RESUMEN
BACKGROUND AND PURPOSE: Clinical results of osanetant and talnetant (selective-NK3 antagonists) indicate that blocking the NK3 receptor could be beneficial for the treatment of schizophrenia. The objective of this study was to characterize the in vitro and in vivo properties of a novel dual NK1/NK3 antagonist, RO4583298 (2-phenyl-N-(pyridin-3-yl)-N-methylisobutyramide derivative). EXPERIMENTAL APPROACH: RO4583298 in vitro pharmacology was investigated using radioligand binding ([³H]-SP, [³H]-osanetant, [³H]-senktide), [³H]-inositol-phosphate accumulation Schild analysis (SP- or [MePhe7]-NKB-induced) and electrophysiological studies in guinea-pig substantia nigra pars compacta (SNpc). The in vivo activity of RO4583298 was assessed using reversal of GR73632-induced foot tapping in gerbils (GFT; NK1) and senktide-induced tail whips in mice (MTW; NK3). KEY RESULTS: RO4583298 has a high-affinity for NK1 (human and gerbil) and NK3 (human, cynomolgus monkey, gerbil and guinea-pig) receptors and behaves as a pseudo-irreversible antagonist. Unusually it binds with high-affinity to mouse and rat NK3, yet with a partial non-competitive mode of antagonism. In guinea-pig SNpc, RO4583298 inhibited the senktide-induced potentiation of spontaneous activity of dopaminergic neurones with an apparent non-competitive mechanism of action. RO4583298 (p.o.) robustly blocked the GFT response, and inhibited the MTW. CONCLUSIONS AND IMPLICATIONS: RO4583298 is a high-affinity, non-competitive, long-acting in vivo NK1/NK3 antagonist; hence providing a useful in vitro and in vivo pharmacological tool to investigate the roles of NK1 and NK3 receptors in psychiatric disorders.
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Amidas/farmacología , Antipsicóticos/farmacología , Mesencéfalo/efectos de los fármacos , Antagonistas del Receptor de Neuroquinina-1 , Piridinas/farmacología , Receptores de Neuroquinina-3/antagonistas & inhibidores , Potenciales de Acción/efectos de los fármacos , Amidas/metabolismo , Amidas/farmacocinética , Aminopiridinas , Animales , Antipsicóticos/metabolismo , Antipsicóticos/farmacocinética , Bencenoacetamidas , Relación Dosis-Respuesta a Droga , Femenino , Gerbillinae , Cobayas , Células HEK293 , Humanos , Técnicas In Vitro , Inositol/metabolismo , Ligandos , Macaca fascicularis , Masculino , Mesencéfalo/fisiología , Ratones , Neuronas/efectos de los fármacos , Neuronas/fisiología , Fosforilación/efectos de los fármacos , Piridinas/metabolismo , Piridinas/farmacocinética , Ratas , Receptores de Neuroquinina-1/agonistas , Receptores de Neuroquinina-1/genética , Receptores de Neuroquinina-1/metabolismo , Receptores de Neuroquinina-3/agonistas , Receptores de Neuroquinina-3/genética , Receptores de Neuroquinina-3/metabolismo , Esquizofrenia/tratamiento farmacológico , Sustancia P/análogos & derivados , Sustancia P/antagonistas & inhibidores , Sustancia Negra/efectos de los fármacos , Sustancia Negra/fisiologíaRESUMEN
BACKGROUND AND PURPOSE: As baclofen is active in patients with anxiety disorders, GABAB receptors have been implicated in the modulation of anxiety. To avoid the side effects of baclofen, allosteric enhancers of GABAB receptors have been studied to provide an alternative therapeutic avenue for modulation of GABAB receptors. The aim of this study was to characterize derivatives of (R,S)-5,7-di-tert-butyl-3-hydroxy-3-trifluoromethyl-3H-benzofuran-2-one (rac-BHFF) as enhancers of GABAB receptors. EXPERIMENTAL APPROACH: Enhancing properties of rac-BHFF were assessed in the Chinese hamster ovary (CHO)-Galpha16-hGABA(B1a,2a) cells by Fluorometric Imaging Plate Reader and GTPgamma[35S]-binding assays, and in rat hippocampal slices by population spike (PS) recordings. In vivo activities of rac-BHFF were assessed using the loss of righting reflex (LRR) and stress-induced hyperthermia (SIH) models. KEY RESULTS: In GTPgamma[35S]-binding assays, 0.3 microM rac-BHFF or its pure enantiomer (+)-BHFF shifted the GABA concentration-response curve to the left, an effect that resulted in a large increase in both GABA potency (by 15.3- and 87.3-fold) and efficacy (149% and 181%), respectively. In hippocampal slices, rac-BHFF enhanced baclofen-induced inhibition of PS of CA1 pyramidal cells. In an in vivo mechanism-based model in mice, rac-BHFF increased dose-dependently the LRR induced by baclofen with a minimum effective dose of 3 mg kg(-1) p.o. rac-BHFF (100 mg kg(-1) p.o.) tested alone had no effect on LRR nor on spontaneous locomotor activity, but exhibited anxiolytic-like activity in the SIH model in mice. CONCLUSIONS AND IMPLICATIONS: rac-BHFF derivatives may serve as valuable pharmacological tools to elucidate the pathophysiological roles played by GABAB receptors in the central and peripheral nervous systems.
