d(CH2)5Tyr(Me)-[Orn8]vasotocin, a potent oxytocin antagonist, antagonizes penile erection and yawning induced by oxytocin and apomorphine, but not by ACTH-(1–24)

doi:10.1016/0014-2999(87)90168-3

European Journal of Pharmacology

Volume 134, Issue 2, 10 February 1987, Pages 221-224

https://doi.org/10.1016/0014-2999(87)90168-3 Get rights and content

Abstract

Intraventricular (i.c.v.) injection of d(CH₂)₅-Tyr(Me)-[Orn⁸]vasotocin, a potent oxytocin antagonist, antagonized in a dose-dependent manner (10–100 ng) penile erection and yawning induced by the systemic injection of apomorphine (80 μg/kg s.c.) or by the i.c.v. injection of oxytocin (30 ng). In contrast, the oxytocin antagonist, even at the dose of 10 μg, did not modify penile erection and yawning induced by the i.c.v. injection of ACTH-(1–24). These results suggest that apomorphine, but not ACTH-(1–24), induce penile erection and yawning by releasing oxytocin in some brain area.

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The cumulative evidence suggests that oxytocin is involved in the male sexual behaviors. However, no significant sexual impairments were observed in oxytocin gene knock-out (KO) mice, suggesting that oxytocin is not necessary for sexual behavior in male mice. To better understand the role of oxytocin in male erection, two types of oxytocin gene KO mice were created. In the first type, the oxytocin gene was deleted in the zygote, while in the second type, the oxytocin gene was mutated in adulthood by injecting the CRISPR/Cas9 AAVs. The results showed that disrupting the oxytocin gene at either the embryonic or adult stage did not affect erection, indicating that oxytocin is not necessary for penile erection. Pharmacologically, injecting oxytocin receptor agonist Carbetocin into the VTA of the oxytocin gene KO mice still evoked penile erection. By employing the Oxt-Ires-Cre mice, we found that specifically activating oxytocinergic neurons through chemogenetics strongly induced penile erection, while inhibiting these neurons blocked the erection responses. Furthermore, ablating PVN oxytocinergic neurons abolished the male erection response. In conclusion, although the neuropeptide oxytocin is not essential for male erection, the activity of oxytocinergic neurons is required. Our results might reflect the redundancy in the central nerve system in the sense that many signals contribute to the activation of oxytocinergic neurons to evoke penile erection during sexual behaviors.
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Yawning behavior is characterized by mouth opening accompanied by deep inspiration, as well as arousal response, and is often observed not only in states of boredom or drowsiness, but also in stressful emotional situations in humans and animals. These phenomena suggest that yawning response may be an emotional behavior, possibly through activation of the central nucleus of amygdala (CeA), which is a critical region for emotional responses. However, the involvement of the CeA in triggering yawning remains unknown. Here, we investigated whether neuronal activation of the CeA by microinjection of L-glutamate into the CeA is able to induce stereotyped yawning responses in anesthetized, spontaneously breathing rats. In addition, we assessed the effects of the CeA stimulation on the activation of oxytocin (OT) and CRF (corticotropin-releasing factor) neurons in the paraventricular nucleus of the hypothalamus (PVN), which is responsible for induction of yawning, using c-Fos immunohistochemistry. Microinjection of L-glutamate into the CeA causes an initial depressor response in the blood pressure and an arousal shift on the electrocorticogram followed by a single inspiration, which is the same as the typical pattern of the stereotyped yawning response induced by the PVN stimulation. In addition, the CeA stimulation activated the neuronal activities of both OT and CRF neurons in the PVN, as well as yawning responses. These results indicate that activation of the CeA is involved in the induction of yawning response, suggesting that yawning is an emotional behavior.
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In male rats, oxytocin impacts both sexual arousal and certain types of consummatory sexual behaviors. However, the role of oxytocin in the motivational aspects of sexual behavior has received limited attention. Given the role that oxytocin signaling plays in consummatory sexual behaviors, it was hypothesized that pharmacological attenuation of oxytocin signaling would reduce sexual motivation in male rats. Sexually experienced Long-Evans male rats were administered either an oxytocin receptor antagonist (L368,899 hydrochloride; 1 mg/kg) or vehicle control into the intraperitoneal cavity 40 min prior to placement into the center chamber of a three-chambered arena designed to assess sexual motivation. During the 20-minute test, a sexually experienced stimulus male rat and a sexually receptive stimulus female rat were separately confined to smaller chambers that were attached to the larger end chambers of the arena. However, physical contact between test and stimulus rats was prevented by perforated dividers. Immediately following the sexual motivation test, test male rats were placed with a sexually receptive female to examine consummatory sexual behaviors. Although both drug and vehicle treated rats exhibited a preference for the female, treatment with an oxytocin receptor antagonist decreased the amount of time spent with the female. There were no differences between drug and vehicle treated rats in either general activity, exploratory behaviors, the amount of time spent near the stimulus male rat, or consummatory sexual behaviors. Extending previous findings, these results indicate that oxytocin receptors are involved in sexual motivation in male rats.
