study was conducted to determine whether OT KO mice demonstrate enhanced intake of Intralipid, a palatable lipid emulsion. Male or female mice of both genotypes that were naive to the test solution were given continuous two-bottle access to Intralipid and water with food available ad libitum for 3 days. Throughout the experiment, mice of both genotypes showed a marked preference for Intralipid over water. On the 1st day, OT KO mice displayed twofold greater preference and consumed nearly twice as much Intralipid compared with WT cohorts. However, on subsequent days of exposure, Intralipid preference and intake did not differ between genotypes over a range of lipid concentrations presented in descending or ascending order. Daily and hourly measures of lipid vs. sucrose intake confirmed that OT KO mice consumed more sucrose solution, but not lipid emulsion, than WT mice. During ad libitum access to Intralipid, both genotypes consumed significantly more calories from the emulsion as concentration increased. Both genotypes maintained consistent total daily caloric intake (lipid plus chow) and compensated by decreasing chow intake over the course of the study. These findings, coupled with prior reports from our laboratory, support the view that OT signaling pathways participate in limiting intake of palatable carbohydrate-containing solutions, but do not appear to play a role in limiting intake of Intralipid.

Maternal behavior deficits in nulliparous oxytocin knockout mice.

The first observations of postpartum oxytocin knockout (OTKO) mice found no maternal behavior deficits. However, it is unclear how detailed those observations were. In this study, we compared maternal behavior exhibited by OTKO and wild-type (WT) nullipara toward six 2-4-day-old foster pups during test sessions conducted on 3 successive days. Each day, subjects were placed in a clean cage 30 min prior to introduction of pups which were deposited in a clump adjacent to the middle of a long wall of each test cage. Behavior was measured for 3.5 h after which pups and test subjects were returned to their home cages. On test days 1 and 3, a significantly smaller proportion of OTKO females retrieved pups to a corner of their cage. Also, significantly fewer pups were retrieved to corners by OTKO females. In contrast to most WTs, most OTKO females mothered pups in the center of the cage where they were initially deposited. Pup-licking frequencies were significantly lower in OTKO females. Their self-grooming frequencies also trended toward being lower. Latencies to retrieve and lick pups, latencies to and frequencies of still crouching over pups and proportion of time in nest did not differ between groups. Our findings suggest that OT stimulates a significant proportion of pup-licking in nulliparous mice, a situation similar to lactating rat mothers. Our results also indicate that OT may play a role in the motivation to retrieve pups to a more secure location.

The effect of trimethoprim on CYP2C8 mediated rosiglitazone metabolism in human liver microsomes and healthy subjects.

AIMS: Rosiglitazone, a thiazolidinedione antidiabetic medication used in the treatment of Type 2 diabetes mellitus, is predominantly metabolized by the cytochrome P450 (CYP) enzyme CYP2C8. The anti-infective drug trimethoprim has been shown in vitro to be a selective inhibitor of CYP2C8. The purpose of this study was to evaluate the effect of trimethoprim on the CYP2C8 mediated metabolism of rosiglitazone in vivo and in vitro. METHODS: The effect of trimethoprim on the metabolism of rosiglitazone in vitro was assessed in pooled human liver microsomes. The effect in vivo was determined by evaluating rosiglitazone pharmacokinetics in the presence and absence of trimethoprim. Eight healthy subjects (four men and four women) completed a randomized, cross-over study. Subjects received single dose rosiglitazone (8 mg) in the presence and absence of trimethoprim 200 mg given twice daily for 5 days. RESULTS: Trimethoprim inhibited rosiglitazone metabolism both in vitro and in vivo. Inhibition of rosiglitazone para-hydroxylation by trimethoprim in vitro was found to be competitive with apparent K(i) and IC(50) values of 29 microm and 54.5 microm, respectively. In the presence of trimethoprim, rosiglitazone plasma AUC was increased by 31% (P = 0.01) from 2774 +/- 645 microg l(-1) h to 3643 +/- 1051 microg l(-1) h (95% confidence interval (CI) for difference 189, 1549), and half-life was increased by 27% (P = 0.006) from 3.3 +/- 0.5 to 4.2 +/- 0.8 h (95% CI for difference 0.36, 1.5). Trimethoprim reduced the para-O-sulphate rosiglitazone/rosiglitazone and the N-desmethylrosiglitazone/rosiglitazone AUC(0-24) ratios by 22% and 38%, respectively. CONCLUSIONS: These results indicate that trimethoprim is a competitive inhibitor of CYP2C8-mediated rosiglitazone metabolism in vitro and that trimethoprim administration increases plasma rosiglitazone concentrations in healthy subjects.

