RESUMEN
The effects of 4NO2PDPMe and 4APDPMe, which are thalidomide (Tha) analogs that act as selective phosphodiesterase (PDE-4) inhibitors, on estrous behavior (lordosis and proceptive behaviors) and on uterine contraction were studied in ovariectomized (OVX) estrogen-primed Sprague Dawley (SD) and in intact non-pregnant Wistar rats, respectively. We found that intracerebroventricular (ICV) infusion of either 4NO2PDPMe or 4APDPMe (20 to 80⯵g) stimulated intense lordosis and proceptive behavior in response to mounts from a sexually active male, within the first 4â¯h after infusion, and persisting for up to 24â¯h. Inhibitors of the progesterone receptor (RU486, administered subcutaneously), the estrogen receptor (tamoxifen, ICV), the adenylate cyclase (AC)/ cyclic AMP (cAMP)/protein kinase A (PKA) pathway (administered ICV), and the mitogen activated protein kinase (MAPK) pathway (administered ICV) significantly decreased lordosis and proceptive behavior induced by Tha analogs. Uterine contractility studies showed that Tha analogs inhibited both the K+- and the Ca2+-induced tonic contractions in rat uterus. Tha analogs were equally effective, but 4APDPMe was more potent than 4NO2PDPMe. These results strongly suggest the central role of cAMP in both processes, sexual behavior, and uterine relaxation, and suggest that Tha analogs may also act as Ca2+-channel blockers.
Asunto(s)
AMP Cíclico/metabolismo , Inhibidores de Fosfodiesterasa 4/farmacología , Ftalimidas/farmacología , Propionatos/farmacología , Conducta Sexual Animal/efectos de los fármacos , Talidomida/análogos & derivados , Contracción Uterina/efectos de los fármacos , Adenilil Ciclasas/efectos de los fármacos , Adenilil Ciclasas/metabolismo , Animales , Calcio , Proteínas Quinasas Dependientes de AMP Cíclico/efectos de los fármacos , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Didesoxiadenosina/farmacología , Estradiol/análogos & derivados , Estradiol/farmacología , Antagonistas de Estrógenos/farmacología , Estrógenos/farmacología , Estro , Femenino , Técnicas In Vitro , Infusiones Intraventriculares , Inyecciones Subcutáneas , Lordosis , Luteolíticos/farmacología , Mifepristona/farmacología , Ovariectomía , Potasio , Ratas , Ratas Sprague-Dawley , Ratas Wistar , Receptores de Progesterona , Tamoxifeno/farmacología , Talidomida/farmacología , Contracción Uterina/metabolismo , Útero/efectos de los fármacosRESUMEN
The present study assessed the participation of membrane G-protein coupled estrogen receptor 1 (GPER-1) and gonadotropin releasing hormone 1 (GnRH-1) receptor in the display of lordosis induced by intracerebroventricular (icv) administration of G1, a GPER-1 agonist, and by unesterified 17ß-estradiol (free E2). In addition, we assessed the participation of both estrogen and progestin receptors in the lordosis behavior induced by G1 in ovariectomized (OVX), E2-benzoate (EB)-primed rats. In Experiment 1, icv injection of G1 induced lordosis behavior at 120 and 240min. In Experiment 2, icv injection of the GPER-1 antagonist G15 significantly reduced lordosis behavior induced by either G1 or free E2. In addition, Antide, a GnRH-1 receptor antagonist, significantly depressed G1 facilitation of lordosis behavior in OVX, EB-primed rats. Similarly, icv injection of Antide blocked the stimulatory effect of E2 on lordosis behavior. In Experiment 3, systemic injection of either tamoxifen or RU486 significantly reduced lordosis behavior induced by icv administration of G1 in OVX, EB-primed rats. The results suggest that GnRH release activates both estrogen and progestin receptors and that this activation is important in the chain of events leading to the display of lordosis behavior in response to activation of GPER-1 in estrogen-primed rats.