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Ansiolíticos/farmacología , Benzofuranos/farmacología , Receptores de GABA-B/efectos de los fármacos , Regulación Alostérica/efectos de los fármacos , Animales , Ansiolíticos/administración & dosificación , Ansiolíticos/química , Baclofeno/efectos adversos , Baclofeno/farmacología , Benzofuranos/administración & dosificación , Benzofuranos/química , Células CHO , Cricetinae , Cricetulus , Relación Dosis-Respuesta a Droga , Agonistas del GABA/efectos adversos , Agonistas del GABA/farmacología , Subunidades gamma de la Proteína de Unión al GTP/metabolismo , Humanos , Masculino , Ratones , Ratones Endogámicos DBA , Células Piramidales/efectos de los fármacos , Células Piramidales/metabolismo , Ratas , Ratas Wistar , Receptores de GABA-B/metabolismo , Reflejo/efectos de los fármacos , EstereoisomerismoRESUMEN
AIM: To test the hypothesis that a brief window of time immediately after delivery may be a particularly sensitive period for olfactory learning by human neonates. METHODS: Fifty-five vaginally delivered newborns were exposed to an odorant for 30 min beginning 4-37 min after birth (Early exposure) or 12-h post-partum (Late exposure). Several days later, newborns' head orientation responses to the exposure odour versus an unfamiliar odour or an odourless control stimulus were tested. RESULTS: Infants in the Early exposure group spent significantly more time oriented towards the familiar scent rather than a novel odour (Z = 2.869; n = 28; p < 0.01), or an odourless stimulus (Z = 2.550; n = 28; p < 0.01). Infants in the Late exposure condition did not respond differentially to the exposure odour versus a novel odour (Z = 1.105; n = 27, p = 0.27), and spent more time oriented towards an odourless stimulus than to the exposure odour (Z = 2.042; n = 27, p < 0.05). CONCLUSION: Infants in the Early exposure group, but not in the Late exposure group, became familiar with the exposure odour and retained a memory trace of it during the test trials.
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Recién Nacido/fisiología , Olfato/fisiología , Adulto , Femenino , Humanos , Aprendizaje , Masculino , OdorantesRESUMEN
Synthesis and evaluation of the activity of new 4-methyl-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indoles as 5-HT(2C) receptor agonists are described. Appropriately substituted, several analogs displayed selectivity against the other 5-HT(2) receptor subtypes of 1 order of magnitude or more. Selectivity was improved for several compounds versus the lead 1, increasing the therapeutic interest in this series of 5-HT(2C) receptor agonists.
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Ingestión de Alimentos/efectos de los fármacos , Agonistas del Receptor de Serotonina 5-HT2 , Agonistas de Receptores de Serotonina/farmacología , Animales , Indoles/síntesis química , Indoles/farmacología , Inyecciones Subcutáneas , Pirazinas/síntesis química , Pirazinas/farmacología , Piridinas/síntesis química , Piridinas/farmacología , Ratas , Ratas Wistar , Agonistas de Receptores de Serotonina/síntesis química , Relación Estructura-ActividadRESUMEN
UNLABELLED: Infant-mother bodily contact is believed to be the species-typical pattern of immediate postpartum child care. Mothers and newborns engage in mutually beneficial interactions. Maternal odours stimulate breastfeeding activity and are implicated in individual recognition. CONCLUSION: Skin-to-skin contact and exposure to maternal odours facilitate infants' adaptation to the early postnatal environment.
