Nitric oxide and ERK/MAPK mediation of estrous behavior induced by GnRH, PGE 2 and db-cAMP in rats (original) (raw)
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GnRH mediates estrous behavior induced by ring A reduced progestins and vaginocervical stimulation
Behavioural Brain Research, 2008
The present study was designed to assess the participation of gonadotropin-releasing hormone (GnRH) in the display of estrous behavior induced by application of vaginal-cervical stimulation (VCS) and by the intracerebroventricular (icv) administration of progesterone and its ring A-reduced metabolites to ovariectomized (ovx), estradiol benzoate (E 2 B) primed rats. Icv injection of Antide, a GnRH-1 receptor antagonist, significantly depressed lordosis behavior in ovx, E 2 B-primed rats treated with icv GnRH. Application of VCS to ovx, E 2 B-primed rats facilitated both lordosis and proceptivity. These behavioral responses were significantly depressed by the icv administration of Antide. Similarly, icv Antide blocked the stimulatory effect on both lordosis and proceptive behaviors elicited by progesterone and its ring A-reduced metabolites: 5␣-pregnandione (5␣-DHP), 5␣-pregnan-3␣-ol-20-one (5␣,3␣-Pgl) and 5-pregnan-3-hydroxy-20-one (5,3-Pgl) in ovx, E 2 B-primed rats. By contrast, icv injection of Antide failed to interfere with the facilitatory effect of the synthetic progestin megestrol acetate on lordosis and proceptive behaviors. This progestin is not reduced in ring A. The results suggest that GnRH release is an important process in the chain of events leading to the display of estrous behavior in response to progesterone, its ring A-reduced metabolites, and VCS in female rats.
Behavioural Brain Research, 2007
In estrogen-primed female rats, vaginal cervical stimulation (VCS) provided by male intromissions or by an experimenter enhances estrous behaviors exhibited by females during subsequent mating with a male. We tested the hypothesis that ␣ 1 -adrenergic receptors, acting via the nitric oxide-cGMP-protein kinase G pathway, mediate VCS-induced facilitation of female reproductive behaviors. Ovariectomized, estradiol-primed rats received intracerebroventricular (icv) infusions of vehicle or pharmacological antagonists 15 or 60 min before VCS. Estrous behaviors (lordosis and proceptivity) in the presence of a male were recorded immediately (0 min), and 120 min following VCS. First we verified that VCS, but not manual flank stimulation alone, enhanced estrous behaviors when females received icv infusion of the vehicles used to administer drugs. Increased estrous behavior was apparent immediately following VCS and persisted for 120 min. We then infused prazosin, phenoxybenzamine (␣ 1 -adrenergic receptor antagonists), yohimbine, idaxozan (␣ 2 -adrenergic receptor antagonists), or propranolol (-adrenergic receptor antagonist) 15 min prior to the application of VCS in females primed with 5 g estradiol benzoate. Only ␣ 1 -adrenergic antagonists inhibited VCS facilitation of estrous behavior, apparent 120 min after VCS. Finally, we administered specific inhibitors of soluble guanylyl cyclase, nitric oxide synthase or protein kinase G icv 15 or 60 min before VCS. All three agents significantly attenuated VCS facilitation of estrous behavior. These data support the hypothesis that endogenously released norepinephrine, acting via ␣ 1 -adrenergic receptors, mediates the facilitation of lordosis by VCS, and are consistent with a mechanism involving ␣ 1 -adrenergic activation of the nitric oxide/cGMP/protein kinase G pathway.
Hormonal and neurotransmitter regulation of GnRH gene expression and related reproductive behaviors
Behavior Genetics, 1996
Gonadotropin-releasing hormone (GnRH), having a highly conserved structure across mammalian species, plays a pivotal role in the control of the neuroendocrine events and the inherent sexual behaviors essential for reproductive function. Recent advances in molecular genetic technology have contributed greatly to the investigation of several aspects of GnRH physiology, particularly steroid hormone and neurotransmitter regulation of GnRH gene expression. Behavioral studies have focused on the actions of GnRH in steroid-sensitive brain regions to understand better its role in the facilitation of mating behavior. To date, however, there are no published reports which directly correlate GnRH gene expression and reproductive behavior. The intent of this article is to review the current understanding of the way in which changes in GnRH gene expression, and modifications of GnRH neuronal activity, may ultimately influence reproductive behavior.