Asunto(s)
Estradiol/farmacología , Postura/fisiología , Receptores de Estrógenos/fisiología , Receptores Acoplados a Proteínas G/agonistas , Receptores LHRH/fisiología , Receptores de Progesterona/fisiología , Conducta Sexual Animal/efectos de los fármacos , Animales , Femenino , Antagonistas de Hormonas/farmacología , Mifepristona/farmacología , Oligopéptidos/farmacología , Ratas , Ratas Sprague-Dawley , Conducta Sexual Animal/fisiología , Tamoxifeno/farmacologíaRESUMEN
We studied the participation of GABA neurotransmission in the medial preoptic area (mPOA) with respect to the onset of the pup retrieval response and nest building. Pregnant female rats were implanted with bilateral cannulae in the mPOA on day 12 of pregnancy and, on day 16, the females were hysterectomised and ovariectomised and given 200 µg/kg of oestradiol benzoate. Two days later, the females received one of the following intracerebral drug treatments: GABAB agonist baclofen (200 ng); GABAB antagonist phaclofen (1 µg); GABAA antagonist bicuculline (60 ng); or physiological saline. Five minutes after intracerebral infusion, three foster pups were introduced into the females' home cage. The subjects were observed for pup grouping (retrieval) during 15 min, after which the pups were left with the female. During the next 12 h, an observation was made every 1 h to determine whether the pups had been grouped (retrieved) or not. The GABAB agonist baclofen reduced the proportion of females retrieving pups from 4 to 8 h following pup introduction. By contrast, both the GABAA antagonist bicuculline and the GABAB antagonist phaclofen enhanced the proportion of females retrieving pups during the first 3 h of observation. The latency to pup retrieval in subjects treated with the GABAB agonist baclofen was significantly longer than that in subjects given any of the antagonists. All females built a nest but baclofen reduced nest quality. These data show that activation of GABAB receptors in the mPOA has an inhibitory effect on basic maternal behaviours, whereas blockade of either the GABAA or GABAB receptor facilitates pup retrieval. It is possible that reduced GABAergic tone in the mPOA is a key element in the initiation of maternal behaviours in postparturient rats.
Asunto(s)
Estradiol/fisiología , Conducta Materna , Área Preóptica/fisiología , Receptores de GABA-A/fisiología , Receptores de GABA-B/fisiología , Animales , Baclofeno/administración & dosificación , Baclofeno/análogos & derivados , Bicuculina/administración & dosificación , Femenino , Antagonistas de Receptores de GABA-A/administración & dosificación , Agonistas de Receptores GABA-B/administración & dosificación , Antagonistas de Receptores de GABA-B/administración & dosificación , Histerectomía , Conducta Materna/efectos de los fármacos , Comportamiento de Nidificación/efectos de los fármacos , Ovariectomía , Embarazo , Área Preóptica/efectos de los fármacos , Ratas WistarRESUMEN
The role of classical estrogen receptors (ERs) in priming female reproductive behavior has been studied previously; however, the participation of this receptor during activation of estrous behavior has not been extensively studied. The purpose of this work was to test the possibility that the facilitation of lordosis behavior in estrogen-primed rats by progesterone (P) and its 5α- and 5ß-reduced metabolites, gonadotropin-releasing hormone (GnRH), leptin, prostaglandin E2 (PGE2) and vagino-cervical stimulation (VCS) involves interactions with classical ERs by using the selective ER modulator, tamoxifen. To further assess the role of ERs, we also explored the effects of the pure ER antagonist, ICI182780 (ICI), on estrous behavior induced by P and GnRH. Ovariectomized, estrogen-primed rats (5µg estradiol benzoate 40h earlier) were injected intraventricularly with the above-mentioned compounds, or they received VCS. All compounds and VCS effectively facilitated estrous behavior when tested at 60, 120 or 240min after infusion or application of VCS. Intraventricular infusion of tamoxifen (5µg), 30min before, significantly attenuated estrous behaviors induced in estradiol-primed rats by P, most of its 5α- and 5ß-reduced metabolites, GnRH, and PGE2, but not by VCS. Although there was a trend for reduction, tamoxifen did not significantly decrease lordosis in females treated with 5ß-pregnan-3,20-dione. ICI also inhibited lordosis behavior induced by P and GnRH at some testing intervals. These results suggest that activation of classical ERs participates in the triggering effects on estrous behavior induced by agents with different chemical structures that do not bind directly to ERs.