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Relaciones Madre-Hijo , Madres , Odorantes , Piel , Tacto , Lactancia Materna/psicología , Llanto/psicología , Femenino , Humanos , Conducta del Lactante/psicología , Recién Nacido , Olfato/fisiología , Conducta en la Lactancia , Percepción VisualRESUMEN
1. The aim of this study was to establish the utility of a fluorometric imaging plate reader (FLIPR) assay to assess human adenosine A(2B) receptor function by characterizing its receptor pharmacology and comparing this profile to that obtained using a microphysiometer. 2. FLIPR was used, in conjunction with a Ca(2+)-sensitive dye (Fluo-3-AM), to measure rapid rises in intracellular calcium in a Chinese Hamster Ovary (CHO-K1) cell line stably transfected with both the human A(2B) receptor and a promiscuous G(alpha16) protein. Microphysiometry was used to measure rapid changes in the rate of extracellular acidification in a Human Embryonic Kidney (HEK-293) cell line also stably transfected with human A(2B) receptor. 3. Activation of A(2B) receptors by various ligands caused a concentration-dependent increase in both the intracellular calcium concentration and the extracellular acidification rate in the cells tested, with a similar rank order of potency for agonists: NECA > N(6)-Benzyl NECA > adenosine > or = R-PIA > CPA > S-PIA > CHA > CGS 21680. No comparable effects were observed in the non-transfected control cell lines. 4. The rank order of potency of the agonists examined was the same in all studies, whereas absolute potency and efficacy varied. Thus, all compounds exhibited greater potency in FLIPR than the microphysiometer and the efficacies obtained with CHO-K1 + G(alpha16) + A(2B) cell line and FLIPR were greater than those obtained with HEK-293 + A(2B) cell line in the microphysiometer. 5. ZM-241385 was the most potent of a range of adenosine antagonists tested with a pA(2) of 8.0 in both the FLIPR and microphysiometer assays. 6. In conclusion, the profile of the responses to both A(2B) receptor agonists and antagonists in FLIPR were similar to those obtained by the microphysiometer, although both potency and efficacy values were higher in the FLIPR assay. With this caveat in mind, this study shows that FLIPR coupled with a cell line transfected with both the human A(2B) receptor and a promiscuous G(alpha16) protein provides a useful, high throughput method for the assessment of A(2B) receptor function.
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Compuestos de Anilina/metabolismo , Receptores Purinérgicos P1/metabolismo , Proteínas Recombinantes/metabolismo , Xantenos/metabolismo , Animales , Células CHO , Línea Celular , Cricetinae , Relación Dosis-Respuesta a Droga , Colorantes Fluorescentes/metabolismo , Fluorometría/métodos , Humanos , Agonistas del Receptor Purinérgico P1 , Receptor de Adenosina A2B , Receptores Purinérgicos P1/genética , Proteínas Recombinantes/agonistas , Proteínas Recombinantes/genéticaRESUMEN
An attempt was made to elicit maternal behavior in non-parturient Welsh pony mares through a combination of hormonal treatment and vaginal-cervical stimulation (VCS). Lactation was induced in 16 nonpregnant, non-parturient mares via a combination of estradiol, progesterone and a dopamine antagonist (sulpiride). During the adoption trials, each lactating mare was confined behind a padded bar and a newborn foal was held near her head. Eight of the mares received two 3-min periods of VCS when the foster foal was introduced. Following VCS, the foal was released and its interactions with the adoptive mare observed until the acceptance criterion was met (i.e. the mare accepted the foal at the udder with no signs of aggression). The remaining eight adoptive mares were treated in the same manner but did not receive VCS. All 16 non-parturient mares eventually accepted and nursed their adopted foal. However, acceptance latencies were significantly shorter for mares in the VCS condition than for those without VCS, and did not differ between the VCS condition and a group of control mares with their biological offspring. In subsequent choice tests, both groups of foster mares (with/without VCS), like the control mares, displayed a preference for their 'own' foal. Once the non-parturient mares accepted their foster foal, their maternal behavior resembled that of control mothers. The positive effect of VCS on maternal acceptance may reflect a release of oxytocin triggered by this treatment.