Anxiety and stress responses in female oxytocin deficient mice.

Oxytocin is believed to attenuate the response of the hypothalamic-pituitary-adrenal axis to stress and to be anxiolytic. Stressors with a psychological component evoke both central and peripheral secretion of oxytocin in laboratory rodents. Oxytocin gene deletion mice provide a novel way to understand the role of oxytocin in stress and anxiety-related behaviours. We present our experience with female oxytocin deficient mice that were tested in an elevated plus maze (EPM), a behavioural test of anxiety, or exposed to psychogenic stressors (platform shaker or novel environment). Oxytocin-deficient mice not only displayed more anxiety-related behaviour, but also released more corticosterone after a psychogenic stressor and manifested greater stress-induced hyperthermia compared to wild-type mice. The diurnal variation of corticosterone and the response of corticosterone to corticotropin-releasing factor were not significantly different between genotypes. We also measured Fos-immunoreactive protein, an index of neuronal activation, in the medial amygdala of female mice after EPM testing. The medial amygdala is important for processing of psychogenic stress and anxiety and also contains oxytocin pathways and oxytocin receptors. The expression of Fos in the medial amygdala of mice not exposed to the EPM was not different between genotypes. Following EPM exposure, Fos expression was greater in oxytocin null compared to wild-type mice. Our findings support the hypothesis that central oxytocin is anxiolytic, and attenuates the stress response to psychogenic provocation in female mice.

Mice deficient in oxytocin manifest increased saline consumption following overnight fluid deprivation.

Male mice (9-13 mo of age) in which the gene for oxytocin (OT) had been deleted (OT -/-) were administered 0.5 M sodium chloride (NaCl) solution or tap water as a two-bottle choice test following overnight fluid deprivation (1600 to 1000 the following day). Compared with wild-type cohorts (OT +/+), OT-deficient mice ingested sevenfold greater amounts of saline in the first hour following reintroduction of fluids, P < 0.001, and fourfold greater amounts at the end of 6 h, P < 0.02. No significant difference in total water ingested was noted between the two genotypes at the end of either 1 or 6 h. If food deprivation accompanied the overnight fluid deprivation and food was reintroduced 1 h after the reintroduction of both water and saline, OT -/- mice still ingested greater amounts of saline, but not water, than OT +/+ mice at both 1 h, P < 0.001, and 6 h, P < 0.02. No differences were noted between genotypes in the daily intake of 0.5 M NaCl solution or water during a 3-day observation period before the overnight fluid deprivation. The volume of saline consumed in each 24-h observation period represented about one-tenth of the total fluids ingested in each genotype. We conclude that OT -/- mice display an enhanced salt appetite compared with OT +/+ mice when fluid deprived overnight. The salt appetite was only apparent in the presence of a perturbation such as fluid deprivation, which predisposes the animal to moderate hypovolemia. The observations support an inhibitory role for OT in the control of sodium appetite in mice.

Enhanced salt intake in oxytocin deficient mice.

