RESUMEN
Previous studies demonstrated that sigma-receptor (σR) antagonists alone fail to alter cocaine self-administration despite blocking various other effects of cocaine. However, σR antagonists when combined with dopamine transporter (DAT) inhibitors substantially decrease cocaine self-administration. To better understand the effects of this combination, the present study examined the effects of σR antagonist and DAT inhibitor combinations in male rats discriminating cocaine (10 mg/kg, i.p.) from saline injections. The DAT inhibitors alone (WIN 35,428 and methylphenidate) at low (0.1 mg/kg) doses that were minimally active, failed to shift the dose-effect function for discriminative-stimulus effects of cocaine to the left more than two-fold. At 0.32 mg/kg the DAT inhibitors alone shifted the cocaine dose-effect function leftward 24- or 6.6-fold, respectively. The σR antagonists (BD1008, BD1047, and BD1063) failed to fully substitute for cocaine, though BD1008 and BD1047 substituted partially. At 10 mg/kg, BD1008, BD1047, or BD1063 alone shifted the cocaine dose-effect function leftward less than 6.0-fold. In combination with 0.1 mg/kg WIN 35,428, the 10 mg/kg doses of σR antagonists shifted the cocaine dose-effect function from 12.3 to 36.7-fold leftward, and with 0.32 mg/kg WIN 35,428 from 14.3 to 440-fold leftward. In combination with 0.1 mg/kg methylphenidate, those σR antagonist doses shifted the cocaine dose-effect function from 5.5 to 55.0-fold leftward and with 0.32 mg/kg methylphenidate from 10.5 to 48.1-fold leftward. The present results suggest that dual DAT/σR inhibition produces agonist-like subjective effects that may promote decreases in self-administration obtained in previous studies. Significance Statement There is currently no approved medication for treating stimulant abuse, though dopamine-uptake inhibitors in combination with sigma-receptor (σR) antagonists decrease cocaine self-administration in laboratory animals. The present study assessed how this combination alters the discriminative-stimulus effects of cocaine in male rats. Results suggest that concurrent dopamine uptake inhibition and σR antagonism together may promote decreases in self-administration possibly by mimicking the subjective effects extant when subjects cease continued cocaine self-administration.
RESUMEN
Sensory integration therapy (SIT) is an intervention to improve the developmental and learning problems in children. It was introduced in China from late 1980 s to early 1990 s and has received considerable attention from scholars. However, due to its late development in China and its specialised nature, it is worth exploring in depth whether it is recognized by the general public and how it is researched by academics. Therefore, we used Internet survey approach to explore the actual feedback of users towards SIT through the Internet. At the same time, bibliometric method and visualization techniques were used to study 892 journal articles on SIT in CNKI, Wanfang Database and VIP Database to analyze the spatial and temporal distribution, subject distribution, keyword co-occurrence, and keyword clustering of SIT research in mainland China since it came to China mainland. We found that the research on SIT in mainland China has been fruitful. However, the public is less aware of its basic function, therapeutic effects, and necessity. Our findings point to the need to raise awareness of sensory integration disorder and sensory integration therapy among the general public, and to strengthen academic research on sensory integration therapy.
Asunto(s)
Bibliometría , Terapia por Relajación , Niño , Humanos , China , Bases de Datos FactualesRESUMEN
Omega-3 fatty acids (FA), as a nutrient, has been proven effective in major depressive disorder (MDD), however, the results of monotherapy in perinatal depression (PND) remain unclear. To examine the efficacy and safety of omega-3 fatty acids (FA) monotherapy for perinatal depression (PND) compared with placebo. PubMed, Embase, PsycINFO, MEDLINE, Cochrane Library, and CINAHL were searched from inception up to November 2019. The reference lists of relevant review articles and included studies were also reviewed. Randomized placebo-controlled trials examining the efficacy and safety of omega-3 FA monotherapy in perinatal women with depressive symptoms were included. Pooled standard mean differences (SMD) were calculated and random-effects models were adopted for all analyses. Subgroups analyses and meta-regression were performed to quantify characteristics of the subjects and trials influencing the omega-3 response. In addition, meta-regression was conducted to identify the source of heterogeneity. The study protocol was registered at PROSPERO, CRD42020159542. Eight eligible randomized placebo-controlled trials were included involving 638 participants. There was a significant effect of omega-3 FA on perinatal depression. Omega-3 with higher ratio of EPA/DHA (≥1.5) had significant efficacy both in mild-to-moderate pregnant and postpartum depression with low incidence of side effects. Among the included trials reporting adverse effects, there was no significant difference in incidence of gastrointestinal and neurologic events between the omega-3 and placebo groups. There was no evidence of publication bias. Our findings suggested that omega-3 FA significantly improved depressive symptoms in perinatal women regardless of pregnant or postpartum and well-tolerated. Furthermore, the omega-3 response was linked to higher EPA proportion in omega-3 formula and mild- to-moderate depression.