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Adopción , Conducta Animal , Caballos/psicología , Conducta Materna , Acetato de Trembolona/análogos & derivados , Administración Tópica , Animales , Cuello del Útero/efectos de los fármacos , Antagonistas de Dopamina/farmacología , Estradiol/farmacología , Femenino , Progesterona/farmacología , Congéneres de la Progesterona/administración & dosificación , Congéneres de la Progesterona/farmacología , Sulpirida/farmacología , Acetato de Trembolona/administración & dosificación , Acetato de Trembolona/farmacología , Vagina/efectos de los fármacosRESUMEN
The pharmacology of several commonly described 5-hydroxytryptamine (5-HT)(2C) receptor agonists was investigated in vivo and in vitro at rat 5-HT(2A), 5-HT(2B), and 5-HT(2C) receptors. The 5-HT(2C) receptor agonist, (S)-2-(6-chloro-5-fluoroindol-1-yl)-1-methylethylamine fumarate (Ro 60-0175), did not induce a significant head-twitch response when given alone, yet when administered to rats subsequent to an acute challenge with the selective 5-HT(2C) receptor antagonist, 6-chloro-5-methyl-1-[6-(2-methylpyridin-3-yloxy) pyridin-3-yl carbomyl] indoline (SB-242084), a robust head-twitch response was observed which was blocked by the selective 5-HT(2A) receptor antagonists R(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl-ethyl)]-4-piperidine-methanol (MDL 100907) or ketanserin. The preferential 5-HT(2C) receptor agonists Ro 60-0175, 6-chloro-2-[1-piperazinyl]-pyrazine HCl (MK-212), 1-(3-chlorophenyl)piperazine hydrochloride (mCPP), 1-(3-trifluoromethylphenyl)piperazine hydrochloride (TFMPP), and (S)-3-[(2,3-dihydro-5-methoxy-1H-inden-4-yl)oxy]-pyrollidine HCl (ORG-37684), the 5-HT(2A/2C) receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI), the 5-HT(2B) receptor agonist 1-[5-thienylmethoxy-1-1H-3-indoyl] propan-2-amine hydrochloride (BW-723C86), and nor-D-fenfluramine were administered to rats subsequent to an acute challenge of SB-242084. Under such conditions, each agonist, with the exception of BW-723C86, induced a dose-dependent increase in the incidence of head twitches. The pharmacology of the same agonists was determined at cloned rat 5-HT(2) receptors using a fluorometric imaging plate reader (FLIPR). Both the in vivo and in vitro data suggest that for some ligands, previous reports have overestimated their in vivo selectivity for the 5-HT(2C) receptor.
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Conducta Animal/efectos de los fármacos , Receptores de Serotonina/metabolismo , Agonistas de Receptores de Serotonina/farmacología , Animales , Conducta Animal/fisiología , Células CHO , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Cricetinae , Fundus Gástrico/efectos de los fármacos , Fundus Gástrico/metabolismo , Masculino , Ratas , Receptor de Serotonina 5-HT2A , Receptor de Serotonina 5-HT2B , Receptor de Serotonina 5-HT2C , Antagonistas de la Serotonina/farmacologíaRESUMEN
The desensitization characteristics of recombinant human 5-HT(2A), 5-HT(2B), and 5-HT(2C) receptors (VSV and INI isoforms) stably expressed in CHO-K1 (Chinese hamster ovary) cells was investigated by calcium fluorimetry. Comparative desensitization characteristics of the agonists 5-HT, m-chlorophenylpiperazine (mCPP), and 2,5-dimethoxy-4-iodoamphetamine hydrobromide (DOI) were performed. Human 5-HT(2C (INI)) receptors exhibited a greater degree of desensitization to all agonists tested than edited 5-HT(2C (VSV)) receptors. A 2-hr exposure to 5-HT resulted in a significantly larger reduction in response upon re-exposure to 5-HT at 5-HT(2C (INI)) receptors, as compared to 5-HT(2C (VSV)) receptors (72% and 47% respectively, P < 0.01). Both receptor isoforms were expressed at similar densities. Human 5-HT(2B) receptors exhibited the most dramatic degree of desensitization, with prior exposure to 5-HT reducing subsequent response to 5-HT by 80%, with an extremely rapid time-course (t(1/2) < 5 min). The response at 5-HT(2A) receptors was reduced by 54%. The partial agonists mCPP and DOI also elicited desensitization, generally in line with their relative efficacies at each receptor, but exhibited more rapid kinetic profiles than 5-HT. Heterologous desensitization of an endogenously expressed G(q/11)-coupled purinergic receptor was also examined following preincubation of the cell lines with 10 microM 5-HT. Only stimulation of 5-HT(2C (VSV)) receptors resulted in a profound attenuation of subsequent ATP mediated responses. These results demonstrate differing degrees of both homologous and heterologous desensitization of 5-HT(2) receptors. Additionally, the different desensitization profiles of 5-HT(2C (INI)) and 5-HT(2C (VSV)) receptor may be due to signal transduction differences caused by RNA editing.
