RESUMEN
Experiments on male outbred albino rats showed that benzodiazepine tranquilizers phenazepam and flunitrazepam in ultralow doses (10(-9)-10(-15) mol/kg) produced an anxiolytic effect in the conflict situation test. This effect was not accompanied by myorelaxing and sedative side effects typical of standard doses of tranquilizers.
Asunto(s)
Ansiolíticos/farmacología , Conducta Animal/efectos de los fármacos , Benzodiazepinas/farmacología , Flunitrazepam/farmacología , Tranquilizantes/farmacología , Animales , Relación Dosis-Respuesta a Droga , Masculino , Medazepam/farmacología , RatasRESUMEN
The effect of activation of GABAA, benzodiazepine, and D2 dopamine receptors on extinction of passive avoidance and their dependence on the initial state of aggressive and submissive C57BL/6J mice were studied. It was found that in mice with the submissive stereotype of behavior produced by experience of defeats in daily agonistic confrontations, extinction of the conditioned reaction occurred faster than in control mice. The activation of D2 receptors by quinpirole and of benzodiazepine receptors by medasepam before training restored the retrieval of the memory trace. A prolongation of extinction was observed in aggressive mice in comparison with control and submissive animals, and activation of GABAA by muscimol and benzodiazepine receptors by medazepam led to acceleration of extinction. Activation of D2 receptors was ineffective. Thus, the difference in initial behavioral strategy determined both the development of extinction of the passive avoidance and variability of participation of D2, GABAA, and benzodiazepine receptors in the maintenance of availability of the memory trace to retrieval.
Asunto(s)
Agresión , Reacción de Prevención/fisiología , Dominación-Subordinación , Agonistas de Dopamina/farmacología , Agonistas de Aminoácidos Excitadores/farmacología , Receptores de Dopamina D2/efectos de los fármacos , Receptores de GABA-A/efectos de los fármacos , Animales , Masculino , Medazepam/farmacología , Ratones , Ratones Endogámicos C57BL , Muscimol/farmacología , Quinpirol/farmacología , Tiempo de ReacciónRESUMEN
EAAC1-mediated glutamate transport concentrates glutamate across plasma membranes of brain neurons and epithelia. In brain, EAAC1 provides a presynaptic uptake mechanism to terminate the excitatory action of released glutamate and to keep its extracellular concentration below toxic levels. Here we report the effect of well known anxiolytic compounds, benzodiazepines, on glutamate transport in EAAC1-stably transfected Chinese hamster ovary (CHO) cells and in EAAC1-expressing Xenopus laevis oocytes. Functional properties of EAAC1 agreed well with already reported characteristics of the neuronal high-affinity glutamate transporter (Km D-Asp,CHO cells: 2.23+/-0.15 microM; Km D-Asp,oocytes: 17.01+/-3.42 microM). In both expression systems, low drug concentrations (10-100 microM) activated substrate uptake (up to 200% of control), whereas concentrations in the millimolar range inhibited (up to 50%). Furthermore, the activation was more pronounced at low substrate concentrations (1 microM), and the inhibition was attenuated. The activity of other sodium cotransporters such as the sodium/D-glucose cotransporter SGLT1, stably transfected in CHO cells, was not affected by benzodiazepines. In electrophysiological studies, these drugs also failed to change the membrane potential of EAAC1-expressing Xenopus laevis oocytes. These results suggest a direct action on the glutamate transporter itself without modifying the general driving forces. Thus, in vivo low concentrations of benzodiazepines may reduce synaptic glutamate concentrations by increased uptake, providing an additional mechanism to modulate neuronal excitability.
Asunto(s)
Sistema de Transporte de Aminoácidos X-AG , Ansiolíticos/farmacología , Proteínas Portadoras/efectos de los fármacos , Ácido Glutámico/metabolismo , Proteínas del Tejido Nervioso/efectos de los fármacos , Simportadores , Animales , Sitios de Unión , Células CHO , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Clozapina/farmacología , Cricetinae , Cricetulus , Diazepam/farmacología , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Proteínas de Transporte de Glutamato en la Membrana Plasmática , Transporte Iónico , Lorazepam/farmacología , Medazepam/farmacología , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Oocitos , Oxazepam/farmacología , Proteínas Recombinantes de Fusión/efectos de los fármacos , Proteínas Recombinantes de Fusión/metabolismo , Sodio/metabolismo , Xenopus laevisRESUMEN
The work discusses the neurochemical correlates of rat brain dopamin-synaptic activity after injection of 0.5 mg/kg rudotel (medazepam) as compared with intact animals. The parameters of functioning of D2-receptors in [3H]-dopamine binding, the content of catecholamines and their metabolites (high-performance liquid chromatography with electrochemical detection) were studied in the dopaminergic system in different brain areas (the striatum, frontal cortex, amygdala, hippocampus, hypothalamus, and accumbence).