Endocrinology, 1998
The present study examined the effect of alterations in GnRH signal pattern (pulsatile vs. continuous; pulse frequency) on mitogenactivated protein kinase (MAPK) activity and whether MAPK plays a role in regulating gonadotrope gene expression. Pituitary MAPK activity was measured by immunoblot, using a phospho-specific MAPK antibody, corrected to the amount of total MAPK per sample. In vivo studies were conducted in adult castrate testosterone-replaced male rats (to suppress endogenous GnRH). Animals received pulsatile or continuous GnRH (or BSA-saline for controls) via jugular cannulas. Initial studies revealed that pulsatile GnRH stimulated a dose-dependent rise in MAPK activity (30 ng, 2-fold increase; 100 ng, 4-fold; 300 ng, 8-fold) 4 min after the pulse. The effect of pulsatile vs. continuous GnRH was examined by administering 50-ng pulses (60-min interval) or a continuous infusion (25 ng/min) for 1, 2, 4, or 8 h. Pulsatile GnRH stimulated a 2-to 4-fold rise in MAPK activity (P Ͻ 0.05 vs. controls) that was maintained over the 8-h duration. In contrast, continuous GnRH only increased MAPK activity (2-to 3-fold; P Ͻ 0.05 vs. controls) for 2 h, with MAPK activity returning to baseline at later time points. The effect of GnRH pulse frequency on MAPK activation was determined by giving GnRH pulses (50 ng) at 30-, 60-, or 120-min intervals for 8 h. Maximal increases (3-fold vs. controls; P Ͻ 0.05) were seen after 120-min pulses, with faster (30-to 60-min interval) pulses stimulating 2-fold increases in MAPK activity (P Ͻ 0.05 vs. controls and 120-min GnRH pulse group). The role of MAPK activation on gonadotrope (␣, LH, FSH, and GnRH receptor) gene expression was determined in vitro. Preliminary studies demonstrated that the MAPK inhibitor, PD-098059 (50 M), completely blocked GnRH-induced increases in MAPK activity in adult male pituitary cells. Further studies revealed that PD-098059 blocked gonadotrope messenger RNA (mRNA) responses to pulsatile GnRH (100 pg/ml, 60-min interval, 24-h duration) in a selective manner, with ␣, FSH, and GnRH receptor (but not LH) mRNA responses being suppressed. These results show that a pulsatile GnRH signal is required to maintain MAPK activation for durations of longer than 2 h, and that slower frequency pulses are more effective. Further, MAPK plays a crucial role in ␣, FSH, and GnRH receptor mRNA responses to pulsatile GnRH. Thus, divergent MAPK responses to alterations in GnRH signal pattern may be one mechanism involved in differential regulation of gonadotrope gene expression.
Neuroscience Letters, 1997
In urethane-anesthetized ovariectomized rats, estrogen-sensitive descending neurons were identified in the midbrain ventral tegmental area (VTA), based on estrogen-induced changes in the excitability in antidromic responses to midbrain central gray stimulation. Estrogen increased the threshold and decreased the firing rate of the identified neurons. Responses of the identified neurons to the microiontophoresis of gonadotropin-releasing hormone (GnRH) or d-Phe 2 , d-Ala 6-GnRH, a behaviorally active analog, but not to glutamate or g-aminobutyric acid (GABA), depended on estrogen. In the ovariectomized rat, GnRH excited a few neurons; the analog had no effect. GnRH suppressed spontaneous or glutamate-induced firing in almost all neurons in the estrogen-primed rat. The analog had mixed effects. The facilitation of female rat sexual behavior induced by infusion of GnRH in the VTA is due to the inhibition of VTA neurons.
GnRH and GnRH receptors in the pathophysiology of the human female reproductive system
Human Reproduction Update, 2015
† Introduction † Methods † GnRH and GnRH receptors GnRH GnRH isoforms GnRHRs GnRH analogues † Development of GnRH neurons and related diseases † GnRH neuron function and GnRH secretion Control of GnRH secretion GnRH action on gonadotrope cells Dysregulation of pulsatile GnRH release GnRH pulsatility in the onset of puberty † GnRH and GnRH receptors in female peripheral sexual organs Peripheral versus central GnRHRs The GnRH/GnRHR system in the endometrium The GnRH/GnRHR system in the ovary † Pharmacology of GnRH and GnRH analogues in human female reproduction and diseases GnRH analogues for stimulating or to blocking the reproductive axis GnRH analogues in benign gynaecological diseases GnRH analogues in gynaecological tumours GnRH analogues for fertility preservation in female patients undergoing chemotherapy † Conclusions and future perspectives background: Human reproduction depends on an intact hypothalamic-pituitary-gonadal (HPG) axis. Hypothalamic gonadotrophin-releasing hormone (GnRH) has been recognized, since its identification in 1971, as the central regulator of the production and release of the pituitary gonadotrophins that, in turn, regulate the gonadal functions and the production of sex steroids. The characteristic peculiar development, distribution and episodic activity of GnRH-producing neurons have solicited an interdisciplinary interest on the etiopathogenesis of several reproductive diseases. The more recent identification of a GnRH/GnRH receptor (GnRHR) system in both the human endometrium and ovary has widened the spectrum of action of the peptide and of its analogues beyond its hypothalamic function.