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Depresión Posparto , Trastorno Depresivo Mayor , Ácidos Grasos Omega-3 , Depresión , Depresión Posparto/tratamiento farmacológico , Trastorno Depresivo Mayor/tratamiento farmacológico , Femenino , Humanos , Embarazo , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
RATIONALE: Dopamine transporter (DAT) conformation plays a role in the effectiveness of cocaine-like and other DAT inhibitors. Cocaine-like stimulants are intolerant to DAT conformation changes having decreased potency in cells transfected with DAT constructs that face the cytosol compared to wild-type DAT. In contrast, analogs of benztropine (BZT) are among compounds that are less affected by DAT conformational change. METHODS: We compared the displacement of radioligand binding to various mammalian CNS sites, acute stimulation of accumbens shell dopamine levels, and place conditioning in rats among cocaine and four BZT analogs with Cl substitutions on the diphenyl-ether system including two with carboalkoxy substitutions at the 2-position of the tropane ring. RESULTS: Binding assays confirmed high-affinity and selectivity for the DAT with the BZT analogs which also produced significant stimulation of mesolimbic dopamine efflux. Because BZT analogs produced temporal patterns of extracellular dopamine levels different from those by cocaine (3-10 mg/kg, i.p.), the place conditioning produced by BZT analogs and cocaine was compared at doses and times at which both the increase in dopamine levels and rates of increase were similar to those produced by an effective dose of cocaine. Despite this equilibration, none of the BZT analogs tested produced significant place conditioning. CONCLUSIONS: The present results extend previous findings suggesting that cocaine-like actions are dependent on a binding equilibrium that favors the outward conformational state of the DAT. In contrast, BZT analogs with reduced dependence on DAT conformation have reduced cocaine-like behavioral effects and may prove useful in development of medications for stimulant abuse.
Asunto(s)
Cocaína/farmacología , Condicionamiento Operante/efectos de los fármacos , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Inhibidores de Captación de Dopamina/farmacología , Dopamina/metabolismo , Núcleo Accumbens/efectos de los fármacos , Análisis de Varianza , Animales , Benzotropina/análogos & derivados , Benzotropina/química , Benzotropina/farmacología , Sitios de Unión/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Masculino , Microdiálisis , Núcleo Accumbens/metabolismo , Conformación Proteica/efectos de los fármacos , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Factores de TiempoRESUMEN
BACKGROUND: Sigma receptors represent a unique structural class of proteins and they have become increasingly studied as viable medication development targets for neurological and psychiatric disorders, including drug abuse. Earlier studies have shown that cocaine and many other abused substances interact with sigma receptors and that antagonism of these proteins can mitigate their actions. METHODS: In the present study, AC927 (1-(2-phenethyl)piperidine oxalate), a selective sigma receptor ligand, was tested against the behavioral and toxic effects of cocaine in laboratory animals. RESULTS: Acute administration of AC927 in male, Swiss Webster mice significantly attenuated cocaine-induced convulsions, lethality, and locomotor activity, at doses that alone had no significant effects on behavior. Subchronic administration of AC927 also attenuated cocaine-induced conditioned place preference in mice, at doses that alone had no effects on place conditioning. In drug discrimination studies in male, Sprague-Dawley rats, AC927 partially substituted for the discriminative stimulus effects of cocaine. When it was administered with cocaine, AC927 shifted the cocaine dose-response curve to the left, suggesting an enhancement of the discriminative stimulus effects of cocaine. In non-human primates, AC927 was self-administered, maintaining responding that was intermediate between contingent saline and a maintenance dose of cocaine. CONCLUSION: The ability of AC927 to elicit some cocaine-like appetitive properties and to also reduce many cocaine-induced behaviors suggests that it is a promising lead for the development of a medication to treat cocaine abuse.