The maternal roles of oxytocin (OT) are well known, but recent work suggests that OT is also a vital component in fluid balance regulation. To explore the role of OT in salt/volume regulation, we studied NaCl intake in a genetically modified mouse strain lacking OT. Using male control and OT knockout mice (OTKO), we determined the circadian pattern of salt and water intake under need-free conditions. For the study of intake, a two-bottle choice system was used to provide access to water and 2% NaCl with computerized monitoring of licking activity. Salt licking activity (licks/24 h) for controls was 59 +/- 22 vs. 380 +/- 105 in OTKO (P < 0.05). The volume of salt consumed (ml/24 h) was 0.4 +/- 0.1 in controls vs. 1.8 +/- 0.4 in OTKO (P < 0.01). There was no statistical difference in the consumption of water between the groups. However, the initiation of water intake was shifted, with an advancement of almost 3 h in OTKO (P < 0.01). Differences in the timing of salt intake could not be determined due to the low volume of salt consumed by controls. Taken together, these data show that removal of OT amplifies the salt-seeking behavior associated with normal daily fluid fluctuations. The fact that OTKO voluntarily consume a normally aversive salt solution further implies that OT is a powerful regulator of circadian salt appetite.

Effect of centrally administered opioid receptor agonists on CSF and plasma oxytocin concentrations in dogs.

OBJECTIVE: To measure oxytocin concentrations in blood and CSF following central administration of opioid agonists in dogs. ANIMALS: 5 male dogs. PROCEDURE: In a crossover design, CSF and blood were collected immediately before and 15 and 30 minutes after cisternal administration of D-Ala2, MePhe4, Gly-ol-enkephalin (DAMGO, a mu-receptor agonist); D-Pen, pCl-Phe4, D-Pen5-enkephalin (a delta-receptor agonist); U50488H (a kappa-receptor agonist); morphine; and saline (0.9% NaCl) solution. RESULTS: Plasma oxytocin concentration was significantly increased 15 minutes after administration of DAMGO and 30 minutes after administration of U50488H, compared with concentrations obtained after administration of saline solution. Concentration of oxytocin in CSF was significantly decreased 30 minutes after administration of U50488H, compared with concentration after administration of saline solution. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that in male dogs, activation of centrally located mu and kappa receptors elicits an overall excitatory effect on neurons that regulate peripheral release of oxytocin, whereas activation of centrally located kappa receptors elicits an overall inhibitory effect on neurons that regulate central release. These results are in contrast to those reported for other species, in which opioids have a pronounced inhibitory effect on release of oxytocin from the neurohypophysis.

Oxytocin responsivity in mothers of infants: a preliminary study of relationships with blood pressure during laboratory stress and normal ambulatory activity.

The neuropeptide oxytocin (OT) enhances maternal behavior and decreases blood pressure (BP) and stress responses in animals. Thus, the relationship of OT responsivity to BP in 14 breast- and 11 bottle-feeding mothers of infants was examined. Laboratory BP was assessed during baseline, speech preparation, active speech, and recovery on 2 days, 1 in which baseline and speech were separated by 10 min of baby holding and the other by no baby contact. Systolic BP reactivity to speech was lower after baby contact. Plasma OT change from baseline to speech after baby contact defined OT increase, minimal OT change, and OT decrease groups. OT increase mothers were primarily breast-feeders, and they had lower BP throughout both stress sessions and after baby feeding at home than OT decrease mothers, who also had greater BP reactivity to preparation and recovery. These results suggest that oxytocin has antistress and BP-lowering effects in humans.

Effect of paroxetine on plasma vasopressin and water load testing in elderly individuals.

Hyponatremia sometimes occurs in elderly depressed patients treated wtih a serotonin reuptake inhibitor (SRI). The cause of the hyponatremia is not yet understood. The objective of this study was to determine the effects of paroxetine, an SRI, on osmoregulated release of vasopressin (also termed antidiuretic hormone) in elderly depressed patients with normal serum sodium. Four women and one man ages 61 to 74 years with a major depressive disorder were administered a water load after they had been treated with a therapeutic dose of paroxetine for 3 to 11 months. Three healthy elderly subjects not receiving paroxetine served as controls. Both the patients and the control subjects excreted > 90% of the ingested water and lowered urine osmolality to < 100 mosmol/kg. We conclude that long-term treatment with paroxetine alone does not appear to affect the ability to excrete a water load or appropriately dilute the urine during a water load (both indices of vasopressin function) in a small group of elderly patients without other risk factors for the development of hyponatremia.

