Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 686
Filtrar
Más filtros

Banco de datos
País/Región como asunto
Tipo del documento
Intervalo de año de publicación
1.
Behav Pharmacol ; 30(1): 59-66, 2019 02.
Artículo en Inglés | MEDLINE | ID: mdl-30299277

RESUMEN

The transient receptor potential vanilloid 1 (TRPV1) can modulate stress-related behaviours, thus representing an interesting target for new antidepressant drugs. TRPV1 can trigger glutamate release and nitric oxide synthesis in the brain, mechanisms also involved in the neurobiology of depression. However, it is not known if these mechanisms are involved in TRPV1-induced behavioural effects. Therefore, the aim of this study was to verify if the antidepressant-like effect induced by a TRPV1 antagonist in mice submitted to the forced swimming test (FST) would be facilitated by combined treatment with neuronal nitric oxide synthase (nNOS) inhibition and N-methyl-D-aspartate (NMDA) blockade. Male Swiss mice were given (intracerebroventricular) injections of capsazepine (CPZ) (TRPV1 antagonist - 0.05/0.1/0.3/0.6 nmol/µl), and AP7 (NMDA antagonist - 1/3/10 nmol/µl) or N-propyl-L-arginine (NPA, nNOS inhibitor - 0.001/0.01/0.1 nmol/µl), and 10 min later, submitted to an open field test, and immediately afterwards, to the FST. An additional group received coadministration of CPZ and AP7 or CPZ and NPA, in subeffective doses. The results demonstrated that CPZ (0.1 nmol/µl), AP7 (3 nmol/µl) and NPA (0.01/0.1 nmol/µl) induced antidepressant-like effects. Moreover, coadministration of subeffective doses of CPZ and AP7 or CPZ and NPA induced significant antidepressant-like effects. Altogether, the data indicate that blockade of TRPV1 receptors by CPZ induces antidepressant-like effects and that both nNOS inhibition and NMDA blockade facilitate CPZ effects in the FST.


Asunto(s)
Antidepresivos/uso terapéutico , Capsaicina/análogos & derivados , Depresión/tratamiento farmacológico , Ácido Glutámico/metabolismo , Óxido Nítrico/metabolismo , Natación/psicología , 2-Amino-5-fosfonovalerato/análogos & derivados , 2-Amino-5-fosfonovalerato/farmacología , Animales , Apomorfina/análogos & derivados , Apomorfina/farmacología , Arginina/farmacología , Capsaicina/uso terapéutico , GMP Cíclico/metabolismo , Depresión/metabolismo , Depresión/fisiopatología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Vías de Administración de Medicamentos , Inhibidores Enzimáticos/farmacología , Conducta Exploratoria/efectos de los fármacos , Masculino , Microinyecciones , Nitroprusiato/metabolismo , Ratas , Receptores de N-Metil-D-Aspartato/metabolismo , Estadísticas no Paramétricas
2.
Cereb Cortex ; 28(4): 1183-1194, 2018 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-28184425

RESUMEN

The formation, plasticity and maintenance of synaptic connections is regulated by molecular and electrical signals. ß-Catenin is an important protein in these events and regulates cadherin-mediated cell adhesion and the recruitment of pre- and postsynaptic proteins in an activity-dependent fashion. Mutations in the ß-catenin gene can cause cognitive disability and autism, with life-long consequences. Understanding its synaptic function may thus be relevant for the treatment of these disorders. So far, ß-catenin's function has been studied predominantly in cell culture and during development but knowledge on its function in adulthood is limited. Here, we show that ablating ß-catenin in excitatory neurons of the adult visual cortex does not cause the same synaptic deficits previously observed during development. Instead, it reduces NMDA-receptor currents and impairs visual processing. We conclude that ß-catenin remains important for adult cortical function but through different mechanisms than during development.


