Evidence that oxytocin is an endogenous stimulator of autonomic sympathetic preganglionics: the pupillary dilatation response to vaginocervical stimulation in the rat

Vaginocervical mechanostimulation (VS) was shown previously to release oxytocin within the spinal cord and to induce pupillary dilatation. In the present study, (a) injection of oxytocin directly to the spinal cord (10 or 25 microg intrathecally [i.t.] in 5 microl saline) induced pupillary dilatation when observed 1 min after the end of the injection and (b) injection of an oxytocin receptor antagonist ([d(CH2)5-Tyr (Me)2-Orn8]-Vasotocin [OTA]; 25 microg i.t. in 5 microl saline) significantly attenuated the pupillary dilatation response to VS, when VS was applied 3 min after the end of the injection. Since activation of autonomic sympathetic preganglionic neurons in the thoracic spinal cord produces pupillary dilatation, we propose that oxytocin is a central nervous system neurotransmitter that stimulates these neurons directly, or perhaps indirectly, and thus is a mediator of VS-produced pupillary dilatation.     

Measurement of septal release of vasopressin and oxytocin by the push-pull technique following electrical stimulation of the paraventricular nucleus of rats

The release of vasopressin (AVP) and oxytocin (OXT) within the septum was studied with the push-pull perfusion technique in 6 conscious, freely behaving male rats. Push-pull perfusion was performed viaa chronically implanted cannula and samples collected for 3 consecutive 30-min periods. Stimulating electrodes were implanted in both the left and right paraventricular nuclei 4 days before the experiment. Bilateral electrical stimulation (10-s trains every 4 min) of the paraventricular nuclei during the second 30-min period resulted in a significant increase in the release of both AVP and OXT (128% and 159% of control values respectively); release returned to the pre-stimulation value during the final 30-min collection.     

Morphine and corticotrophin-releasing factor potentiate maternal acceptance in multiparous ewes after vaginocervical stimulation

The effects of intracerebroventricular infusions of morphine, oxytocin, and corticotrophin-releasing factor (CRF) on maternal behaviour alone, or in conjunction with vaginocervical stimulation were determined in both nulliparous and multiparous ovariectomized ewes, primed with oestrogen for 3 days proir to testing. Both plasma and cerebrospinal fluid levels of oxytocin were measured under similar conditions, following CRF and morphine treatments. In nulliparous ewes, i.c.v. oxytocin and morphine reduced rejection behaviours, but neither these treatments nor vaginocervical stimulation promoted proceptive acceptance behaviour. Ewes that were maternally experienced showed increases in acceptance and a reduction of rejection behaviours following vaginocervical stimulation or i.c.v. oxytocin. Morphine and CRF potentiated the effects of vaginocervical stimulation on these behaviours. No treatment influenced oxytocin release per se, but i.c.v. morphine increased both peripheral and central release of oxytocin in response to vaginocervical stimulation. The results show that maternal experience is essential for oxytocin to promote proceptive behaviours and that morphine and CRF potentiate the effects of vaginocervical stimulation on acceptance behaviour. Since morphine also potentiated the release of oxytocin in response to vaginocervical stimulation it is difficult to separate the relative contribution of direct versus indirect effects of opiates in potentiating maternal bonding.     

Autoradiographic detection of vasopressin binding sites, but not of oxytocin binding sites, in the sheep olfactory bulb

Oxytocin facilitates maternal behaviour in sheep. In the present study, we searched for the presence of oxytocin and vasopressin binding sites in the sheep olfactory bulb, a brain area which is thought to be involved in specific bond formation between the ewe and its lamb. Using in vitro autoradiography, we observed binding of tritiated vasopressin to the glomerular layer of the olfactory bulb. Competition studies performed with structural analogues and the use of a 125I-labelled linear vasopressin antagonist suggested that sites which bind vasopressin are V1 type receptors. In contrast, specific binding sites for oxytocin in the olfactory bulb could be detected neither in control females, nor in ovariectomized females treated with estradiol nor in postparturient ewes, although such sites were present in the uterus.     