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Receptores de Serotonina/metabolismo , Agonistas de Receptores de Serotonina/farmacología , Animales , Células CHO , Cricetinae , Relación Dosis-Respuesta a Droga , Humanos , Piperazinas/farmacología , Receptores Purinérgicos/metabolismo , Receptores de Serotonina/genética , Proteínas Recombinantes/agonistas , Proteínas Recombinantes/metabolismo , Serotonina/farmacología , Factores de Tiempo , TransfecciónRESUMEN
The 5-HT2C receptor is expressed in different isoforms as a result of mRNA editing. Both INI (unedited) and VSV (a fully edited version) isoforms are abundant in rat brain. The VSV isoform lacks the high affinity recognition site for 5-HT, which may be caused by low efficiency coupling to G-proteins. In this study we have investigated the pharmacology of the agonist binding site of these two isoforms of the 5-HT2C receptor. The VSV isoform was expressed in Chinese hamster ovary cells (CHO) and the INI isoform in both Chinese hamster ovary cells and human embryonic kidney cells (HEK-293). Saturation analysis using [3H]5-HT revealed high and low affinity recognition sites on the INI isoform in both cell types whilst the VSV isoform did not have the high affinity binding site for [3H]5-HT. Displacement studies were undertaken using [3H]5-HT to label the receptors. In these studies the affinity of agonists (5-HT, Ro600175 ((S)-2-(6-Chloro-5-fluoroindol-1-yl)-1-methylethylamine), MK212 (6-Chloro-2-(piperazinyl) pyrazine), mCPP (1-(m-chlorophenyl)-piperazine), TfMPP (N-(m-trifluoromethylphenyl)piperazine), DOI (1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane), DOB (1-(4-bromo-2,5-dimethoxyphenyl)-2-aminopropane) and 8OH-DPAT (8-hydroxy-2-(di-N-propylamino)tetralin) was higher at the INI isoform, whilst antagonist affinity (ketanserin and mesulergine) did not change between the two receptor isoforms. There were no differences between the INI isoform expressed in the CHO and HEK-293. This suggests that the INI isoform of the 5-HT2C receptor is pharmacologically similar to the VSV form of the 5-HT2C receptor but that it couples more efficiently to G-proteins.
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Proteínas de Unión al GTP/metabolismo , Isoformas de Proteínas/metabolismo , Receptores de Serotonina/metabolismo , Antagonistas de la Serotonina/farmacología , Agonistas de Receptores de Serotonina/farmacología , Animales , Sitios de Unión , Células CHO , Cricetinae , Humanos , Isoformas de Proteínas/efectos de los fármacos , Receptor de Serotonina 5-HT2C , Receptores de Serotonina/efectos de los fármacosRESUMEN
UNLABELLED: In previous studies, newborn infants placed on their mother's chest grasped a nipple and sucked without assistance. Furthermore, neonates sucked preferentially from an untreated breast rather than the alternative breast that had been washed to eliminate its natural odour. This study investigated the influence of breast odours per se on orientated physical movement of neonates. In total, 22 babies were observed during two trials on a warming bed. In one trial, a pad carrying the mother's breast odour was placed 17 cm in front of the baby's nose; in the other trial a clean pad was used. More babies moved towards and reached the breast pad than the clean pad. CONCLUSION: Natural breast odous unsupported by other maternal stimuli therefore appear to be sufficient to attract and guide neonates to the odour source.