Asunto(s)
Receptores de N-Metil-D-Aspartato/metabolismo , Corteza Visual/metabolismo , beta Catenina/metabolismo , 2-Amino-5-fosfonovalerato/análogos & derivados , 2-Amino-5-fosfonovalerato/farmacología , Animales , Estimulación Eléctrica , Antagonistas de Aminoácidos Excitadores/farmacología , Regulación de la Expresión Génica/genética , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , N-Metilaspartato/metabolismo , Parvalbúminas/metabolismo , Técnicas de Placa-Clamp , ARN Mensajero/metabolismo , Privación Sensorial , Potenciales Sinápticos/efectos de los fármacos , Potenciales Sinápticos/genética , Corteza Visual/efectos de los fármacos , Sustancia Blanca/efectos de los fármacos , Sustancia Blanca/fisiología , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiónico/metabolismo , beta Catenina/genética
3.
Eur J Neurosci ; 47(7): 858-865, 2018 04.
Artículo en Inglés | MEDLINE | ID: mdl-29405453

RESUMEN

In sensory systems, the neuronal representation of external stimuli is enhanced along the sensory pathway. In the auditory system, strong enhancement of binaural information takes place between the brainstem and the midbrain; however, the underlying cellular mechanisms are unknown. Here we investigated the transformation of binaural information in the dorsal nucleus of the lateral lemniscus (DNLL), a nucleus that connects the binaural nuclei in the brainstem and the inferior colliculus in the midbrain. We used in vitro and in vivo electrophysiology in adult Mongolian gerbils to show that N-methyl-D-aspartate receptor (NMDARs) play a critical role in neuronal encoding of stimulus properties in the DNLL. While NMDARs increase firing rates, the timing and the accuracy of the neuronal responses remain unchanged. NMDAR-mediated excitation increases the information about the acoustic stimulus. Taken together, our results show that NMDARs in the DNLL enhance the auditory information content in adult mammal brainstem.


Asunto(s)
Tronco Encefálico/fisiología , Receptores de N-Metil-D-Aspartato/fisiología , 2-Amino-5-fosfonovalerato/análogos & derivados , 2-Amino-5-fosfonovalerato/farmacología , Estimulación Acústica , Potenciales de Acción/fisiología , Animales , Vías Auditivas/fisiología , Femenino , Gerbillinae , Masculino , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores
4.
J Neurosci ; 35(12): 5043-50, 2015 Mar 25.
Artículo en Inglés | MEDLINE | ID: mdl-25810533

RESUMEN

The perirhinal cortex (PRc) is essential for visual recognition memory, as shown by electrophysiological recordings and lesion studies in a variety of species. However, relatively little is known about the functional contributions of perirhinal subregions. Here we used a systematic mapping approach to identify the critical subregions of PRc through transient, focal blockade of glutamate receptors by intracerebral infusion of kynurenic acid. Nine macaques were tested for visual recognition memory using the delayed nonmatch-to-sample task. We found that inactivation of medial PRc (consisting of Area 35 together with the medial portion of Area 36), but not lateral PRc (the lateral portion of Area 36), resulted in a significant delay-dependent impairment. Significant impairment was observed with 30 and 60 s delays but not with 10 s delays. The magnitude of impairment fell within the range previously reported after PRc lesions. Furthermore, we identified a restricted area located within the most anterior part of medial PRc as critical for this effect. Moreover, we found that focal blockade of either NMDA receptors by the receptor-specific antagonist AP-7 or AMPA receptors by the receptor-specific antagonist NBQX was sufficient to disrupt object recognition memory. The present study expands the knowledge of the role of PRc in recognition memory by identifying a subregion within this area that is critical for this function. Our results also indicate that, like in the rodent, both NMDA and AMPA-mediated transmission contributes to object recognition memory.


Asunto(s)
Receptores AMPA/antagonistas & inhibidores , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Reconocimiento en Psicología/fisiología , Lóbulo Temporal/fisiología , 2-Amino-5-fosfonovalerato/análogos & derivados , 2-Amino-5-fosfonovalerato/farmacología , Animales , Antagonistas de Aminoácidos Excitadores/farmacología , Ácido Quinurénico/farmacología , Macaca , Masculino , Quinoxalinas/farmacología , Receptores AMPA/fisiología , Receptores de N-Metil-D-Aspartato/fisiología , Reconocimiento en Psicología/efectos de los fármacos , Lóbulo Temporal/efectos de los fármacos , Factores de Tiempo , Percepción Visual/efectos de los fármacos , Percepción Visual/fisiología
5.
Hippocampus ; 26(3): 275-81, 2016 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-26663094

RESUMEN

The effects of cannabinoids are mostly mediated by two types of cannabinoid receptors--CB1 receptors in the nervous system and CB2 receptors in the immune system. However, CB2 cannabinoid receptors have recently been discovered in the brain and also implicated in neurophysiological functions. The deletion of CB2 receptors in mice induces long-term memory deficits and schizophrenia-like behaviors, implying that endogenous activity of CB2 receptors might be involved in neuropsychiatric effects. Little is known about the cellular mechanisms by which physiological activation of CB2 receptors modulates neuronal functions. We aimed to determine how deletion of CB2 receptors in mice affects synaptic transmission and plasticity. Electrophysiological and morphological studies indicated that CB2 receptor knockout resulted in decreases in excitatory synaptic transmission, long-term potentiation, and dendritic spine density in the hippocampus. Our data imply that endogenous activity of CB2 receptors might contribute to the maintenance of synaptic functions and the expression of normal long-term potentiation. This study provides insights into the role of CB2 cannabinoid receptors in regulating cognitive functions such as long-term memory.