Arginine vasopressin concentrations in the cerebrospinal fluid of children

Cerebrospinal fluid (CSF) arginine vasopressin (AVP) levels are reported in a group of 22 children (median age 24 months) investigated for possible bacterial meningitis and subsequently found not to be suffering from this disease. The mean CSF AVP concentration was 0.80±0.33 pg/ml. The results obtained in patients suffering from febrile convulsions (mean 0.71 pg/ml), other convulsive disorders (mean 0.80 pg/ml) and miscellaneous infectious disease (mean 0.85 pg/ml) did not differ significantly from one another. Our findings confirm the presence of AVP in the CSF of children and provide reference values for further investigations into the functions of CSF AVP in children.     

Differential release of vasopressin and oxytocin in response to abdominal vagal afferent stimulation or apomorphine in the ferret

The aim of this study was to investigate whether direct afferent stimulation of the abdominal vagus promote release of the neurohypophyseal hormones. The nucleus of the solitary tract is the major recipient of vagal afferent information, and this region of the brainstem may also be activated by stimulation of the area postrema. For this reason apomorphine, a D₂ dopaminergic agonist which acts on the area postrema, and can evoke vasopressin secretion in man, was also investigated for its effect on vasopressin and oxytocin release. Our results show that vasopressin, but not oxytocin is released in vast amounts in response to electrical afferent stimulation of the abdominal vagus. Administration of apomorphine also evoked a massive vasopressin release with less marked effects on oxytocin. The possible functional implications of these results are discussed especially in the context of nausea and vomiting.     

Cerebrospinal fluid and plasma clusterin levels in Parkinson's disease

Clusterin is a multifunctional chaperone protein that has repeatedly been linked to Alzheimer's disease (AD) pathogenesis and, more recently, also to Parkinson's disease (PD) by both genetic and proteomic analyses. Although clusterin is detectable in cerebrospinal fluid (CSF) and plasma, studies comparing clusterin levels in PD patients and controls have been scarce and yielded conflicting data. The aim of the present study was to determine whether CSF and/or plasma clusterin levels differ between PD patients and controls and are related to disease severity. We measured CSF and plasma clusterin levels in a group of 52 PD patients and in 50 age-matched neurologically healthy controls and found that clusterin levels in CSF and plasma were not different between the two groups. Furthermore, clusterin levels in CSF and plasma were not associated with disease duration, stage or severity. CSF clusterin levels did, however, correlate with CSF levels of total tau, phospho-tau and amyloid-β-42. We elaborate on the identified correlations between levels of clusterin and AD related proteins and on possible explanations for the discrepant findings in clusterin studies in PD so far.     

Cerebrospinal fluid immunoglobulins in sheep with visna, a slow virus infection of the central nervous system

Icelandic sheep were injected intracerebrally with visna virus, which produces a persistent infection of the CNS accompanied by encephalomyelitis and focal demyelinating lesions. Studies were conducted on two groups of sheep, with short-term infections (25 sheep sampled 1–3 months after infection) and long-term infections (14 sheep sampled 5–6 years after infection). Quantitative determination of CSF immunoglobulin levels 5 years after infection indicated that IgM concentrations was usually elevated, IgG2 was occasionally elevated and IgG1 was rarely elevated. CSF oligoclonal bands were seen in about half the sheep examined 5 years after infection. There was a correlation between high titers of CSF antiviral antibody and both elevated CSF IgM concentration and CSF oligoclonal bands. Serum/CSF IgG1 ratios indicated that the blood-brain barrier was apparently intact in long-term visna infection, consistent with intrathecal synthesis of IgM and of antiviral antibody. The alterations in CSF immunoglobulins in visna resemble those found in other persistent CNS virus infections and in multiple sclerosis.     