Asunto(s)
Ansiolíticos/farmacología , Medazepam/farmacología , Neuronas/efectos de los fármacos , Receptores Dopaminérgicos/efectos de los fármacos , Transmisión Sináptica/efectos de los fármacos , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Química Encefálica/efectos de los fármacos , Catecolaminas/metabolismo , Masculino , Ratas , Ratas WistarRESUMEN
Experiments were conducted on C57B1 mice to study the role of the social status on the reproduction of a conditioned reaction of passive avoidance and the effect of medazepam on the processes of reproduction. Aggressive and submissive animals were selected according to the test for agonistic confrontations. No effect of the animals' social status on the formation of a conditioned habit was revealed, but a significant increase in the level of defecation was recorded in the aggressive mice. Medazepam administration before the test reduced the reproduction of the conditioned reaction only in the control mice. An amnestic effect blocked reproduction in control and submissive mice but did not change it in the aggressors. Medazepam restored the amnestic memory trace only in submissive individuals. In aggressive mice it reduced the emotional response but did not change reproduction. The data obtained suggest that variations of the social status determine both the behavioral responsiveness to training and the changes in reproduction in response to medazepam.
Asunto(s)
Agresión/efectos de los fármacos , Amnesia/fisiopatología , Ansiolíticos/farmacología , Dominación-Subordinación , Aprendizaje/efectos de los fármacos , Medazepam/farmacología , Memoria/efectos de los fármacos , Ratones Endogámicos C57BL/fisiología , Análisis de Varianza , Animales , Condicionamiento Clásico/efectos de los fármacos , Masculino , RatonesAsunto(s)
Ansiolíticos/farmacología , Anticonvulsivantes/farmacología , Ansiedad , Emociones , Postura , Animales , Clordiazepóxido/farmacología , Cruzamientos Genéticos , Diazepam/farmacología , Emociones/efectos de los fármacos , Aprendizaje por Laberinto , Medazepam/farmacología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos , Receptores de GABA-A/efectos de los fármacosRESUMEN
Se evaluó el comportamiento, la actividad sedante y la actividad anticonvulsivante en ratones tratados con medazepam, tabletas de 10 mg, en relación con el similar comercial de procedencia italiana. Los estudios realizados demuestran que la actividad exploratoria, el efecto anticonvulsivante, así como la disminución de la agresividad en ratones no difieren al evaluar ambas formulaciones
Asunto(s)
Animales , Ratones , Medazepam/farmacología , Ratones , Comprimidos , Industria FarmacéuticaRESUMEN
Se evaluó el comportamiento, la actividad sedante y la actividad anticonvulsivante en ratones tratados con medazepam, tabletas de 10 mg, en relación con el similar comercial de procedencia italiana. Los estudios realizados demuestran que la actividad exploratoria, el efecto anticonvulsivante, así como la disminución de la agresividad en ratones no difieren al evaluar ambas formulaciones
Asunto(s)
Animales , Ratones , Medazepam/farmacología , Ratones , Industria Farmacéutica , ComprimidosRESUMEN
Behavioral methods were used to examine the features of effects of fenazepam. gidazepam, and medazepam in young and mature non-inbred albino male rats. There were age- [correction of sex-]specific differences in responses to a drug. The higher effects the drug possesses, the greater differences there are in its effects on animals of different ages. It is suggested that different maturities of benzodiazepine receptors can affect the behavior of rats of different ages in the proposed tests.