Gonadotropin-inhibitory hormone (GnIH), GnIH receptor and cell signaling
General and Comparative Endocrinology, 2013
Gonadotropin-inhibitory hormone (GnIH) is an inhibitor of gonadotropin synthesis and release, which was originally identified in the hypothalamus of the Japanese quail (Coturnix japonica). The GnIH precursor polypeptide encodes one GnIH and two GnIH related peptides (GnIH-RP-1 and GnIH-RP-2) in birds that share the same C-terminal LPXRFamide (X = L or Q) motif. The receptor for GnIH is thought to be the G protein-coupled receptor 147 (GPR147) which has been shown to couple predominantly through the G ai protein to inhibit cAMP production. The crude membrane fraction of COS-7 cells transfected with GPR147 cDNA specifically bound GnIH and GnIH-RPs in a concentration-dependent manner. Scatchard plot analysis of the binding showed that GPR147 possessed a single class of high-affinity binding sites. GnIH neurons project to the median eminence to control anterior pituitary function and GPR147 is expressed in the gonadotropes. GnIH neurons also project to gonadotropin-releasing hormone (GnRH)-I and GnRH-II neurons, and GnRH-I and GnRH-II neurons express GPR147. Thus, GnIH may inhibit gonadotropin synthesis and release by decreasing the activity of GnRH-I neurons as well as directly inhibiting the effects of GnRH on gonadotropes. GnIH may also partially inhibit reproductive behaviors by inhibiting GnRH-II neurons. GnIH and GPR147 are also expressed in the gonads, possibly acting in an autocrine/paracrine manner. The cell signaling process of GPR147 was extensively studied using LbT2 cells, a mouse gonadotrope cell line. In this cell line, mouse GnIH inhibits GnRH-induced gonadotropin subunit, LHb, FSHb, and common a, gene transcriptions by inhibiting adenylate cyclase/cAMP/PKA dependent ERK pathway. This review summarizes the functions of GnIH, GnIH receptor and its cell signaling processes in birds and discusses related findings in mammals.
A role for Src kinase in progestin facilitation of estrous behavior in estradiol-primed female rats
Hormones and Behavior, 2010
Estradiol Lordosis behavior MAPK PP2 Progesterone 5α-dihydroprogesterone 5α-pregnan,3α-20-dione Progesterone metabolism Src kinase This study tested the hypothesis that the Src/Raf/MAPK signaling pathway is involved in the facilitation of the lordosis and proceptive behaviors induced by progesterone (P) and its ring A-reduced metabolites in ovariectomized, estradiol-primed rats. Intraventricular (icv) infusion of PP2 (7.5, 15 and 30 µg), a Src kinase inhibitor, significantly depressed P-dependent estrous behavior (lordosis and proceptivity) in estradiolprimed rats. Icv infusion of 30 µg of PP2 also significantly attenuated estrous behavior induced by the ring Areduced P metabolites 5α-dihydroprogesterone (5α-DHP) and 5α-pregnan-3α-ol-20-one (allopregnanolone). PP2 did not inhibit estrous behavior induced by administration of high doses of estradiol alone to ovariectomized rats. We also assessed if the ventromedial hypothalamus (VMH) is one of the neural sites at which progestins activate Src signaling to facilitate estrous behavior. Bilateral administration of 15 µg of PP2 into the VMH inhibited the stimulation of both lordosis and proceptive behaviors elicited by subcutaneous P administration to estradiol-primed rats. These results suggest that progestins act through Src/Raf/MAPK signaling to initiate estrous behaviors in estrogen-primed rats. This event is one component of the cellular pathways leading to the display of estrous behaviors induced by P and its ring A-reduced metabolites in female rats.