Vasopressin and oxytocin in CSF and plasma of patients with aneurysmal subarachnoid haemorrhage

Objective

Clinicopathological studies on patients succumbing to subarachnoid haemorrhage (SAH) demonstrated hypothalamic lesions. The implication of the hypothalamic neuropeptides arginine-vasopressin (AVP) and oxytocin (OXT) has not been linked to aneurysmal SAH yet. This study investigates AVP and OXT in CSF and plasma of patients with spontaneous aneurysmal SAH and their association with outcome.

Methods

CSF and plasma samples of 12 patients with aneurysmal SAH were prospectively studied for 2 weeks. AVP and OXT were measured by radioimmunoassay. Outcome was assessed on Glasgow-Outcome-Scale. Twenty-nine patients without neuropsychiatric disturbances served as controls. Differences in neuropeptide concentration time courses were assessed by regression models. Group comparisons were performed by Kruskal–Wallis and correlations by Spearman tests.

Results

Regression of CSF levels between patients with poor and good outcome revealed significantly lower levels of AVP in patients with poor outcome (p = 0.012) while OXT showed a trend towards lower levels (p = 0.063). In plasma, no significant differences between outcome groups were found. Group comparisons between poor outcome patients and controls revealed significant differences in CSF for AVP (p = 0.001) and OXT (p = 0.015). In plasma, AVP yielded significantly different results while OXT did not. No differences were found between the good outcome group and controls. Plasma and CSF concentrations showed no significant correlation.

Conclusion

Patients with poor outcome after aneurysmal SAH have lower AVP and OXT levels in CSF than patients with good outcome while neuropeptide levels in plasma failed to reflect differences in outcome. The data indicate hypothalamic damage as an aetiologic factor for outcome after aneurysmal SAH.     

Action of estrogen and mechanical vaginocervical stimulation on the membrane excitability of hypothalamic and midbrain neurons

The effect of vaginocervical stimulation (VCS) and estrogen iontophoresis on the electrical activity recorded in urethane-anesthetized female rats from medial preoptic-septal (MPO-S) and midbrain central gray (MCG) neurons was studied during two phases of the estrous cycle, namely metestrus (M) and late proestrus-estrus (LP-E). The spontaneous discharge rate of both MPO-S and MCG neurons varied over the two stages of the estrous cycle. The spontaneous electrical activity of the MPO-S neurons was higher during M than during LP-E whereas MCG unit activity was low during M and higher during LP-E. The VCS-evoked changes in unit activity were specific, in that they were observed in response to mechanical genital stimulation and not in response to painful stimuli and/or nonspecific arousal. These responses were not dependent on the stage of estrous cycle. Finally, the iontophoresis of 17β-estradiol hemisuccinate evoked electrophysiological responses from MPO-S and MCG neurons. More MPO-S neurons were responsive to estrogen in LP-E than in M, while fewer MCG neurons were responsive to estrogen in LP-E than in M. The results clearly show that ongoing electrical activity of hypothalamic and midbrain nerve cells can fluctuate between M and LP-E phases of the estrous cycle and change with vaginocervical probing as well as iontophoretically applied estrogen. Furthermore, the results suggest the existence of a reciprocal relationship between the membrane activity of MPO-S and MCG neurons which may be related to CNS control of reproductive activities.     

Effects of oxytocin and vasopressin on thoracic sympathetic preganglionic neurones in the cat

When applied by iontophoresis onto single sympathetic preganglionic neurones in the intermediolateral nucleus of segments T₁–T₃ in the cat, oxytocin and vasopressin each had an excitatory effect. This effect consisted of a prolonged (30–300 sec) after-discharge following termination of application. These results indicate that oxytocin and vasopressin each exert excitatory effects on sympathetic preganglionic neurones and support the possibility that they may be chemical mediators of synaptic transmission in the intermediolateral nucleus, perhaps in cardioacceleratory and/or pressor pathways descending from the paraventricular nucleus of the hypothalamus.     