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Cocaína/toxicidad , Inhibidores de Captación de Dopamina/toxicidad , Oxalatos/farmacología , Piperidinas/farmacología , Receptores sigma/antagonistas & inhibidores , Animales , Conducta Animal , Cocaína/administración & dosificación , Cocaína/farmacología , Condicionamiento Operante , Inhibidores de Captación de Dopamina/administración & dosificación , Inhibidores de Captación de Dopamina/farmacología , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Ligandos , Macaca mulatta , Masculino , Ratones , Modelos Animales , Terapia Molecular Dirigida , Actividad Motora , Oxalatos/toxicidad , Piperidinas/toxicidad , Ratas , Ratas Sprague-Dawley , Receptores sigma/metabolismo , Convulsiones/inducido químicamente , Convulsiones/prevención & control , AutoadministraciónRESUMEN
Previous studies suggested that differences between the behavioral effects of cocaine and analogs of benztropine were related to the relatively slow onset of action of the latter compounds. Several N-substituted benztropine analogs with a relatively fast onset of effects were studied to assess whether a fast onset of effects would render the effects more similar to those of cocaine. Only one of the compounds increased locomotor activity, and the increases were modest compared with those of 10 to 20 mg/kg cocaine. In rats trained to discriminate 10 mg/kg cocaine from saline none of the compounds produced more than 40% cocaine-like responds up to 2 h after injection. None of the compounds produced place-conditioning when examined up to 90 min after injection, indicating minimal abuse liability. The compounds had 5.6 to 30 nM affinities at the dopamine transporter (DAT), with uniformly lower affinities at norepinephrine and serotonin transporters (from 490-4600 and 1420-7350 nM, respectively). Affinities at muscarinic M(1) receptors were from 100- to 300-fold lower than DAT affinities, suggesting minimal contribution of those sites to the behavioral effects of the compounds. Affinities at histaminic H(1) sites were from 11- to 43-fold lower than those for the DAT. The compounds also had affinity for sigma, 5-hydroxytryptamine(1) (5-HT(1)), and 5-HT(2) receptors that may have contributed to their behavioral effects. Together, the results indicate that a slow onset of action is not a necessary condition for reduced cocaine-like effects of atypical DAT ligands and suggest several mechanisms that may contribute to the reduced cocaine-like efficacy of these compounds.
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Conducta Animal/efectos de los fármacos , Benzotropina/análogos & derivados , Cocaína/farmacología , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Animales , Benzotropina/metabolismo , Cocaína/administración & dosificación , Condicionamiento Psicológico/efectos de los fármacos , Aprendizaje Discriminativo/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Cobayas , Ligandos , Masculino , Actividad Motora/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , AutoadministraciónRESUMEN
Vascular endothelial growth factor (VEGF) is one of the best characterized angiogenic factors controlling placental angiogenesis; however, how VEGF regulates placental angiogenesis has not yet completely understood. In this study, we found that all the components of assembling a functional NADPH oxidase (NOX2, p22(phox), p47(phox), p67(phox), and Rac1) are expressed in ovine fetoplacental artery endothelial cells (oFPAECs) in vitro and ex vivo. Treatment with VEGF (10 ng/ml) rapidly and transiently activated Rac1 in oFPAECs in vitro and increased Rac1 association with p67(phox) in 5 min. Intracellular superoxide formation began to significantly increase after 25-30 min of VEGF stimulation, which was mediated by both VEGFR1 and VEGFR2. VEGF also stimulated oFPAE cell proliferation and migration and enhanced the formation of tube-like structures on Matrigel matrix. In oFAPEC transfected with specific Rac1 small interfering RNA (siRNA, 40 nm), VEGF-induced intracellular superoxide formation was completely abrogated in association with a 78% reduction of endogenous Rac1. In oFPAE cells transfected with the specific Rac1 siRNA, but not with transfection reagent alone or scrambled control siRNA, VEGF-induced cell proliferation, migration, and tube-like structure formation were dramatically inhibited. Pretreatment of an NADPH oxidase inhibitor apocynin also abrogates the VEGF-stimulated intracellular superoxide production and DNA synthesis in oFPAECs. Taken together, our results demonstrated that a Rac1/Nox2-based NADPH oxidase system is present in placental endothelial cells. This NADPH oxidase system appears to generate the second messenger superoxide that plays a critical role in the signaling control of the VEGF-induced placental angiogenesis.