An ovarian steroid hormone regimen that increases hypothalamic oxytocin expression alters [3H] muscimol binding in the hypothalamic supraoptic nucleus of the female rat.

Administration of sequential estradiol (E(2)) and progesterone (P) for 2 weeks followed by withdrawal of P 48 h prior to sacrifice will increase oxytocin (OT) messenger ribonucleic acid (mRNA) levels in the paraventricular and supraoptic nuclei (PVN and SON) of the ovariectomized rat. Progesterone is known to mediate certain of its effects via binding to the gamma aminobutyric acid A (GABA(A)) receptor. E(2) and P are known to modulate the specific binding of the GABA(A) receptor agonist, muscimol, in certain brain regions. In the present study ovariectomized rats received empty or steroid-filled Silastic capsules for 2 weeks according to one of the following schedules: E(2) only (E(2) group) vs. sequential E(2) and P in which P was either removed 48 h prior to killing (E(2)/P- group) or sustained until sacrifice (E(2)/P+ group). [3H]muscimol binding was measured in several brain regions of the animals. The steroid sequence that is known to increase SON OT mRNA (E(2)/P-) selectively decreased [3H]muscimol binding in the SON of ovariectomized rats. The results suggest that changes in GABA(A) receptor binding may, in part, play a role in the regulation of steroid-induced increases in hypothalamic OT expression.

The neurosteroid allopregnanolone modulates oxytocin expression in the hypothalamic paraventricular nucleus.

Virgin, ovariectomized rats exposed to 2 wk of sequential estradiol (E(2)) and progesterone (P) followed by P withdrawal have increased hypothalamic oxytocin (OT) mRNA and peptide levels relative to sham-treated animals. This increase is prevented if P is sustained. In the central nervous system, P is metabolized to the neurosteroid allopregnanolone (3alpha-hydroxy-5alpha-pregnan-20-one), which exerts effects by acting as a positive allosteric modulator of GABA(A) receptor/Cl(-)-channel complexes. In the present study, ovariectomized rats that received sequential E(2) and P for 2 wk followed by P withdrawal were administered allopregnanolone at the time of P withdrawal. Hypothalamic and plasma allopregnanolone concentrations, serum E(2) and P concentrations, and hypothalamic OT mRNA levels were measured at death. Steroid-induced increases in OT mRNA were attenuated in animals treated with allopregnanolone at the time of P withdrawal. The results suggest that allopregnanolone plays an important modulatory role in steroid-mediated increases in hypothalamic OT.

The effects of progesterone on oxytocin mRNA levels in the paraventricular nucleus of the female rat can be altered by the administration of diazepam or RU486.

Oxytocin (OT) facilitates the onset of maternal behaviour in the late pregnant rat, enhances uterine contractility at parturition, and elicits milk ejection during lactation. If the rising estradiol (E2 and declining progesterone (P) of late pregnancy is reproduced in a virgin ovariectomized rat by implanting E2- and P-filled capsules for 2 weeks followed by removal of P-containing implants 36-48 h prior to death, OT messenger ribonucleic acid (mRNA) levels increase in the paraventricular and supraoptic nuclei (PVN and SON) of the rat. Both E2 administration and P withdrawal are necessary to increase OT mRNA, but the mechanisms of these effects are not understood. P may work within the PVN although P receptors are reported to be sparse or non-existent in the PVN or outside the PVN on PR-containing neurones that project to OT-containing neurones or via membrane bound receptors that are known to bind neurosteroids and gamma aminobutyric acid (GABA). To determine the mechanism through which P may inhibit or P withdrawal may increase OT mRNA levels, virgin ovariectomized (OVX) rats received sequential E2 and P via Silastic implants for 14 days. On day 13, prior to removal of P capsules on day 14, the rats were given the benzodiazepine agonist, diazepam, or saline injections subcutaneously (s.c.) twice daily until death on day 16. OT mRNA levels were increased in the steroid-treated group that received saline but not diazepam. In experiment 2, P capsules were removed on day 14 or pharmacological P withdrawal was induced by injecting RU486 injections s.c. twice daily until death 48 h later. OT mRNA levels were increased in the steroid-treated group that received RU486. Subsequent studies demonstrated the expression of PR mRNA within the rat PVN. The data suggest that gonadal steroids may influence PVN OT mRNA levels by modulating the GABA(A) receptor or by directly altering gene transcription via the PR.