Effects of intranasal oxytocin and vasopressin on cooperative behavior and associated brain activity in men

The neural mechanisms supporting social bonds between adult men remain uncertain. In this double-blind, placebo-controlled study, we investigate the impact of intranasally administered oxytocin (OT) and vasopressin (AVP) on behavior and brain activity among men in the context of an iterated Prisoner's Dilemma game, which models a real-life social situation. fMRI results show that, relative to both AVP and placebo, OT increases the caudate nucleus response to reciprocated cooperation, which may augment the reward of reciprocated cooperation and/or facilitate learning that another person can be trusted. OT also enhances left amygdala activation in response to reciprocated cooperation. Behaviorally, OT was associated with increased rates of cooperation following unreciprocated cooperation in the previous round compared with AVP. AVP strongly increased cooperation in response to a cooperative gesture by the partner compared with both placebo and OT. In response to reciprocated cooperation, AVP increased activation in a region spanning known vasopressin circuitry implicated in affiliative behaviors in other species. Finally, both OT and AVP increase amygdala functional connectivity with the anterior insula relative to placebo, which may increase the amygdala's ability to elicit visceral somatic markers that guide decision making. These findings extend our knowledge of the neural and behavioral effects of OT and AVP to the context of genuine social interactions.     

Intracerebroventricular arginine vasopressin causes intracranial pressure to rise in conscious goats

The effects of intracerebroventricular (i.c.v.) infusion of arginine vasopressin (AVP) on intracranial pressure (ICP), blood pressure (BP) and plasma AVP were investigated in conscious goats. The animals were implanted with ventricular (V) and cisternal (C) cannulae under halothane anaesthesia and allowed to recover prior to experimentation. After 30 min infusion of 20 microliter/min artificial cerebrospinal fluid (CSF) alone, to allow the animals to settle, ICP (estimated at both C and V cannulae), BP and plasma AVP were measured. Then the animals were infused with either artificial CSF alone or 1 or 10 pmol/min AVP for a further 150 min. One pmol/min AVP i.c.v. resulted in significant ICP increases of +2.2 cm CSF (C) and +3.1 cm CSF (V) when compared with artificial CSF alone. Ten pmol/min AVP also led to significant ICP rises of +3.2 cm CSF (C) and +4.2 cm CSF (V). There were no significant changes of BP or plasma AVP during the infusions. We conclude that central infusion of AVP leads to elevated ICP in conscious goats by a mechanism that does not involve BP alteration or changes in plasma AVP.     

Dexamethasone differentially alters naltrexone effects on vasopressin and oxytocin release during tail electroshock

The origin of endogenous opioid peptides that inhibit release of vasopressin (VP) and oxytocin (OT) into the bloodstream after tail electroshock was investigated. We hypothesized that endogenous opioid peptides derived from the anterior pituitary reduced secretion of VP and OT during this stimulus. To test this hypothesis, dexamethasone (DEX) was used to preferentially suppress release of endorphins with ACTH from the anterior pituitary. We evaluated the effects of an opiate receptor antagonist, naltrexone, on the rise in plasma [VP] and [OT] after tail electroshock in male Sprague-Dawley rats given DEX either chronically or acutely before the shock. In the chronic study rats were injected SC daily with saline (3.2 ml/kg) or DEX (0.2 mg/kg) for 17 days. In the short term study, rats were injected IP with saline (5 ml/kg) or DEX (0.5 mg/kg) the day before and again 105 min prior to tail electroshock. Thirty min (chronic study) or 90 min (acute study) after saline or DEX was given on the last day, rats were injected SC with saline (1 ml/kg) or naltrexone (1 mg/kg). Fifteen min later, animals received tail electroshock (41 V, 30 sec) and were decapitated 15 sec after shock was completed. Control animals were treated similarly but not shocked. Amounts of VP and OT in plasma and the neurointermediate lobe were quantified by RIA. [VP] and [OT] were elevated in plasma of all rats given tail electroshock. Greater increases (p less than 0.05) in hormone concentrations were measured in plasma of shocked rats treated with DEX.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of enhanced cerebrospinal fluid levels of vasopressin, vasopressin antagonist or vasoactive intestinal polypeptide on circadian sleep-wake rhythm in the rat