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NADPH Oxidasas/metabolismo , Neovascularización Fisiológica/fisiología , Placenta/fisiología , Superóxidos/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Proteína de Unión al GTP rac1/metabolismo , Análisis de Varianza , Animales , Western Blotting , Movimiento Celular/fisiología , Proliferación Celular , Células Cultivadas , Células Endoteliales/metabolismo , Femenino , Microscopía Fluorescente , Placenta/irrigación sanguínea , Embarazo , ARN Interferente Pequeño , Ovinos , Transducción de Señal/fisiologíaRESUMEN
Dopaminergic (DA) agonist-induced yawning in rats seems to be mediated by DA D3 receptors, and low doses of several DA agonists decrease locomotor activity, an effect attributed to presynaptic D2 receptors. Effects of several DA agonists on yawning and locomotor activity were examined in rats and mice. Yawning was reliably produced in rats, and by the cholinergic agonist, physostigmine, in both the species. However, DA agonists were ineffective in producing yawning in Swiss-Webster or DA D2R and DA D3R knockout or wild-type mice. The drugs significantly decreased locomotor activity in rats at one or two low doses, with activity returning to control levels at higher doses. In mice, the drugs decreased locomotion across a 1000-10 000-fold range of doses, with activity at control levels (U-91356A) or above control levels [(+/-)-7-hydroxy-2-dipropylaminotetralin HBr, quinpirole] at the highest doses. Low doses of agonists decreased locomotion in all mice except the DA D2R knockout mice, but were not antagonized by DA D2R or D3R antagonists (L-741 626, BP 897, or PG01037). Yawning does not provide a selective in-vivo indicator of DA D3R agonist activity in mice. Decreases in mouse locomotor activity by the DA agonists seem to be mediated by D2 DA receptors.
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Agonistas de Dopamina/farmacología , Actividad Motora/efectos de los fármacos , Bostezo/efectos de los fármacos , Análisis de Varianza , Animales , Inhibidores de la Colinesterasa/farmacología , Antagonistas de Dopamina/farmacología , Antagonistas de los Receptores de Dopamina D2 , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Ratones , Ratones Endogámicos C3H , Ratones Noqueados , Actividad Motora/genética , Fisostigmina/farmacología , Ratas , Ratas Sprague-Dawley , Receptores de Dopamina D2/deficiencia , Bostezo/genéticaRESUMEN
OBJECTIVE: To investigate the relationship between the renal tubular function and the severity of tubulo interstitial lesion and the effects of Astragalus Injection (AI) on renal tubular function in patients with IgA nephropathy (IgAN). METHODS: Sixty-seven patients with IgAN were randomly divided into the control group and the astragalus group, both received dipyridamole and benazepril orally, while the astragalus group treated with AI by intravenous dripping additionally. The indices for renal tubular function, including protein in blood and urine, urinary retinol binding protein (RBP) and N-acetyl-beta-D-glucosaminidase (UNAG), were detected. Area of glomerular Bowman capsule, renal tubules, and capillary were measured with color magic image analysis system type CMIAS2000. RESULTS: Urinary RBP and UNAG were correlated with tubulointerstitial lesion. Urine protein concentration decreased, blood albumin increased remarkably and renal tubular function improved after treatment in the astragalus group, with the improvement significantly different to those in the control group respectively. CONCLUSION: The severity of tubulointerstitial lesion was positively related to urinary RBP concentration, and astragalus injection has obvious effect on IgAN.
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Astragalus propinquus , Medicamentos Herbarios Chinos/administración & dosificación , Glomerulonefritis por IGA/tratamiento farmacológico , Túbulos Renales/fisiopatología , Fitoterapia , Adolescente , Adulto , Benzazepinas/uso terapéutico , Dipiridamol/uso terapéutico , Quimioterapia Combinada , Femenino , Glomerulonefritis por IGA/fisiopatología , Humanos , Inyecciones Intravenosas , Masculino , Persona de Mediana EdadRESUMEN
OBJECTIVE: To access the pathological changes of the functional localization of the primary auditory cortex in auditory neuropathy patients using magnetoencephalography (MEG). METHODS: The M100 waves of cortical evoked magnetic fields (AEF) evoked by 0.5, 1, 2, 4, 6, 8 kHz pure tones were measured respectively in 10 auditory neuropathy patients (20 ears) and 15 healthy young subjects (30 ears) using a whole head 306 channel magnetoencephalography (MEG) system. The auditory cortex magnetic source imaging obtained by superimposing functional MEG data on structural magnetic resonance image (MRI). RESULTS: The M100 sources were obtained in all 15 healthy young subjects in all frequency except for 8 kHz in 16 ears. But in auditory neuropathy patients, the ratio of M100 from 0.5 to 6 kHz were 27.5% (11/40), 22.5% (9/40), 7.5% (3/40), 5% (2/40), 5% (2/40) respectively and no any waves in 8 kHz. The evoked ratio of M100 in low frequency was high and that decreased gradually with increasing of evoked pure tone frequency. The M100 latentencies and amplitudes were longer and lower in patient group than that in control group (P < 0.01). CONCLUSIONS: Auditory neuropathy is an audiology disease with pathological lesions from the VIII cranial nerve to auditory cortex. MEG might become an important reference in decision making for therapies.