Asunto(s)
Envejecimiento/efectos de los fármacos , Ansiolíticos/farmacología , Conducta Animal/efectos de los fármacos , Benzodiazepinas , Benzodiazepinonas/farmacología , Medazepam/farmacología , Animales , Relación Dosis-Respuesta a Droga , Ingestión de Líquidos/efectos de los fármacos , Masculino , Actividad Motora/efectos de los fármacos , RatasRESUMEN
EEGs were recorded for Fp1, C3 and O1 once a week for 4 weeks after the withdrawal of medazepam, a benzodiazepine with a long half-life, from 7 normal males. Quantified analyses of them showed 2 types of change: A maximum change during the administration of medazepam that later tapered off. It consisted mainly of an increase in fast wave, and was uniform across areas though most significant in C3. A rebound phenomenon that reversed the change produced by the drug, the decrease in fast wave being significant in C3 during week 2. These results suggest that fast wave is the most sensitive EEG element and these 2 types of change must be investigated hereafter in terms of significant changes after the discontinuation of medazepam.
Asunto(s)
Ansiolíticos/farmacología , Electroencefalografía/efectos de los fármacos , Medazepam/farmacología , Lóbulo Temporal/fisiología , Adulto , Análisis de Varianza , Electrofisiología , Humanos , Masculino , Síndrome de Abstinencia a SustanciasRESUMEN
1. The effect of 7-day treatment with the benzodiazepine tranquilizer medazepam (5 mg/kg), the nootropic agent meclofenoxate (100 mg/kg) and their combination in the same doses on the binding activity of muscarinic receptors in four rat brain structures (cerebral cortex, striatum, hippocampus and hypothalamus) were studied using the antagonist [3H]-1-quinuclidinyl benzylate [( 3H]-QNB) as radio-ligand. 2. Medazepam treatment caused significant decrease of muscarinic receptor binding affinity (Kd) and of the receptor binding capacity (Bmax) in the brain structures studied. The number of muscarinic binding sites was unsignificantly decreased only in the hippocampus. 3. Meclofenoxate treatment caused an increase of muscarinic receptor affinity and a decrease of the binding capacity in the cerebral cortex and hypothalamus and an increase of the binding affinity in the striatum and hippocampus. 4. The combination of medazepam and meclofenoxate caused no significant changes of both muscarinic receptor characteristics in the hippocampus and of the receptor affinity in the striatum and hypothalamus in comparison with control rats. The Bmax values were decreased in the cerebral cortex, striatum and hypothalamus when compared with control animals. The differences observed were slighter than those determined after the comparison of medazepam treated rats with control rats. 5. The results obtained afford an opportunity to suggest that the nootropic agent meclofenoxate acts to moderate the effect of the benzodiazepine tranquilizer medazepam on the activity of rat brain muscarinic receptors.
Asunto(s)
Encéfalo/metabolismo , Corteza Cerebral/metabolismo , Meclofenoxato/farmacología , Medazepam/farmacología , Receptores Muscarínicos/metabolismo , Animales , Combinación de Medicamentos , Hipocampo/metabolismo , Hipotálamo/metabolismo , Masculino , Meclofenoxato/administración & dosificación , Medazepam/administración & dosificación , Ratas , Ratas Endogámicas , Receptores Muscarínicos/efectos de los fármacosRESUMEN
Experiments on male albino rats were carried out in order to study the effects of diazepam and medazepam on the clonic-tonic convulsions in kindling phenomena evoked by multiple injections of a subconvulsive dose (40 mg/kg) pentylenetetrazol (PTZ). In the two doses used, both diazepam (0.25 and 1.0 mg/kg) and medazepam (2.0 and 5.0 mg/kg) manifest a marked anticonvulsive effect on the clonic-tonic convulsions in PTZ-kindled rats, with a marked dose-effect dependence. The evidence in the literature that the hippocampus plays the role of a pathologically determining structure in the realization of the PTZ kindling and that neurotransmission in the inhibitory synapses in the hippocampus is achieved by gamma-aminobutyric acid (GABA), gives grounds to accept that the anticonvulsive effects of diazepam and medazepam, observed in PTZ kindling, occur through GABA-ergic mechanisms, because the facilitating effect of benzodiazepines on the GABA-ergic neurotransmission is well known.