Several endogenous peptides have been implicated in the regulation of sleep and wakefulness. The present study was carried out in order to determine whether the light-dark rhythm of vasopressin (VP) in the cerebrospinal fluid (CSF) had functional significance in relaying information from the circadian pacemaker, i.e. the suprachiasmatic nuclei (which synthesize VP as well as vasoactive intestinal polypeptide (VIP], to the centra regulating sleep. After constant delivery of VP in the CSF via an Accurel/collodion implant in the lateral ventricle, the VP CSF level was raised from 20-35 pg/ml to ca. 265 pg/ml whereby a VP rhythm in the CSF could no longer be detected. Under these conditions VP was found to increase the arousal state of the rat in the dark period, which resulted in a higher amplitude of the circadian sleep-wake rhythm. Application of the VP antagonist d(CH2)5[Tyr(Me)2]VP partly had opposite effects. A similar approach with central application of VIP resulted in an increase in rapid eye movement and quiet sleep but did not affect the amplitude of the circadian rhythm. It was concluded that although peptide levels in the CSF may show clear temporal variations with the light-dark cycle, this rhythmicity is not causally related to the circadian aspect of sleep-wakefulness. However, both VP and VIP contribute to the regulation of the amount of time spent in sleep and wakefulness and the level of VP in the CSF is correlated with the amplitude of the rhythm.     

Melatonin inhibits the substance P-induced secretion of vasopressin and oxytocin from the rat hypothalamo-neurohypophysial system: in vitro studies

The aim of the present investigations was to study the influence of substance P (a member of a family of peptides known as tachykinins) on basal and K(+)-evoked vasopressin (AVP) and oxytocin (OT) release from rat hypothalamo-neurohypophysial system in vitro as well as to determine whether this effect of substance P is sensitive to melatonin.The present results show that substance P stimulates basal AVP and OT release from isolated hypothalamo-neurohypophysial system, when used at the concentrations of 10(-6) and 10(-7)M/l. At the concentration of 10(-9)M/l, however, substance P was found to stimulate the in vitro secretion of AVP, but not that of OT. Melatonin diminished basal release of AVP; it also significantly inhibited the substance P-stimulated secretion of AVP and OT. K(+)-evoked release of the neurohypophysial hormones was not further modified by either substance P or melatonin.The present results show that the stimulatory effect of substance P on basal release of AVP and OT from rat hypothalamo-neurohypophysial system in vitro is sensitive to inhibitory influence of melatonin.     

Identification of hypothalamic vasopressin and oxytocin neurons activated during the exercise pressor reflex in cats

Blood pressure and heart rate reflexly increase during static muscle contraction in anesthetized cats. Previous studies have demonstrated that vasopressin (AVP) and oxytocin (OT) may act as neuromodulators to regulate cardiovascular responses elicited by contraction of skeletal muscle. In this study, we tested the hypothesis that neurons containing AVP and OT in the paraventricular nucleus (PVN) and the supraoptic nucleus (SON) of the hypothalamus are activated during static muscle contraction. A laminectomy was performed to expose the spinal cord and the peripheral cut ends of L7 and S1 ventral roots were stimulated electrically to induce muscle contraction. Hypothalamic neurons activated during the muscle contraction were identified by Fos-like immunoreactivity (FLI). Static muscle contraction significantly increased FLI in the PVN and SON, compared with sham-opeated cats. Double-staining of neurons in the PVN for AVP and OT showed that 22±4% of the AVP and 26±3% of the OT neurons in the PVN expressed FLI. In contrast, only 4±1% of the AVP and 3±1% of the OT neurons in the PVN were labeled with FLI in sham-operated animals. These results indicate that neurons in the PVN and SON of the hypothalamus were activated during static muscle contraction. Furthermore, as FLI was present in AVP and OT neurons, this suggests these neurons may constitute a part of the neural pathway involved in cardiovascular regulation during static muscle contraction.     