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Corteza Auditiva/patología , Corteza Auditiva/fisiopatología , Enfermedades del Nervio Vestibulococlear/patología , Enfermedades del Nervio Vestibulococlear/fisiopatología , Adolescente , Estudios de Casos y Controles , Corteza Cerebral/patología , Corteza Cerebral/fisiopatología , Potenciales Evocados Auditivos , Femenino , Humanos , Magnetoencefalografía , Masculino , Adulto JovenRESUMEN
Several dopamine (DA) indirect agonists have been proposed as potential medications for treating cocaine abuse. The objective of the present study was to quantify the interactions among cocaine and DA uptake inhibitors or DA releasers to better understand how these drugs may be working when administered in combination. The DA uptake inhibitors GBR 12909 [1-{2-[bis-(4-fluorophenyl)methoxy]-ethyl}-4-(3-phenylpropyl)piperazine], WIN 35,428 [2beta-carbomethoxy-3beta-(4-fluorophenyl)tropane], methylphenidate, indatraline, nomifensine, and mazindol and DA releasers methamphetamine, d-amphetamine, methcathinone, cathinone, fencamfamine, and phentermine were examined alone and in combination with cocaine in rats trained to discriminate cocaine (10 mg/kg i.p.) from saline injections. All of the DA indirect agonists dose-dependently substituted for cocaine and shifted the cocaine dose-effect curve leftward. Isobolographic analysis indicated the interactions were generally additive, although both methamphetamine and d-amphetamine were quantitatively determined to be more potent than DA uptake inhibitors in shifting the cocaine dose-effect function to the left. The potential of d-amphetamine as an effective treatment for cocaine abuse and negative clinical results with dopamine uptake inhibitors suggest that differences in shifts in dose-effect curves should be further examined with emerging clinical data as a predictive index of potential treatments for cocaine abuse.
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Cocaína/farmacología , Aprendizaje Discriminativo/efectos de los fármacos , Inhibidores de Captación de Dopamina/farmacología , Dopamina/metabolismo , Animales , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
Ovariectomized (OVX) ewes were assigned to receive vehicle, progesterone (P4, 0.9-g controlled internal drug release vaginal implants), estradiol-17beta (E2, 5 microg/kg bolus + 6 microg kg(-1) day(-1)), or P4 + E2 for 10 days (n = 3/group). Uterine artery endothelial proteins were mechanically isolated on Day 10. The samples were used for protein expression profiling by the Ciphergen Proteinchip system and immunoblotting analysis of endothelial nitric oxide synthase (NOS3, also termed eNOS) and caveolin 1. Uterine artery rings were cut and analyzed by immunohistochemistry to localize NOS3 and caveolin 1 expression. With the use of the IMAC3 protein chip with loading as little as 2 microg protein/sample, many protein peaks could be detected. Compared to vehicle controls, a approximately 133.1-kDa protein was identified to be upregulated by 2- to 4-fold in OVX ewes receiving E2, P4, and their combination, whereas a approximately 22.6-kDa protein was downregulated by 2- to 4-fold in OVX ewes receiving E2 and E2/P4, but not P4 treatments. Western blot analysis revealed that E2, P4, and their combination all increased NOS3 protein, whereas E2 and its combination with P4, but not P4 alone, downregulated caveolin 1 expression. Immunohistochemical analysis revealed that NOS3 was mainly localized in the endothelium and upregulated by E2, whereas caveolin 1 was localized in both endothelium and smooth muscle and downregulated by E2. Thus, our data demonstrate that uterine artery endothelial NOS3 and caveolin 1 are regulated reciprocally by estrogen replacement therapy. In keeping with the facts that E2, but not P4, causes uterine vasodilatation and that E2 and P4 increase NOS3 expression, but only E2 decrease caveolin 1 expression, our current study suggests that both increased NOS3 expression and decreased caveolin 1 expression are needed to facilitate estrogen-induced uterine vasodilatation.