The variable penetrance and spectrum of manifestations of multiple endocrine neoplasia type 1.

BACKGROUND: Some experts maintain that (1) > 90% of patients with multiple endocrine neoplasia type 1 (MEN1) are first seen with hyperparathyroidism (HPTH) so that routine screening for other features is unnecessary and (2) MEN1 has > or = 94% penetrance by age 50 years. METHODS: We constructed a regional registry of patients with or at risk for MEN1 and examined phenotypic profiles in 34 patients. MEN1 was defined as (1) endocrinopathy of 2 of the 3 principal related tissues (parathyroid, gastrointestinal endocrine, pituitary) or (2) 1 such feature plus a first-degree relative with MEN1. RESULTS: The initial feature of MEN1 was HPTH in 50%, pituitary tumor in 18%, and gastrointestinal endocrine tumor in 32% of patients, with overall incidences of 82%, 65%, and 74%, respectively. HPTH developed by age 50 years in 73% of patients and by age 70 years in 83%. Penetrance of MEN1 at age 50 years was 82%. Associated features included renal (1) and rectal (1) cancer, malignant thymic carcinoid (1), and malignant pheochromocytoma (1). CONCLUSIONS: Expression of MEN1 can vary considerably from established patterns. In our geographic region HPTH does not routinely precede other features of MEN1 and cannot be used to distinguish affected patients among those at risk. MEN1 can be inapparent until late in life and may be significantly underdiagnosed.

Vasopressin, oxytocin, corticotrophin-releasing factor, and sodium responses during fluoxetine administration in the rat.

Hyponatremia has been observed in elderly patients treated with the selective serotonin reuptake inhibitor (SSRI) fluoxetine. The pathogenesis of this effect is not known, but enhanced release of vasopressin (VP) and its renal actions may be a possible mechanism. Excess secretion of VP in combination with large fluid intake is known to induce hyponatremia. We determine if chronic fluoxetine administration in association with liberal fluid intake will induce hyponatremia via enhanced release of VP. We used a previously described model in which fluid intake is forced by administering rats a nutritionally balanced liquid diet. Male Sprague-Dawley rats in groups of 10 were randomized to solid and liquid diets, and each diet group administered daily i.p. injections of fluoxetine (10 mg/kg) or saline for 10 d. Water was given ad libitum to all groups. Daily weight, fluid and food intake, and urine output were measured. On d 10, rats were killed by rapid guillotine decapitation 1-3 h after injection. Trunk blood was collected for measurements of plasma VP and oxytocin (OT) and serum sodium (Na), BUN, creatinine, and glucose. Pituitary glands were assayed for VP and OT content. VP mRNA in the paraventricular and supraoptic nuclei (PVN and SON) and corticotrophin-releasing factor (CRF) mRNA in the PVN were measured by in situ hybridization histochemistry. Fluid intake was significantly higher in groups maintained on liquid vs solid diet (p < 0.0001), as was urine output (p < 0.0001). Fluoxetine-treated rats gained significantly less weight than placebo-treated rats (p = 0.01), in keeping with fluoxetine's anorexigenic properties. However, no significant differences were found among the groups in Na, plasma VP or OT, pituitary VP or OT, or PVN CRF or VP mRNA levels. We conclude that administration of fluoxetine to laboratory rats in the dose and duration used in this study does not significantly affect hypothalamic expression, pituitary stores, or peripheral secretion of VP.