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Lactancia Materna , Mama/fisiología , Recién Nacido/fisiología , Odorantes , Olfato/fisiología , Femenino , Humanos , MasculinoRESUMEN
The defining characteristic of mammals is that females nurse and care for their young; without this, the neonate has no chance to survive. Studies on wild and domestic species show that the neonatal period is the most critical step in the lifetime of a mammal. This review compares three well-studied species (the rabbit, pig and sheep) that differ in their parental strategies and in the problems that neonates have to overcome. As a general trend, mother-young interactions vary according to the maturity of the newborn, and the size of the litter. Neonatal survival relies to a great extent on an environment that is ecologically appropriate for the developmental stage of the neonate, and on optimum interactions with the mother. Adaptive maternal care supposes that the mother provides the basic needs of the neonate: warmth (in pigs and rabbits) or shelter, food, water and immunological protection (via colostrum) and, in some instances, protection from predators and other conspecifics. A major risk facing all neonates, other than the birth process itself, is inadequate colostrum intake owing to delayed suckling or competition with siblings, which leads to starvation, hypothermia or even crushing, as has been observed in pigs.
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Animales Domésticos/fisiología , Animales Recién Nacidos , Conducta Materna , Animales , Conducta Animal , Femenino , Lactancia , Tamaño de la Camada , Conejos , Ovinos , Conducta en la Lactancia , PorcinosAsunto(s)
Antioxidantes/síntesis química , Depuradores de Radicales Libres/síntesis química , Peroxidación de Lípido/efectos de los fármacos , Fármacos Neuroprotectores/síntesis química , Estrés Oxidativo/efectos de los fármacos , Piridonas/síntesis química , Animales , Antioxidantes/química , Antioxidantes/farmacología , Encéfalo/citología , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Evaluación Preclínica de Medicamentos , Depuradores de Radicales Libres/química , Depuradores de Radicales Libres/farmacología , Técnicas In Vitro , Yodoacetatos , Fármacos Neuroprotectores/química , Fármacos Neuroprotectores/farmacología , Piridonas/química , Piridonas/farmacología , Ratas , Relación Estructura-ActividadRESUMEN
1. The aim of the study was to compare the effects of 14 day subcutaneous infusion of the 5-HT(2C) receptor agonists, m-chlorophenylpiperazine (mCPP, 12 mg kg(-1) day(-1)) and Ro 60-0175 (36 mg kg(-1) day(-1)) and the 5-HT releasing agent and re-uptake inhibitor, d-fenfluramine (6 mg kg(-1) day(-1)), on food and water intake, body weight gain and locomotion in lean male Lister hooded rats. 2. Chronic infusion of all three drugs significantly reduced food intake and attenuated body weight gain. In contrast, drug infusion did not lead to significant reductions in locomotor activity in animals assessed 2 and 13 days after pump implantation. 3. In a subsequent 14 day study that was designed to identify possible tolerance during days 7 - 14, animals were given a subcutaneous infusion of mCPP (12 mg kg(-1) day(-1)) or d-fenfluramine (6 mg kg(-1) day(-1)) for either 7 or 14 days. During the first 7 days both drugs significantly reduced body weight gain compared to saline-infused controls; however, from day 7 onwards animals withdrawn from drug treatment exhibited an increase in body weight such that by day 14 they were significantly heavier than their 14-day drug-treated counterparts. 4. Both mCPP and d-fenfluramine reduced daily food intake throughout the infusion periods. For 14-day treated animals this hypophagia was marked during the initial week of the study but only minor during the second week. In light of the sustained drug effect on body weight, the data suggest that weight loss by 5-HT(2C) receptor stimulation may be only partly dependent on changes in food consumption and that 5-HT(2C) receptor agonists may have effects on thermogenesis. 5. These data suggest tolerance does not develop to the effects of d-fenfluramine, mCPP and Ro 60-0175 on rat body weight gain.
