Oxytocin in the Male Reproductive Tract; The Therapeutic Potential of Oxytocin-Agonists and-Antagonists.

In this review, the role of oxytocin and oxytocin-like agents (acting via the oxytocin receptor and belonging to the oxytocin-family) in the male reproductive tract is considered. Previous research (dating back over 60 years) is revised and connected with recently found aspects of the role oxytocin plays in male reproductive health. The local expression of oxytocin and its receptor in the male reproductive tract of different species is summarized. Colocalization and possible crosstalk to other agents and receptors and their resulting effects are discussed. The role of the newly reported oxytocin focused signaling pathways in the male reproductive tract, other than mediating contractility, is critically examined. The structure and effect of the most promising oxytocin-agonists and -antagonists are reviewed for their potential in treating male disorders with origins in the male reproductive tract such as prostate diseases and ejaculatory disorders.

Oxytocin in the anterior cingulate cortex is involved in helping behaviour.

Empathy toward the distress of others is thought to motivate helping behaviour, in the form of voluntary action to eliminate that distress. Neuropeptide oxytocin is associated with various social cognitive abilities, including empathy and prosocial behaviour. The anterior cingulate cortex is known to be one of the brain regions underlying empathy, and one in which oxytocin receptors are expressed. However, the relationship between helping behaviour and oxytocin in the anterior cingulate cortex is still unclear. The present study investigated whether oxytocin in the anterior cingulate cortex is involved in rats' helping behaviour. In Experiment 1, we examined the influence of blockading the oxytocin receptors in the anterior cingulate cortex on helping behaviour. Impeding oxytocin in the anterior cingulate cortex delayed learning of the helping behaviour. In Experiment 2, we examined immunofluorescent colocalization of oxytocin receptors and c-fos proteins in the anterior cingulate cortex, the anterior insular cortex, and the amygdala in rats that acquired helping behaviour. We found increased c-fos expression in oxytocin receptor-containing neurons in the anterior cingulate cortex and amygdala when the rats acquired helping behaviour. In addition, the change in neural activation was found in the late phase of the learning. These results suggest that the oxytocin in the cingulate-amygdala pathways may play an important role in helping behaviour.

Neuropeptide S Activates Paraventricular Oxytocin Neurons to Induce Anxiolysis.

Neuropeptides, such as neuropeptide S (NPS) and oxytocin (OXT), represent potential options for the treatment of anxiety disorders due to their potent anxiolytic profile. In this study, we aimed to reveal the mechanisms underlying the behavioral action of NPS, and present a chain of evidence that the effects of NPS within the hypothalamic paraventricular nucleus (PVN) are mediated via actions on local OXT neurons in male Wistar rats. First, retrograde studies identified NPS fibers originating in the brainstem locus coeruleus, and projecting to the PVN. FACS identified prominent NPS receptor expression in PVN-OXT neurons. Using genetically encoded calcium indicators, we further demonstrated that NPS reliably induces a transient increase in intracellular Ca2+ concentration in a subpopulation of OXT neurons, an effect mediated by NPS receptor. In addition, intracerebroventricular (i.c.v.) NPS evoked a significant somatodendritic release of OXT within the PVN as assessed by microdialysis in combination with a highly sensitive radioimmunoassay. Finally, we could show that the anxiolytic effect of NPS seen after i.c.v. or intra-PVN infusion requires responsive OXT neurons of the PVN and locally released OXT. Thus, pharmacological blockade of OXT receptors as well as chemogenetic silencing of OXT neurons within the PVN prevented the effect of synthetic NPS. In conclusion, our results indicate a significant role of the OXT system in mediating the effects of NPS on anxiety, and fill an important gap in our understanding of brain neuropeptide interactions in the context of regulation of emotional behavior within the hypothalamus.SIGNIFICANCE STATEMENT Given the rising scientific interest in neuropeptide research in the context of emotional and stress-related behaviors, our findings demonstrate a novel intrahypothalamic mechanism involving paraventricular oxytocin neurons that express the neuropeptide S receptor. These neurons respond with transient Ca2+ increase and somatodendritic oxytocin release following neuropeptide S stimulation. Thereby, oxytocin neurons seem essential for neuropeptide S-induced anxiolysis, as this effect was blocked by pharmacological and chemogenetic inhibition of the oxytocin system.

Functional selective oxytocin-derived agonists discriminate between individual G protein family subtypes.