Asunto(s)
Diazepam/farmacología , Excitación Neurológica/efectos de los fármacos , Medazepam/farmacología , Pentilenotetrazol/antagonistas & inhibidores , Animales , Relación Dosis-Respuesta a Droga , Electroencefalografía , Masculino , Ratas , Ratas EndogámicasRESUMEN
Topographic EEG changes with medazepam and diazepam in normals were analyzed by the computerized wave form recognition method. A principal component (PC) analysis, using such EEG elements as wave percent-time (8 bands) and average amplitude (7 bands), resulted in a considerable reduction of variables (4 PCs). In O1, because of high positive loadings in the average amplitude in all bands and a decrease in the mean score with either drug, PC-1 represents a component which reacts in the form of diminution of average amplitude as a whole. In Fp1, C3 and O1, PC-2, with a bipolarity of alpha 2 versus beta 1 and beta 2 in the wave percent-time in loading profile, could be a component showing characteristic changes common to the 2 benzodiazepines. In C3, because of a significant difference in the mean score between the 2 drugs, PC-4 might be a between-drug difference component in which diazepam (medazepam) increases (decreases) slow activity. The relationship between the score at PC-4 in C3 and daytime sleepiness may signify that the slow components are associated with sedation. Based on the correlation at PC-2 in Fp1, a marked increase in beta 1 and beta 2 components (responder) rather means less sleepiness, and relative preservation of alpha 1 and alpha 2 (non-responder) more sleepiness.
Asunto(s)
Ansiolíticos/farmacología , Diazepam/farmacología , Electroencefalografía , Medazepam/farmacología , Procesamiento de Señales Asistido por Computador , Adulto , Humanos , MasculinoRESUMEN
Studies were made of the effect of 19-day administration of diazepam (1 mg.kg-1, i.p.) and medazepam (5 mg.kg-1, i.p.) on the level of biogenic monoamines in different rat brain areas: cerebral cortex, striatum, hippocampus, and hypothalamus. The noradrenaline (NA), dopamine (DA) and serotonin (5-HT) levels were determined. After chronic treatment with diazepam no alterations in the NA content in the cortex, striatum and hypothalamus were found. Medazepam increased the NA level in the cortex, striatum, and hippocampus without changing it in the hypothalamus. Repeated administration of diazepam or medazepam led to an increase in the DA level in the striatum. Both benzodiazepines provoked a significant increase in the hippocampal 5-HT level, which could be attributed to the antianxiety effect of these drugs.
Asunto(s)
Ansiolíticos/farmacología , Aminas Biogénicas/análisis , Química Encefálica/efectos de los fármacos , Diazepam/farmacología , Medazepam/farmacología , Animales , Corteza Cerebral/análisis , Dopamina/análisis , Hipocampo/análisis , Hipotálamo/análisis , Masculino , Norepinefrina/análisis , Ratas , Ratas Endogámicas , Serotonina/análisisAsunto(s)
Ansiolíticos/farmacología , Diazepam/farmacología , Etanol/farmacología , Medazepam/farmacología , Hipófisis/efectos de los fármacos , Efectos Tardíos de la Exposición Prenatal , Glándula Tiroides/efectos de los fármacos , Animales , Animales Recién Nacidos , Femenino , Masculino , Hipófisis/fisiología , Embarazo , Ratas , Ratas Endogámicas , Glándula Tiroides/fisiologíaRESUMEN
Experiments were made on rats using step-through passive avoidance method to study the effect of the benzodiazepine medazepam (Mz) on the retention of the memory traces during tests on the 3rd hour, 24th hour and 7th day after training, as well as the influencing of this effect by the nootropic agents meclofenoxate (Mf), aniracetam (Anc) and Euclidan (Eucl.). All substances tested (Mz in a dose of 5 mg/kg weight, Mf - 100 mg/kg, Anc and Eucl - 50 mg/kg), applied both independently and in combination, were administered orally for six days prior to the training. Mz was found to impair the retention of the memory traces in all three tests. Meclofenoxate totally eliminated the memory-impairing effect of Mz. A marked antiamnestic effect of both Anc and Eucl was observed in similar experiments with scopolamine-induced (2 mg/kg i.p.) amnesia. Bearing in mind the results of other behavioural and biochemical studies, including radioligand tests, an attempt is made to justify the idea that the basic mechanism of the amnestic action of Mz is connected with the cerebral cholinergic neurotransmission. The results of the experiments using Opto-Varimex and Automex equipment for testing the effects of Mz, Mf, Anc and Eucl, and of the combination of Mz with the nootropic agents studied, on the spontaneous motor activity of the experimental rats, lead to the most general conclusion that Mz impedes the development of habituation, considered as a specific type of learning and memory process. To one degree or another, Mf, Anc and Eucl cancel this effect of Mz.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Ansiolíticos/farmacología , Medazepam/farmacología , Memoria/efectos de los fármacos , Psicotrópicos/farmacología , Animales , Reacción de Prevención/efectos de los fármacos , Interacciones Farmacológicas , Habituación Psicofisiológica/efectos de los fármacos , Masculino , Meclofenoxato/farmacología , Actividad Motora/efectos de los fármacos , Ácidos Nicotínicos/farmacología , Pirrolidinonas/farmacología , Ratas , Ratas Endogámicas , Escopolamina/farmacologíaAsunto(s)