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Central oxytocin (OT) and arginine-vasopressin (AVP) have been shown to play an important role in sexual behavior and neuroendocrine secretion in rodents. The results of exogenous OT administration on sexual behaviors in male and female mice are controversial. This study aimed to analyze the role of OT in sexual behavior, the number of oocytes and the density of dendritic spines in the posterodorsal medial amygdala (MePD) of female mice with selective deletion of the OT gene (OTKO). Female C57BL/6 mice were genotyped and divided into control (WT) and OTKO groups (n = 11 each). All experiments were performed in the proestrus phase. Compared to WT data, our results showed that the OTKO group had a significant increase in the latency for the display of lordosis behavior (490.8 ± 113.8 and 841.9 ± 53.9, respectively) and a decrease in both the frequency (6.3 ± 2.4 and 0.5 ± 0.4) and duration (49.3 ± 19.9 and 7.2 ± 7.1) of lordosis and a reduction in the number of oocytes (12.2 ± 0.8 and 9.9 ± 0.6). However, the OTKO group showed a higher density of proximal dendritic spines in the MePD compared to the WT group (2.4 ± 0.1 and 1.9 ± 0.1 spines/dendritic μm, respectively). No significant difference was observed in the plasma levels of AVP between the groups (OTKO: 617.1 ± 96.0 and WT: 583.3 ± 112.0 pg/mL). Our data suggest that OT plays a crucial role in the sexual behavior display, number of released oocytes and density of dendritic spines in the MePD of female mice. The AVP plasma concentration was not affected in the OTKO animals.
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Of the numerous neuropeptides identified in the central nervous system, only a few are involved in the control of sexual behaviour. Among these, the most studied are oxytocin, adrenocorticotropin, α-melanocyte stimulating hormone and opioid peptides. While opioid peptides inhibit sexual performance, the others facilitate sexual behaviour in most of the species studied so far (rats, mice, monkeys and humans). However, evidence for a sexual role of gonadotropin-releasing hormone, corticotropin releasing factor, neuropeptide Y, galanin and galanin-like peptide, cholecystokinin, substance P, vasoactive intestinal peptide, vasopressin, angiotensin II, hypocretins/orexins and VGF-derived peptides are also available. Corticotropin releasing factor, neuropeptide Y, cholecystokinin, vasopressin and angiotensin II inhibit, while substance P, vasoactive intestinal peptide, hypocretins/orexins and some VGF-derived peptide facilitate sexual behaviour. Neuropeptides influence sexual behaviour by acting mainly in the hypothalamic nuclei (i.e., lateral hypothalamus, paraventricular nucleus, ventromedial nucleus, arcuate nucleus), in the medial preoptic area and in the spinal cord. However, it is often unclear whether neuropeptides influence the anticipatory phase (sexual arousal and/or motivation) or the consummatory phase (performance) of sexual behaviour, except in a few cases (e.g., opioid peptides and oxytocin). Unfortunately, scarce information has been added in the last 15 years on the neural mechanisms by which neuropeptides influence sexual behaviour, most studied neuropeptides apart. This may be due to a decreased interest of researchers on neuropeptides and sexual behaviour or on sexual behaviour in general. Such a decrease may be related to the discovery of orally effective, locally acting type V phosphodiesterase inhibitors for the therapy of erectile dysfunction.
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Citation Excerpt :
It is, thus, possible that diffusible NO produced within CRF neurons activates descending oxytocinergic system in the PVN and its actions on oxytocinergic neurons elicit yawning. This possibility could be supported by previous studies showing that NO could be involved in induction of yawning via an activation of oxytocinergic neurons projecting to the pons and medulla oblongata (Argiolas et al., 1987; Argiolas and Melis, 1998; Kita et al., 2006b; Melis and Argiolas, 1997; Sato-Suzuki et al., 1998). CRF neurons in the PVN generally play an important role as the initiators of activation of the hypothalamic-pituitary-adrenal axis (HPA axis) during stress (Rivier and Plotsky, 1986; Vale et al., 1981).
We previously reported that intracerebroventricular (icv) administration of corticotropin-releasing factor (CRF) antagonist attenuates the arousal response during yawning behavior in rats. However, the CRF-related pathway involved in the arousal response during yawning is still unclear. In the present study, we assessed the involvement of the CRF-containing pathway from the hypothalamic paraventricular nucleus (PVN) to the locus coeruleus (LC) and the dorsal raphe nucleus (DRN) in the arousal response during frequent spontaneous yawning, which was induced by several microinjections of l-glutamate into the PVN in anesthetized rats, using c-Fos immunohistochemistry. The PVN stimulation showed significant increases in activation of PVN CRF neurons, LC noradrenalin (NA) neurons and DRN serotonin (5-HT) neurons as well as arousal response during yawning. But icv administration of a CRF receptor antagonist, α-helical CRF (9-41), significantly inhibited the activation of both LC NA neurons and DRN 5-HT neurons except the activation of CRF neurons in the PVN, and significantly suppressed the arousal response during yawning. These results suggest that the CRF-containing pathway from PVN CRF neurons to LC NA neurons and DRN 5-HT neurons can be involved in the arousal response during yawning behavior.

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Short communicationd(CH2)5Tyr(Me)-[Orn8]vasotocin, a potent oxytocin antagonist, antagonizes penile erection and yawning induced by oxytocin and apomorphine, but not by ACTH-(1–24)

Abstract

Adv. Biochem. Psychopharmacol.

Trends Neurosci.

Design and synthesis of potent in vivo antagonists of oxytocin

Int. J. Pept. Prot. Res.

The effect of dopamine on neurohypophyseal hormone release in vivo and from the rat neural lobe and hypothalamus in vitro

J. Physiol. (London)

Short communication
d(CH₂)₅Tyr(Me)-[Orn⁸]vasotocin, a potent oxytocin antagonist, antagonizes penile erection and yawning induced by oxytocin and apomorphine, but not by ACTH-(1–24)