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Caveolina 1/efectos de los fármacos , Endotelio Vascular/efectos de los fármacos , Estrógenos/farmacología , Óxido Nítrico Sintasa de Tipo III/efectos de los fármacos , Útero/irrigación sanguínea , Animales , Arterias , Western Blotting , Caveolina 1/metabolismo , Endotelio Vascular/metabolismo , Femenino , Inmunohistoquímica , Óxido Nítrico Sintasa de Tipo III/metabolismo , Ovariectomía , Progesterona/farmacología , Análisis por Matrices de Proteínas , Ovinos , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción , Útero/efectos de los fármacosRESUMEN
OBJECTIVE: To investigate the effect of alpha-zearalenol on angiotensin II-induced beta3 integrin mRNA expression in human umbilical vein endothelial cells (HUVECs). METHODS: The mRNA level in integrin beta3 was determined by reverse transcription-polymerase chain reaction. Endothelial NF-kappaB activity was determined by the luciferase activity assay of plasmid NF-kappaB-LUC. RESULTS: The angiotensin II-induced beta3 integrin mRNA expression was inhibited by alpha-zearalenol and 17beta-estradiol (10 nmol/L -1 micromol/L), but not influenced by ICI 182, 780, a pure competitive antagonist for estrogen receptor or a nitric oxide inhibitor Nomega-Nitro-L-arginine methyl ester hydrochloride. Alpha-zearalenol and 17beta-estradiol suppressed the angiotensin II-induced activation of NF-kappaB in endothelial cells. CONCLUSION: Alpha-zearalenol inhibits angiotensin II-induced integrin beta3 mRNA expression by suppressing NF-kappaB activation in endothelial cells.
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Integrina beta3/biosíntesis , FN-kappa B/antagonistas & inhibidores , Fitoestrógenos/farmacología , Zeranol/análogos & derivados , Angiotensina II/antagonistas & inhibidores , Células Cultivadas , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/metabolismo , Estradiol/farmacología , Femenino , Regulación de la Expresión Génica , Humanos , Integrina beta3/genética , FN-kappa B/fisiología , Óxido Nítrico/antagonistas & inhibidores , ARN Mensajero/metabolismo , Receptores de Estrógenos/antagonistas & inhibidores , Zeranol/farmacologíaRESUMEN
Acute H(2)O(2) exposure to placental artery endothelial cells induced an array of tyrosine-phosphorylated proteins, including caveolin 1 (CAV1) rapid and transient tyr(14) phosphorylated in a time- and concentration-dependent manner. Basal tyr(14) phosphorylated CAV1 was primarily located at the edges of cells and associated with actin filaments. Phosphorylated CAV1 was markedly increased and diffused with the disorganization of actin filaments at 20 min, disappeared at 120 min treatment with 0.2 mM H(2)O(2). Treatment with H(2)O(2) also disorganized actin filaments and changed cell shape in a time-dependent manner. Pretreatment with antioxidants catalase completely, whereas the other tested superoxide dismutase, N-acetyl-l-cysteine and sodium formate partially attenuated H(2)O(2)-induced CAV1 phosphorylation in a concentration-dependent manner. Acute treatment with H(2)O(2) activated multiple signaling pathways, including the mitogen-activated protein kinases (MAPK) members (MAPK3/1-ERK2/1, MAPK8/9-JNK1/2, and MAPK11-p38(mapk)) and the c-src tyrosine kinase (CSK). Pharmacological studies demonstrated that, among these pathways, only the blockade of CSK activation abolished H(2)O(2)-induced CAV1 phosphorylation. Additionally, H(2)O(2)-induced CAV1 phosphorylation was reversible rapidly (<10 min) upon H(2)O(2) withdrawal. Because maternal and fetal endothelia must make dynamic adaptations to oxidative stress resulting from enhanced pregnancy-specific oxygen metabolism favoring prooxidant production, which is emerging as one of the leading causes of the dysfunctional activated endothelium during pregnancy, these unique features of CAV1 phosphorylation on oxidative stress observed implicate an important role of CAV1 in placental endothelial cell biology during pregnancy.