We used a bioluminescence resonance energy transfer biosensor to screen for functional selective ligands of the human oxytocin (OT) receptor. We demonstrated that OT promoted the direct engagement and activation of G(q) and all the G(i/o) subtypes at the OT receptor. Other peptidic analogues, chosen because of specific substitutions in key OT structural/functional residues, all showed biased activation of G protein subtypes. No ligand, except OT, activated G(oA) or G(oB), and, with only one exception, all of the peptides that activated G(q) also activated G(i2) and G(i3) but not G(i1), G(oA), or G(oB), indicating a strong bias toward these subunits. Two peptides (DNalOVT and atosiban) activated only G(i1) or G(i3), failed to recruit ß-arrestins, and did not induce receptor internalization, providing the first clear examples of ligands differentiating individual G(i/o) family members. Both analogs inhibited cell proliferation, showing that a single G(i) subtype-mediated pathway is sufficient to prompt this physiological response. These analogs represent unique tools for examining the contribution of G(i/o) members in complex biological responses and open the way to the development of drugs with peculiar selectivity profiles. This is of particular relevance because OT has been shown to improve symptoms in neurodevelopmental and psychiatric disorders characterized by abnormal social behaviors, such as autism. Functional selective ligands, activating a specific G protein signaling pathway, may possess a higher efficacy and specificity on OT-based therapeutics.

Effect of the oxytocin antagonist antocin and agonist decomoton on baboon luteal cell production and release of progesterone.

OBJECTIVE: To evaluate the effect of oxytocin, its antagonist antocin, and agonist decomoton on baboon luteal cell P secretion. DESIGN: Prospective study. SETTING: Academic department of obstetrics and gynecology in a US medical school. ANIMAL(S): Luteal-phased timed corpora lutea (CL) from a cohort of adult cycling baboons (Papio anubis). INTERVENTION(S): Dispersed luteal cells from luteal phase baboon CL were cultured and treated with nothing (control), oxytocin (4-400 mU), antocin (4-400 microg), oxytocin with antocin, decomoton (4-400 microg), or oxytocin with decomoton. MAIN OUTCOME MEASURE(S): Basal and hCG (10 U)-stimulated P were measured in the incubate. RESULT(S): Basal P secretion did not change significantly with all peptides studied. The hCG-stimulated P secretion was significantly inhibited by oxytocin (4-400 mU), antocin (4-400 microg), and antocin combined with oxytocin, and with oxytocin, decomoton, and decomoton combined with oxytocin. Antocin (-12%) was less inhibitory than oxytocin (-25% to -22%). Antocin combined with oxytocin enhanced the inhibition to -35% to -39%. Decomoton had stronger (not significant) inhibition than oxytocin. Mean inhibition was 28%-35% with all doses of oxytocin, decomoton, or combined together. CONCLUSION(S): Although decomoton, an oxytocin agonist inhibited hCG-stimulated luteal cell P secretion in vitro, antocin also acted like an agonist, rather than an antagonist, in inhibiting P secretion.

Effects of prostaglandins and oestradiol-17 beta on oxytocin binding in cultured bovine luteal cells.

The aim of the investigation was to evaluate the possible action of prostaglandins (PGs) and oestradiol-17 beta (oestradiol) on the specific binding for oxytocin in bovine luteal cells. Cultured cells of bovine corpora lutea at the mid-luteal stage (Day 8-12 of the oestrous cycle) were examined for the presence of oxytocin receptors by a radioreceptor assay using the 125I-labelled oxytocin antagonist [d(CH2)5,Tyr(Me)2,Thr4,Tyr-NH29]-vasotocin (125I-OVT) as a ligand. The cells were cultured for 48 h in total. In the final 15 h of culture, the luteal cells were exposed to varying concentrations of PGF2 alpha, PGE2 and/or oestradiol. After culture, the cells were incubated with 37,000 dpm (0.5 nM) 125I-OVT with or without 100 nM of unlabelled oxytocin. PGF2 alpha, at 10(-8) M and 10(-7) M, stimulated the specific binding for oxytocin to levels as high as 128% of controls (P < 0.01); by contrast, PGE2, PGI2 or oestradiol had no effect on oxytocin binding. Scatchard analysis revealed that the concentration of oxytocin receptors was increased (P < 0.05) from 6.7 fmol micrograms-1 DNA to 8.4 fmol micrograms-1 DNA by stimulation with 10(-7) M of PGF2 alpha without changing the binding affinity. No further increase in the specific binding was observed when PGF2 alpha was used in combination with PGE2, PGI2 or oestradiol at a concentration of 10(-7) M. Addition of indomethacin (28 microM) resulted in the inhibition of PGF2 alpha secretion, coinciding with a significant decrease in oxytocin binding (P < 0.01). However, addition of arachidonic acid (100 microM) caused a significant increase in the secretion of PGF2 alpha and the specific binding for oxytocin concomitantly (P < 0.05). When the protein kinase C (PKC) activity of the luteal cells was inactivated by preincubating cells for 13 h with 1 microM phorbol 12-myristate 13-acetate before PGF2 alpha stimulation, the specific binding for oxytocin was not affected by PGF2 alpha stimulation (10(-7) M) in the final 15 h of culture. These data suggest that PGF2 alpha may be one of the potent regulators for luteal oxytocin receptors in a paracrine and/or autocrine manner, and that its action is mediated by PKC.