Asunto(s)
Conducta Animal/efectos de los fármacos , Dinoprostona/farmacología , Ciclo Estral/efectos de los fármacos , Péptidos/farmacología , Progestinas/farmacología , Receptores de Estrógenos/fisiología , Animales , Antagonistas de Estrógenos/farmacología , Femenino , Hormona Liberadora de Gonadotropina/farmacología , Inyecciones Intraventriculares , Leptina/farmacología , Ratas , Ratas Sprague-Dawley , Receptores de Estrógenos/antagonistas & inhibidores , Receptores de Estrógenos/efectos de los fármacos , Tamoxifeno/farmacologíaRESUMEN
AIMS: The effect of i.p. injection or oral ingestion of glycinamide, a glycine pro-drug, on two tests for nociception was assessed in ovariectomized Sprague Dawley rats. MAIN METHODS: To explore the potential analgesic effect of glycinamide the vocalization threshold to tail shock (VT) and the tail flick latency (TFL) were used. Glycinamide was administered both through the intraperitoneal route (doses 0, 25, 100, 400, 800 mg/kg) and through ad libitum oral ingestion of glycinamide solution (40 mg/ml) following a 24h period of water deprivation. KEY FINDINGS: Glycinamide exerted a significant analgesic effect on VT when injected i.p. at doses of 400 or 800 mg/kg. Analgesia occurred 10-20 min post-injection and persisted approx 45 min. At the high dose level, glycinamide exerted a weaker and more delayed effect on TFL than on the VT test. I.p. injection of 800 mg/kg glycinamide inhibited vocalizations induced by the application of suprathreshold tail shocks (30% above threshold) with a latency of approx 3 min and duration of approx 1h. The volume of a glycinamide solution (40 mg/ml) ingested by rats deprived of water for 24h was positively correlated with the degree of analgesia in the VT test. Values between 100 and 200mg glycinamide exerted clear analgesic responses. SIGNIFICANCE: Thus, glycinamide, either by systemic or oral routes, exerts a clear analgesic effect in the VT test of nociception and a much weaker action in the TFL test. This effect is probably due to the conversion of glycinamide to glycine in the brain.
Asunto(s)
Analgésicos/farmacología , Glicina/análogos & derivados , Dolor Nociceptivo/tratamiento farmacológico , Administración Oral , Analgésicos/administración & dosificación , Animales , Relación Dosis-Respuesta a Droga , Femenino , Glicina/administración & dosificación , Glicina/farmacología , Inyecciones Intraperitoneales , Ovariectomía , Dimensión del Dolor/efectos de los fármacos , Dimensión del Dolor/métodos , Ratas , Ratas Sprague-Dawley , Tiempo de Reacción/efectos de los fármacos , Factores de TiempoRESUMEN
Brief vaginocervical stimulation using a glass rod (VCS) combined with manual flank-perineal stimulation (FS) rapidly (within 5 min) induced both receptive and proceptive behavioural responses to males in ovariectomised, oestrogen-primed rats. This receptive-proceptive response to males, resulting from a single brief (5-s duration) instance of manual VCS + FS, declined markedly within 4 h. However, the decline was prevented if the females were mounted by males immediately after the manual VCS + FS and 2 h later. We tested the participation of the cAMP-dependent protein kinase A system and the mitogen-activated protein kinase (MAPK) system in the response to VCS + FS by infusing either 100 ng of Rp-adenosine 3',5'-cyclic monophosphorothiate triethylamonium salt (a protein kinase A blocker) or 3.3 microg of PD98059 (a MAPK blocker) i.c.v. 15 min prior to VCS + FS. Both inhibitors blocked the ability of VCS + FS to induce the proceptive-receptive responses to males at all testing intervals. In experiment 2, systemic administration of 5 mg of RU486 1 h before VCS + FS also blocked the ability of VCS + FS to induce the proceptive-receptive responses to males. The present findings suggest that both VCS + FS and mating stimuli provided by males release neurotransmitters and neuromodulators that trigger the protein kinase A and the MAPK signalling systems, which interact with the progestin receptor to rapidly (within 5 min) induce proceptive-receptive behaviour in females.