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Arterias/metabolismo , Caveolina 1/metabolismo , Sistema de Señalización de MAP Quinasas , Placenta/metabolismo , Proteínas Tirosina Quinasas/metabolismo , Tirosina/metabolismo , Animales , Antioxidantes/farmacología , Arterias/citología , Arterias/efectos de los fármacos , Proteína Tirosina Quinasa CSK , Células Cultivadas , Relación Dosis-Respuesta a Droga , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Femenino , Peróxido de Hidrógeno/farmacología , Estrés Oxidativo , Fosforilación , Placenta/citología , Placenta/efectos de los fármacos , Embarazo , Ovinos , Familia-src QuinasasRESUMEN
Previous studies demonstrated that analogs of benztropine [3alpha-(diphenyl-methoxy)tropane (BZT)] bind to the dopamine (DA) transporter with high affinity, inhibit DA uptake, but do not maintain rates of responding in self-administration procedures comparable with those maintained by cocaine. Some BZT analogs have an onset of action that is slower than that for cocaine that may contribute to this decreased effectiveness. In addition, some BZT analogs have affinity for muscarinic-M1 receptors that may interfere with reinforcing effects. The present study assessed effects of BZT analogs in place-conditioning procedures designed to accommodate variations in onset of effect. BZT analogs with variations in relative affinities for the DA transporter over M1 receptors from equal [AHN 1-055 (3alpha-[bis(4'-fluorophenyl)methoxy]-tropane)] to 16-fold [JHW 007 (N-(n-butyl)-3alpha-[bis(4'-fluorophenyl)methoxy]-tropane)] were compared with cocaine and the muscarinic antagonist, atropine. Cocaine (10-20 mg/kg) but not atropine (1.0-5.6 mg/kg) produced dose-related place conditioning. The N-methyl-substituted BZT analog, AHN 1-055, was without significant effects at doses that ranged from 0.3 to 3.0 mg/kg and when administered up to 90 min before conditioning trials. In contrast, effects of AHN 2-005 (N-allyl-3alpha-[bis(4'-fluorophenyl)methoxy]-tropane; 0.1-10.0 mg/kg) were significant, and those of JHW 007 approached significance when administered 45 min but not immediately or 90 min before trials. Atropine blocked the effect of AHN 2-005 and approached significant antagonism of cocaine. The present study further supports and extends previous results showing minimal preclinical indications of abuse liability of BZT analogs and suggests that these differences from cocaine are not entirely accounted for by a slower onset of action or muscarinic M1 receptor affinity.
Asunto(s)
Benzotropina/análogos & derivados , Benzotropina/farmacología , Condicionamiento Psicológico/efectos de los fármacos , Actividad Motora/efectos de los fármacos , Animales , Atropina/farmacología , Cocaína/farmacología , Relación Dosis-Respuesta a Droga , Ratas , Ratas Sprague-Dawley , Receptor Muscarínico M1/efectos de los fármacosRESUMEN
OBJECTIVE: To evaluate the value of magnetic source imaging (MSI) in the functional localization of the primary auditory cortex. METHODS: The M100 waves of cortical auditory evoked magnetic fields (AEFs) evoked by 0.5, 1, 2, 4 and 8 kHz pure tones in 5 subjects and by 2 kHz pure tones in 25 healthy young subjects were measured respectively (16 males and 14 females, with the age from 20 to 32 years old) using a whole head 306 channel magnetoencephalography (MEG) system. The MSI obtained by superimposing functional MEG data on structural magnetic resonance image (MRI) was used to localize the M100 sources on the auditory cortex. RESULTS: The M100 waves of AEFs were clear and replicable in both hemispheres. The M100 sources were localized on the bilateral transverse temporal gyri in all 30 subjects. The localization of M100 on transverse temporal gyri varied with the changes of stimulus frequency. The localization of primary auditory cortex was asymmetrical between bilateral hemispheres, and the left hemisphere M100 dipoles were significantly posterior compared to the right M100 dipoles. The M100 responses appeared significantly earlier to the contralateral stimuli than that to the ipsilateral stimuli in both hemispheres. The dipole positions of M100 were independent of the side of the stimuli. CONCLUSIONS: The functional localization of the primary auditory cortex could be determined precisely by magnetic source imaging (MSI) with high spatiotemporal resolution. MSI would hold great promise as a noninvasive tool for the fundamental and clinical research in otology.