Ansiolíticos/farmacología , Diazepam/farmacología , Etanol/farmacología , Medazepam/farmacología , Efectos Tardíos de la Exposición Prenatal , Reproducción/efectos de los fármacos , Alcoholismo/fisiopatología , Animales , Interacciones Farmacológicas , Femenino , Masculino , Embarazo , Ratas , Conducta Sexual Animal/efectos de los fármacosRESUMEN
1. The effect of chronic (19-day) treatment with the benzodiazepine tranquilizers diazepam (1 mg/kg/day, i.p.) and medazepam (5 mg/kg/day, i.p.) on the binding characteristics of muscarinic receptors in four rat brain structures: cerebral cortex, striatum, hippocampus and hypothalamus were studied using [3H]l-quinuclidinyl benzylate ([3H]QNB) as radioligand. 2. Diazepam and medazepam treatment caused an overall decrease in muscarinic receptor binding affinity (Kd). 3. The number (Bmax) of muscarinic receptors declined in the hippocampus and striatum and rose in the hypothalamus after both benzodiazepines. The Bmax of muscarinic receptors in the cerebral cortex was increased after diazepam treatment. 4. The changes in the binding characteristics of muscarinic receptors might be due to benzodiazepine-induced occurrence of two populations of muscarinic binding sites: P1 (high affinity, low capacity) and P2 (low affinity, high capacity). 5. The altered brain muscarinic receptor functions after chronic diazepam- or medazepam treatment suggest the role of cholinergic neurotransmission in the mechanism of action of benzodiazepines.
Asunto(s)
Ansiolíticos/farmacología , Química Encefálica/efectos de los fármacos , Diazepam/farmacología , Medazepam/farmacología , Receptores Muscarínicos/efectos de los fármacos , Animales , Técnicas In Vitro , Cinética , Masculino , Quinuclidinil Bencilato , Ratas , Ratas EndogámicasRESUMEN
The effects of the benzodiazepine, medazepam, were investigated in current and voltage-clamped cultured chick dorsal root ganglion neurons. Under current clamp, micromolar concentrations initially elevated the action potential threshold and blocked both the sodium and calcium components of the spike. In voltage clamp, low (I(Ca.T)) and high (I(CA.N/L)) threshold calcium, sodium (I(Na)) and the delayed rectifier potassium (I(K)) currents were isolated by the use of appropriate solutions and voltage command protocols. Medazepam depressed both subtypes of I(Ca) equally well with calculated half-maximal depression at 77 microM. At a fixed concentration of 200 microM, medazepam depressed I(Na) (70 +/- 9%) and I(K) (73 +/- 6%) to a degree comparable to I(Ca) (75 +/- 3%). The results show that benzodiazepines can modulate the activity of several voltage-gated ion currents in chick dorsal root ganglion neurons.
Asunto(s)
Ansiolíticos/farmacología , Canales Iónicos/efectos de los fármacos , Medazepam/farmacología , Neuronas Aferentes/metabolismo , Animales , Células Cultivadas , Embrión de Pollo , Electrofisiología , Neuronas Aferentes/efectos de los fármacosRESUMEN
Immature oviduct implants from quails stimulated by estrogen to induce ciliogenesis were submitted to the in vitro action of benzodiazepines in organotypic culture. Diazepam and medazepam were added to the culture medium for 24 or 48 hours and tissues were examined by transmission and scanning electron microscopy for alterations in ciliary differentiation. Ciliogenesis was inhibited by both diazepam and medazepam, which affected mainly the migration of the basal bodies. Assembly of basal bodies was achieved normally in the cytoplasm, but their separation from generative complexes and migration toward the apical membrane were prevented. They remained in clusters around a deuterosome or eventually anchored to the close lateral plasma membrane. Furthermore, the drugs affected mature beating cilia, which then appeared lying tangentially to the cell surface. Relation between basal bodies and cortical cytoskeleton seemed to be altered by the drugs, which implies that the bearing of cilia and probably the ciliary beating movement were modified. Microvillus development was also altered by the action of these drugs.