Renal cell carcinoma metastatic to the pituitary gland: clinical manifestations and successful treatment with transsphenoidal resection.

OBJECTIVE: To describe two cases of metastatic involvement of the pituitary gland by renal cell carcinoma (RCCA) and review the medical literature regarding this entity. METHODS: We present two case reports and discuss the published literature to illustrate the clinical findings, radiographic features, and recommended management of RCCA metastatic to the pituitary gland. RESULTS: During a 12-month period, we encountered two patients, one with visual deficits and both with anterior pituitary dysfunction, who had large sellar lesions that were histologically proved to be RCCA. Both patients were successfully treated with transsphenoidal surgical resection of the lesion, one of whom is alive and well more than 2 years later. A pituitary metastatic tumor is an uncommon complication of RCCA; it may be difficult to diagnose and potentially fatal. Anterior pituitary dysfunction and visual disturbances are more common initial features than is diabetes insipidus, in contrast to pituitary metastatic involvement from other tumors. CONCLUSION: Transsphenoidal resection is a safe and effective method of treatment of RCCA metastatic to the pituitary gland.

Concentrations of leptin in the serum of pregnant, lactating, and cycling rats and of leptin messenger ribonucleic acid in rat placental tissue.

Leptin concentrations were measured in the serum of cycling, pregnant, and lactating Sprague-Dawley rats. Serum leptin concentrations did not vary significantly during the estrous cycle. In contrast, as gestation advanced, serum leptin concentrations increased significantly, p < 0.0001. Following delivery, leptin concentrations declined and remained stable during lactation. Leptin messenger ribonucleic acid (mRNA) was identified in the visceral adipose tissue and placenta of rats sacrificed on days 14 and 21 of pregnancy. The relative abundance of placental leptin mRNA increased approximately 4 to 5 fold from day 14 to 21 of gestation. The pattern of elevated leptin concentrations in the serum of late pregnant rats is similar to that reported in pregnant women, therefore the rat may be a useful model for the study of leptin during pregnancy. The increase in leptin in the serum of late pregnant rats, as well as an increase in placental mRNA, raises the possibility that leptin may serve a physiological role for the late parturient rat and/or its young.

Vasopressin can increase coronary perfusion pressure during human cardiopulmonary resuscitation.

OBJECTIVES: To determine the hemodynamic effect of vasopressin on coronary perfusion pressure (CPP) in prolonged human cardiac arrest. METHODS: A prospective, open-label clinical trial of vasopressin during cardiac resuscitation was performed. Ten patients presenting in cardiac arrest initially received resuscitative measures by emergency physicians according to Advanced Cardiac Life Support (ACLS) guidelines. A central venous catheter for fluid and drug administration and a femoral artery catheter for measurement of CPP (aortic minus right atrial relaxation phase pressures) were placed. When each patient was deemed nonsalvageable, 1.0 mg epinephrine was given and CPP was measured for 5 minutes, followed by a dose of vasopressin (1.0 U/kg). CPP measurements were continued for another 5 minutes. RESULTS: The mean duration of cardiac arrest (out-of-hospital interval plus duration of ED ACLS) was 39.6 +/- 16.5 min. There was no improvement in CPP after 1.0 mg of epinephrine. Vasopressin administration resulted in a significant increase of CPP in 4 of the 10 patients. Patients responding to vasopressin had a mean increase in CPP of 28.2 +/- 16.4 mm Hg (range: 10-51.5), with these peak increases occurring at 15 seconds to 4 minutes after administration. The increases in the vasopressin levels after administration did not differ between the responders and nonresponders. CONCLUSIONS: In this human model of prolonged cardiac arrest, 40% of the patients receiving vasopressin had a significant increase in CPP. This pilot study suggests that investigation of earlier use of vasopressin as a therapeutic alternative in the treatment of cardiac arrest is warranted.