Asunto(s)
Corteza Auditiva/fisiología , Magnetoencefalografía , Adulto , Femenino , Humanos , Campos Magnéticos , Imagen por Resonancia Magnética/métodos , Masculino , Adulto JovenRESUMEN
OBJECTIVE: To investigate the characteristics of somatosensory evoked magnetic fields (SEF) in patients with acute cerebral infarction by magnetoencephalgraphy (MEG). METHODS: SEFs were recorded from 17 patients with acute cerebral infarction and 18 healthy volunteers using 306-channel whole-head MEG. The electric stimuli were presented with interstimulus intervals of 0.5 s. The peaks of SEF were estimated by equivalent current dipole (ECD), which were superimposed on MRI. RESULTS: M20 was the most elemental components of SEF in all subjects, originating from the area close to the "hand area" of the primary somatosensory cortex. There appeared several abnormal SEF parameters in the patient group: (1) the value of interhemispheric difference of the M20 positions was (8 +/- 4) mm in the normal group and (11 +/- 3) mm in the patient group (P < 0.01); (2) the peak latency of M20 responses in the healthy group was (20.7 +/- 1.1) ms, significantly shorter than those in both the unaffected hemisphere and affected hemisphere in the patient group, (21.8 +/- 1.2) ms and (23.6 +/- 1.9) ms, (both P < 0.01); (3) the strength of ECD in the affected hemisphere was (17 +/- 10) nAm, significantly smaller than that in the unaffected hemisphere, (26 +/- 10) nAm (P < 0.01). CONCLUSION: Latent cortical impairment may be evaluated by MEG with higher spatial and temporal resolution. MEG provides objective and sensitive indexes to evaluate the function of somatosensory cortex in patients with acute cerebral infarction.
Asunto(s)
Infarto Cerebral/fisiopatología , Potenciales Evocados Somatosensoriales/fisiología , Magnetoencefalografía/métodos , Enfermedad Aguda , Adulto , Anciano , Encéfalo/fisiopatología , Infarto Cerebral/diagnóstico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Corteza Somatosensorial/fisiopatologíaRESUMEN
The study investigated the role of nitric oxide (NO) in the relapse to drug-seeking behavior induced by D-methamphetamine. After the induction of D-methamphetamine (1 mg/kg) conditioned place preference, the rewarding effect became extinct 6 weeks later. The extinguished place preference was reinstated by D-methamphetamine (0.125 mg/kg) injection, an effect which was attenuated by 7-nitroindazole (12.5 and 25 mg/kg) pretreatment. The results demonstrate that NO is involved in relapse primed by D-methamphetamine injection.
Asunto(s)
Trastornos Relacionados con Anfetaminas/psicología , Condicionamiento Psicológico/efectos de los fármacos , Indazoles/farmacología , Metanfetamina/farmacología , Óxido Nítrico Sintasa/antagonistas & inhibidores , Animales , Fenómenos de Retorno al Lugar Habitual/efectos de los fármacos , Masculino , Metanfetamina/administración & dosificación , Metanfetamina/química , Óxido Nítrico/fisiología , Óxido Nítrico Sintasa de Tipo I , Ratas , Ratas Sprague-Dawley , Recurrencia , EstereoisomerismoRESUMEN
The present study investigated the role of nitric oxide (NO) in the rewarding effects of D-methamphetamine using 7-nitroindazole, a potent inhibitor of neuronal nitric oxide synthase (nNOS), as determined by the conditioned place preference paradigm. Male Sprague-Dawley rats treated with D-methamphetamine (1 mg/kg) or saline every other day for 8 days (four drug and four saline sessions) developed marked place preference for the drug-paired side. The administration of 7-nitroindazole (12.5-50 mg/kg) 30 min prior to the exposure to D-methamphetamine dose-dependently attenuated the acquisition of D-methamphetamine-induced conditioned place preference. In addition, when it was acutely administered 30 min prior to the testing session of an already established D-methamphetamine-induced conditioned place preference, 7-nitroindazole (12.5-50 mg/kg) attenuated the expression of this conditioned response in a dose-dependent manner, while 7-nitroindazole (25 and 50 mg/kg) alone showed no place preference effects. These findings indicate that nitric oxide (NO) is involved in the rewarding properties of methamphetamine and suggest that selective nNOS inhibitors maybe useful in the management of methamphetamine abuse.