Asunto(s)
Hipocampo/citología , Potenciación a Largo Plazo/genética , Receptor Cannabinoide CB2/deficiencia , 2-Amino-5-fosfonovalerato/análogos & derivados , 2-Amino-5-fosfonovalerato/farmacología , Animales , Canfanos/farmacología , Estimulación Eléctrica , Antagonistas de Aminoácidos Excitadores/farmacología , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Potenciales Postsinápticos Excitadores/genética , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Técnicas In Vitro , Potenciación a Largo Plazo/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Microscopía Confocal , Técnicas de Placa-Clamp , Pirazoles/farmacología , Receptor Cannabinoide CB2/antagonistas & inhibidores , Receptor Cannabinoide CB2/genética
6.
Am J Physiol Heart Circ Physiol ; 311(2): H433-44, 2016 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-27402666

RESUMEN

Hypothalamic arcuate nucleus (ARCN) stimulation elicited increases in sympathetic nerve activity (IBATSNA) and temperature (TBAT) of interscapular brown adipose tissue (IBAT). The role of hypothalamic dorsomedial (DMN) and paraventricular (PVN) nuclei in mediating these responses was studied in urethane-anesthetized, artificially ventilated, male Wistar rats. In different groups of rats, inhibition of neurons in the DMN and PVN by microinjections of muscimol attenuated the increases in IBATSNA and TBAT elicited by microinjections of N-methyl-d-aspartic acid into the ipsilateral ARCN. In other groups of rats, blockade of ionotropic glutamate receptors by combined microinjections of D(-)-2-amino-7-phosphono-heptanoic acid (D-AP7) and NBQX into the DMN and PVN attenuated increases in IBATSNA and TBAT elicited by ARCN stimulation. Blockade of melanocortin 3/4 receptors in the DMN and PVN in other groups of rats resulted in attenuation of increases in IBATSNA and TBAT elicited by ipsilateral ARCN stimulation. Microinjections of Fluoro-Gold into the DMN resulted in retrograde labeling of cells in the ipsilateral ARCN, and some of these cells contained proopiomelanocortin (POMC), α-melanocyte-stimulating hormone (α-MSH), or vesicular glutamate transporter-3. Since similar projections from ARCN to the PVN have been reported by us and others, these results indicate that neurons containing POMC, α-MSH, and glutamate project from the ARCN to the DMN and PVN. Stimulation of ARCN results in the release of α-MSH and glutamate in the DMN and PVN which, in turn, cause increases in IBATSNA and TBAT.


Asunto(s)
Tejido Adiposo Pardo/efectos de los fármacos , Núcleo Arqueado del Hipotálamo/efectos de los fármacos , Núcleo Hipotalámico Dorsomedial/efectos de los fármacos , Núcleo Hipotalámico Paraventricular/efectos de los fármacos , Sistema Nervioso Simpático/efectos de los fármacos , Termogénesis/efectos de los fármacos , 2-Amino-5-fosfonovalerato/análogos & derivados , 2-Amino-5-fosfonovalerato/farmacología , Tejido Adiposo Pardo/inervación , Animales , Núcleo Arqueado del Hipotálamo/fisiología , Núcleo Hipotalámico Dorsomedial/fisiología , Agonistas de Aminoácidos Excitadores/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Colorantes Fluorescentes , Agonistas de Receptores de GABA-A/farmacología , Ácido Glutámico/metabolismo , Inmunohistoquímica , Masculino , Microinyecciones , Muscimol/farmacología , N-Metilaspartato/farmacología , Inhibición Neural , Núcleo Hipotalámico Paraventricular/fisiología , Proopiomelanocortina/metabolismo , Quinoxalinas/farmacología , Ratas , Ratas Wistar , Receptor de Melanocortina Tipo 3/antagonistas & inhibidores , Receptor de Melanocortina Tipo 4/antagonistas & inhibidores , Estilbamidinas , Sistema Nervioso Simpático/fisiología , Temperatura , Termogénesis/fisiología , Proteínas de Transporte Vesicular de Glutamato/metabolismo , alfa-MSH/metabolismo
7.
Proc Natl Acad Sci U S A ; 108(31): 12931-6, 2011 Aug 02.
Artículo en Inglés | MEDLINE | ID: mdl-21768371