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Peso Corporal/efectos de los fármacos , Ingestión de Líquidos/efectos de los fármacos , Ingestión de Alimentos/efectos de los fármacos , Actividad Motora/efectos de los fármacos , Serotoninérgicos/farmacología , Análisis de Varianza , Animales , Etilaminas/farmacología , Fenfluramina/farmacología , Hipotálamo/efectos de los fármacos , Hipotálamo/metabolismo , Indoles/farmacología , Bombas de Infusión , Piperazinas/farmacología , ARN Mensajero/efectos de los fármacos , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Receptor de Serotonina 5-HT2C , Receptores de Serotonina/genética , Factores de TiempoRESUMEN
Nigrostriatal dopaminergic denervation is associated with complex changes in the functional and neurochemical anatomy of the basal ganglia. The excitatory neurotransmitter glutamate mediates neural signaling at crucial points of this circuitry, and glutamate receptors are differentially distributed in the basal ganglia. Available evidence suggests that the glutamatergic corticostriatal and subthalamofugal pathways become overactive after nigrostriatal dopamine depletion. In this study, we have analyzed the regulation of the GluR1 subunit of the a-amino-3-hydroxy-5-methyl-4-isoxazole propionate glutamate receptor in the basal ganglia of primates following 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced dopamine denervation. The dopamine denervation resulted in distinct alterations in GluR1 distribution: (1) GluR1 protein expression was markedly increased in caudate and putamen, and this was most pronounced in the striosomes; (2) GluR1 protein was altered minimally in subthalamic nucleus; (3) expression of GluR1 was down-regulated in the globus pallidus by 63% and in the substantia nigra by 57%. The down-regulation of GluR1 expression in the output nuclei of the basal ganglia, the internal segment of the globus pallidus and the substantia nigra pars reticulata, may be a compensation for the overactive glutamatergic input from subthalamic nucleus, which arises after striatal dopamine denervation. Our results indicate that the glutamatergic system undergoes regulatory changes in response to altered basal ganglia activity in a primate model of Parkinson's disease. Targeted manipulation of the glutamatergic system may be a viable approach to the symptomatic treatment of Parkinson's disease.
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Ganglios Basales/metabolismo , Cuerpo Estriado/fisiología , Dopamina/fisiología , Receptores AMPA/metabolismo , Sustancia Negra/fisiología , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/farmacología , Animales , Cuerpo Estriado/efectos de los fármacos , Desnervación , Dopaminérgicos/farmacología , Femenino , Globo Pálido/metabolismo , Macaca mulatta , Sustancia Negra/efectos de los fármacos , Núcleo Subtalámico/metabolismoRESUMEN
The neuroprotective efficacy of antioxidant molecules against iodoacetate (IAA) neurotoxicity in rat cerebellar granule cell (CGC) cultures was investigated. Transient exposure to IAA caused a concentration-dependent decrease in cell viability (ED50 = 9.8 microM). Dizocilpine maleate (MK-801), and 1,2,3,4-tetrahydro-6-nitro-2,3-dioxobenzo[f]quinoxaline-7-sulfonamide (NBQX), failed to prevent IAA toxicity. Certain antioxidant molecules were shown to be neuroprotective against IAA when combined with MK-801 but were ineffective when administered alone. (S)-(-)-Trolox, butylated hydroxytoluene (BHT), and U-83836E exhibited EC50 values of 78, 5.9, and 0.25 microM, respectively, in the presence of 10 microM MK-801. IAA also induced an increase in intracellular oxidative stress, which was quenched by the antioxidants (in the presence of MK-801) in cultures loaded with the oxidant sensitive dye 2'7'-dichlorodihydrofluorescein diacetate (DCFH-DA).
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Antioxidantes/farmacología , Corteza Cerebelosa/efectos de los fármacos , Yodoacetatos/toxicidad , Fármacos Neuroprotectores/farmacología , Neurotoxinas/toxicidad , Receptores de N-Metil-D-Aspartato/efectos de los fármacos , Animales , Hidroxitolueno Butilado/farmacología , Células Cultivadas , Corteza Cerebelosa/citología , Cromanos/farmacología , Maleato de Dizocilpina/farmacología , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Fluoresceínas/metabolismo , Colorantes Fluorescentes/metabolismo , Estrés Oxidativo , Piperazinas/farmacología , Quinoxalinas/farmacología , Ratas , Ratas Sprague-DawleyRESUMEN
1. The goal of this study was to characterize the agonist pharmacology of human 5-HT2A, 5-HT2B and 5-HT2C (VSV) receptors expressed in CHO-K1 (Chinese hamster ovary) cells. 2. We used a fluorometric imaging plate reader (FLIPR) which allows rapid detection of rises in intracellular calcium levels upon the addition of agonists. 3. Stimulation of all three receptors by 5-HT caused a robust concentration dependent increase in intracellular calcium levels. No such effect was observed from non-transfected control CHO-K1 cells. 4. The rank order of potency of agonists at the different receptor subtypes varied. Tryptamines, BW-723C86, d-norfenfluramine, Ro 60-0175 and LSD exhibited the following rank order of potency; 5-HT2B>5-HT2C>5-HT2A. Piperazines such as m-Chlorophenylpiperazine (mCPP), ORG-12962, MK-212 and also ORG-37684 exhibited a rank order of potency of 5-HT2C>5-HT2B>5-HT2A. The phenylisopropylamines DOI and DOB had a rank order of 5-HT2A>5-HT2B>5-HT2C. 5. Many agonists tested had partial agonist actions when compared to 5-HT, and a wide range of relative efficacies were exhibited, which was cell line dependent. For example, mCPP had a relative efficacy of 65% at 5-HT2C receptors but <25% at either 5-HT2A or 5-HT2B receptors. 6. Interpretation of literature values of functional assays using different cell lines, different receptor expression levels and different receptor isoforms, is complex. Species differences and the previous use of antagonist radioligands to characterize agonist potency in binding assays emphasizes the importance of studying agonists in the same experiment using the same assay conditions and parental cell lines.
