Oxytocin stimulates the release of luteinizing hormone-releasing hormone from medial basal hypothalamic explants by releasing nitric oxide

Abstract

Oxytocin induces mating behavior in rats of both sexes. Previous experiments revealed that progesteroneinduced sex behavior in ovariectomized, estrogen-primed rats was caused by release of NO from NOergic neurons that stimulated the release of luteinizing hormone-releasing hormone (LHRH). The LHRH activated brain-stem neurons that initiated the lordosis ref lex. We hypothesized that oxytocin might similarly release NO in the medial basal hypothalamic region that would stimulate release of LHRH into the hypophyseal portal vessels to release luteinizing hormone. To investigate this hypothesis, medial basal hypothalamic explants were preincubated in Krebs-Ringer bicarbonate buffer for 30 min, followed by a 30-min incubation in fresh Krebs-Ringer bicarbonate buffer containing the compounds to be tested. Oxytocin stimulated LHRH release 3-to 4-fold at the lowest concentration tested (10 ؊10 M). Values remained at a plateau as the concentration was increased to 10 ؊7 M and then declined in a concentration-dependent manner, so that there was no stimulation with a concentration of 10 ؊5 M. Oxytocin (10 ؊7 M) stimulated release of prostaglandin E 2 into the medium, a finding consistent with a role of NO in the response. That NO indeed mediated the action of oxytocin was supported by blockade of the action of oxytocin by the competitive inhibitor of NO synthase (NOS), N G -monomethyl-L-arginine (300 M). Furthermore, oxytocin (10 ؊9 to 10 ؊7 M) activated NOS as measured at the end of the experiments. Oxytocin appeared to act to stimulate norepinephrine terminals in the medial basal hypothalamus, which activated NOS by ␣ 1 -adrenergic receptors, because prazocine, an ␣ 1 receptor blocker, inhibited the LHRH-releasing action of oxytocin. Finally, incubation of neural lobe explants with sodium nitroprusside, a NO releasor, revealed that nitroprusside (300-600 M, but not 900 M) inhibited oxytocin release. Therefore, the NO released by oxytocin also diffuses into the oxytocin neuronal endings and inhibits oxytocin release, forming a negative feedback loop. The results indicate that oxytocin is important not only in induction of mating, but also in stimulating LHRH release with subsequent luteinizing hormone discharge that plays a crucial role in reproduction.Although oxytocin is one of the most abundant peptides in the body, little is known about its function. In the female, it is critical for milk ejection during lactation and plays an important role in parturition by inducing uterine contractions (1, 2). Oxytocin also appears to influence maternal and mating behavior, because intraventricular injection of the peptide induces these behaviors in female rats (3, 4).Although the amounts of oxytocin present in the neurohypophysis of male and female rats are similar, its function in the male has not been established (1). It induces natriuresis in both sexes (1), and recent evidence indicates that it may do so by releasing atrial natriuretic peptide (5).Intraventricular injection of oxytocin causes penile erection in male ra...

Pup removal suppresses estrogen-induced surges of LH secretion and activation of GnRH neurons in lactating rats

“…However, at least, suppression of LH surges in pup-removed lactating rats is not attributable to blockade of oxytocin action at the pituitary level, because the primary cause of the suppression of LH surges by pup removal is at the hypothalamic level, i.e., it is attributable to the failure of activation of the GnRH surge generator in the hypothalamus as evidenced by the GnRH/c-Fos immunohistochemical studies. On the other hand, several studies have demonstrated the central action of oxytocin on GnRH release (Rettori et al 1994, Selvage & Johnston 2001. These findings may support our conclusion regarding the involvement of Photomicrographs showing c-Fos-positive GnRH neurons in lactating rats.…”

“…This hypothesis is based on the finding that suckling induces oxytocin release and oxytocin regulates LH secretion by acting at the hypothalamic level (Rettori et al 1994, Selvage & Johnston 2001. To mimic oxytocin release in response to the suckling stimulus, oxytocin was intracerebroventricularly injected into nonsuckled and, therefore, LH surge-suppressed rats.…”

β-Endorphin blocks luteinizing hormone-releasing hormone release by inhibiting the nitricoxidergic pathway controlling its release

“…These glutamergic neurons appear to play a physiological role in the preovulatory release of LHRH by stimulating the noradrenergic neurons. Oxytocin similarly stimulates these neurons; therefore, there is a multisynaptic input to the noradenergic terminals that brings about a large increase in NO release that is responsible for the preovulatory surge of LHRH (14). We hypothesize that the inhibitory ␤-endorphinergic input into the system uses this NOergic pathway.…”

Castration increases and androgens decrease nitric oxide synthase activity in the brain: Physiologic implications

“…NO functions as a neurotransmitter (2)(3)(4)(5)(6)(7)(8)(9)(10) and nNOS is present near gonadotropin-releasing hormone terminals (14) and in regions of the brain that appear to regulate emotional behaviors (15,16). Estradiol (E 2 ) up-regulates endothelial NOS in endothelial cells (17,18) and nNOS in the brain (18)(19)(20)(21), and many of the actions of E 2 on the brain have been suggested to be through a NO-mediated mechanism (2)(3)(4)(5)(6)(7)(8)(9)(10)(18)(19)(20)(21)(22). Administration of E 2 and progesterone to ovariectomized rats leads to an increase in the luteinizing hormone surge, the magnitude of which is significantly attenuated after administration of nNOS antisense oligonucleotides into the third ventricle (22), suggesting an intermediary role of NO in modulating some actions of E 2 by up-regulating nNOS activity.…”