The duration of estradiol and progesterone exposure prior to progesterone withdrawal regulates oxytocin mRNA levels in the paraventricular nucleus of the rat.

The nonapeptide oxytocin (OT) is important for milk ejection during lactation, uterine contractility at parturition, and the onset of maternal behavior. Sequential exposure to estradiol (E2) and progesterone (P) followed by P withdrawal increases OT mRNA in the paraventricular nucleus (PVN), and to a lesser degree the supraoptic nucleus (SON), of the rat 48 hours after the P is removed. Although increases in PVN OT mRNA are not accompanied by changes in posterior pituitary OT peptide content, the PVN contains OT neurons that project to both the posterior pituitary (magnocellular group) and extra pituitary sites (parvocellular groups). Steroid-induced increases in OT mRNA occur in both the magnocellular and the parvocellular regions of the PVN. The latter are believed to contribute to CNS release of OT which may be important for certain behaviors including the onset of maternal behavior. The same steroid sequence that increases PVN OT mRNA also induces maternal behavior in virgin ovariectomized rats. Exposure of animals to E2 and P for 2 weeks resulted in the shortest latency to the onset of maternal behavior in ovariectomized rats, whereas exposure for 6 days was associated with a longer latency. In this study we questioned if the duration of E2 and P exposure prior to P withdrawal is an important regulator of PVN OT mRNA levels. We compared OT mRNA levels in the PVN of virgin ovariectomized rats administered no steroid or sequential E2 and P for 2 weeks versus 6 days. On day 1 animals received steroid-filled or empty capsules followed by P-filled or empty capsules on day 3. In one steroid-treated group, E2 and P were continued for 6 days and in the other group for 14 days prior to P removal. Animals were sacrificed 48 hours after P removal. Levels of OT mRNA were compared among 6 day and 2 week steroid-treated animals and sham-treated animals. The relative abundance of OT mRNA was significantly increased, P < 0.05, in animals receiving the 2-week, but not the 6-day, steroid treatment compared to sham-treated animals. Pituitary OT peptide content was not significantly different among the three groups. We conclude that the duration of steroid exposure may be an important regulator of the level of OT mRNA in the PVN of the rat.

Administration of long-term estradiol and progesterone followed by progesterone withdrawal does not alter the plasma oxytocin secretory response to cholecystokinin or the pituitary oxytocin content in ovariectomized rats.

The hormone oxytocin (OT) is important for several pre- and postpartum events, including uterine contractions at parturition, the induction of maternal behavior, and milk ejection during nursing. During late pregnancy, OT mRNA is increased in the paraventricular nucleus (PVN) due to high estrogen and declining progesterone levels. Administration of sequential estrogen and progesterone to, followed by withdrawal of progesterone from, an ovariectomized rat also increases OT mRNA. However, pituitary OT peptide is not affected. In the present experiment, we determined if this steroid exposure alters peripheral OT secretion during a provocative stimulus to OT release, such as cholecystokinin (CCK). Adult ovariectomized Sprague-Dawley rats were implanted on day 1 with either estrogen or empty silastic capsules, on day 3 with progesterone or empty capsules, and on day 14 progesterone or empty capsules were removed. Forty-eight hrs after removal of the progesterone capsules, plasma OT was measured before and after i.v. injection of 10 micrograms/kg of CCK. At the completion of the study, pituitary glands were removed and OT peptide was measured. No significant differences were found between the sham and hormone-treated animals either in their basal or CCK-stimulated plasma OT levels or their pituitary content of OT peptide. Although sequential exposure to estradiol and progesterone followed by withdrawal of progesterone has been shown previously to increase PVN OT mRNA, neither pituitary OT immunoreactivity nor basal and CCK-stimulated release of plasma OT is affected by this treatment. Although the mechanism of this steroid effect is not yet understood, our observations suggest a unique action of gonadal steroids upon PVN OT neurons.