Asunto(s)
Receptores de Serotonina/metabolismo , Agonistas de Receptores de Serotonina/farmacología , Animales , Células CHO , Calcio/metabolismo , Señalización del Calcio/efectos de los fármacos , Cricetinae , Relación Dosis-Respuesta a Droga , Colorantes Fluorescentes , Humanos , Receptor de Serotonina 5-HT2A , Receptor de Serotonina 5-HT2B , Receptor de Serotonina 5-HT2C , Receptores de Serotonina/genética , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Agonistas de Receptores de Serotonina/química , Factores de Tiempo , TransfecciónRESUMEN
A simple procedure for testing newly hatched chicks' responses to olfactory stimuli is described. Chicks that were hand held under a heatlamp became inactive and closed their eyes (as if asleep) within 2 min. Sleeping chicks displayed overt behavioral responses to an odorized q-tip (head shaking, beak clapping) that were not observed in awake chicks. Sleeping latencies were shorter for 1-day-old chicks that had been food deprived prior to testing than for chicks that had ad lib access to food and water. When airborne odors were presented by squeezing a soft plastic odor bottle near the beak, sleeping chicks' reactions to mint were of a greater magnitude than their responses to lavender or orange scents. Nonetheless, all three odors elicited more pronounced behavioral responses than did the water control stimulus. This method allows rapid testing of individual chicks for odor detection and discrimination.
Asunto(s)
Animales Recién Nacidos/psicología , Conducta Animal/fisiología , Discriminación en Psicología/fisiología , Odorantes , Olfato/fisiología , Análisis de Varianza , Animales , Pollos , Intervalos de Confianza , Femenino , Privación de Alimentos/fisiología , Masculino , Psicofísica/métodos , Sueño/fisiología , Privación de Agua/fisiologíaRESUMEN
Human infants are particularly responsive to olfactory cues emanating from their mother's nipple/areola region. Beginning within minutes after birth, maternal breast odors elicit preferential head orientation by neonates and help guide them to the nipple. Such odors also influence babies' general motor activity and arousal, which may contribute further to successful nipple localization and sucking. The role of maternal olfactory signals in the mediation of early breast-feeding is functionally analogous to that of nipple-search pheromone as described in nonhuman mammals. To some extent, the chemical profile of breast secretions overlaps with that of amniotic fluid. Therefore, early postnatal attraction to odors associated with the nipple/areola may reflect prenatal exposure and familiarization. Although newborns are generally attracted to breast odors produced by lactating women, breast-fed infants rapidly learn their mother's characteristic olfactory signature while sucking at her breasts and can subsequently recognize her by that unique scent alone. Early odor-based recognition may be an important factor in the development of the infant-mother bond.
Asunto(s)
Mama/fisiología , Odorantes , Animales , Femenino , Humanos , Recién Nacido , Aprendizaje/fisiología , Glándulas Mamarias Animales/fisiología , Relaciones Madre-HijoRESUMEN
A series of experiments was conducted to assess whether lambs are discriminatively responsive to visual images of conspecifics. Lambs (3-4-week-old) consistently responded with more interest and less avoidance when exposed to a life-like image of an unfamiliar lamb, a ewe or the silhouette of a ewe, than to a meaningless mosaic of the same conspecific stimulus. In each instance, lambs preferentially sniffed the head region of the conspecific image. Slides of a ewe and a dog likewise elicited differential responses by lambs, but there were no clear differences in their attraction to, or avoidance of these two categories of stimuli. In contrast, adult ewes responded more negatively to the dog image than to the ewe slide. Overall, lambs appeared to respond to conspecific images as social stimuli, however, social discrimination by visual cues alone may improve with age and experience.