Intracerebroventricular choline increases plasma vasopressin and augments plasma vasopressin response to osmotic stimulation and hemorrhage

Intracerebroventricular (i.c.v.) injection of choline (50-150 microg), a precursor of the neurotransmitter acetylcholine, produced a time-and dose-dependent increase in plasma vasopressin levels in conscious, freely moving rats. The increase in plasma vasopressin in response to i.c.v. choline (150 microg) was inhibited by pretreatment with the nicotinic receptor antagonist, mecamylamine (50 microg; i.c.v.), but not by the muscarinic receptor antagonist, atropine (10 microg; i.c.v). The choline-induced rise in plasma vasopressin levels was greatly attenuated by hemicholinium-3 (HC-3; 20 microg; i.c.v.), a neuronal choline uptake inhibitor. Choline (50 or 150 microg; i.c.v.) produced a much greater increase in plasma vasopressin levels in osmotically stimulated or hemorrhaged rats than in normal rats. Choline (150 microg; i.c.v.) also enhanced plasma vasopressin response to graded hemorrhage; the enhancing effect of choline was also attenuated by HC-3 (20 microg; i.c.v.). Choline and acetylcholine concentrations in hypothalamic dialysates increased significantly following i.c.v. injection of choline (150 microg). It is concluded that choline increases plasma vasopressin levels by stimulating central nicotinic receptors indirectly, through the enhancement of acetylcholine synthesis and release, and augments the ability of osmotic stimulations or hemorrhage to stimulate vasopressin release.     

Influence of histamine and pentobarbitone on plasma and CSF vasopressin levels of hypophysectomized rats

Histamine increased vasopressin levels, as measured by radioimmunoassay (RIA), in both cerebrospinal fluid (CSF) and plasma of hypophysectomized rats, while histamine enhanced plasma but not CSF levels of vasopressin in sham operated rats. Pentobarbitone increased CSF vasopressin levels in hypophysectomized rats and in sham operated animals. The present data demonstrate that the histamine induced elevation of vasopressin levels in the blood is only temporarily disturbed after hypophysectomy, while the effect of histamine on CSF vasopressin levels of hypophysectomized rats is of a more permanent nature.     

Oxytocin and vasopressin immunoreactivity in rabbit hypothalamus during estrus, late pregnancy, and postpartum

Mother rabbits construct an elaborate maternal nest before parturition and display a single, brief, daily nursing bout throughout lactation. These features present a unique model for investigating the relevance of changes in neuroendocrine secretion associated with pregnancy and parturition for the regulation of maternal behavior. In the present study we analyzed changes in the location, somal size, and number of oxytocin (OT)and arginine vasopressin (AVP)-immunoreactive (IR) neurons in the hypothalamus of rabbits in estrus, late pregnancy (day 29), and postpartum day 1. From estrus to late pregnancy, the number of OT-IR neurons increased in the scattered cell groups located in the lateral hypothalamic area (LHA), but not in the magnocellular nuclei, i.e., paraventricular nucleus (PVN) and supraoptic nucleus (SON). On postpartum day 1 the increase in the number of OT-IR neurons was sustained in the LHA and became apparent also in the main body of the PVN, in which the number of OT-IR neurons doubled. Increases in the somal size of OT-IR cells were seen in all three nuclei only on postpartum day 1. No OT-IR cells were found in the suprachiasmatic nucleus (SCN). From late pregnancy and into postpartum day 1 increases in the somal size of AVP-IR neurons were detected in the PVN, SON, and LHA but not in the SCN. The number of AVP-IR neurons increased between late pregnancy and postpartum day 1 in the SON only. The changes observed in OT and AVP expression in specific hypothalamic nuclei may be related to specific somatic and behavioral events occurring around the time of parturition, e.g., nest-building, maintenance of homeothermy, elevation of blood volume, and nursing in mother rabbits.