RESUMEN

Long-term memory (LTM) consolidation requires the synthesis of plasticity-related proteins (PRPs). In addition, we have shown recently that LTM formation also requires the setting of a "learning tag" able to capture those PRPs. Weak training, which results only in short-term memory, can set a tag to use PRPs derived from a temporal-spatial closely related event to promote LTM formation. Here, we studied the involvement of glutamatergic, dopaminergic, and noradrenergic inputs on the setting of an inhibitory avoidance (IA) learning tag and the synthesis of PRPs. Rats explored an open field (PRP donor) followed by weak (tag inducer) or strong (tag inducer plus PRP donor) IA training. Throughout pharmacological interventions around open-field and/or IA sessions, we found that hippocampal dopamine D1/D5- and ß-adrenergic receptors are specifically required to induce PRP synthesis. Moreover, activation of the glutamatergic NMDA receptors is required for setting the learning tags, and this machinery further required α-Ca(2+)/calmodulin-dependent protein kinase II and PKA but not ERK1/2 activity. Together, the present findings emphasize an essential role of the induction of PRPs and learning tags for LTM formation. The existence of only the PRP or the tag was insufficient for stabilization of the mnemonic trace.


Asunto(s)
Reacción de Prevención/fisiología , Memoria a Largo Plazo/fisiología , Memoria a Corto Plazo/fisiología , Plasticidad Neuronal/fisiología , 1-(5-Isoquinolinesulfonil)-2-Metilpiperazina/análogos & derivados , 1-(5-Isoquinolinesulfonil)-2-Metilpiperazina/farmacología , 2-Amino-5-fosfonovalerato/análogos & derivados , 2-Amino-5-fosfonovalerato/farmacología , Antagonistas Adrenérgicos beta/farmacología , Animales , Benzazepinas/farmacología , Región CA1 Hipocampal/metabolismo , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/antagonistas & inhibidores , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Dobutamina/farmacología , Inhibidores Enzimáticos/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Conducta Exploratoria/fisiología , Masculino , Memoria a Largo Plazo/efectos de los fármacos , Memoria a Corto Plazo/efectos de los fármacos , Propranolol/farmacología , Ratas , Ratas Wistar , Receptores Adrenérgicos beta/metabolismo , Receptores de Dopamina D1/antagonistas & inhibidores , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D5/antagonistas & inhibidores , Receptores de Dopamina D5/metabolismo , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Receptores de N-Metil-D-Aspartato/metabolismo
8.
Bioorg Med Chem ; 21(17): 4958-67, 2013 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-23891162

RESUMEN

Rhizocticins and Plumbemycins are natural phosphonate antibiotics produced by the bacterial strains Bacillus subtilis ATCC 6633 and Streptomyces plumbeus, respectively. Up to now, these potential threonine synthase inhibitors have only been synthesized under enzymatic catalysis. Here we report the chemical stereoselective synthesis of the non-proteinogenic (S,Z)-2-amino-5-phosphonopent-3-enoic acid [(S,Z)-APPA] and its use for the synthesis of Rhizocticin A and Plumbemycin A. In this work, (S,Z)-APPA was synthesized via the Still-Gennari olefination starting from Garner's aldehyde. The Michaelis-Arbuzov reaction was used to form the phosphorus-carbon bond. Oligopeptides were prepared using liquid phase peptide synthesis (LPPS) and were tested against selected bacteria and fungi.


Asunto(s)
Antiinfecciosos/síntesis química , Liasas de Carbono-Oxígeno/antagonistas & inhibidores , Inhibidores Enzimáticos/síntesis química , Oligopéptidos/síntesis química , Compuestos Organofosforados/síntesis química , 2-Amino-5-fosfonovalerato/análogos & derivados , 2-Amino-5-fosfonovalerato/síntesis química , 2-Amino-5-fosfonovalerato/química , Antiinfecciosos/química , Antiinfecciosos/farmacología , Bacillus subtilis/metabolismo , Liasas de Carbono-Oxígeno/metabolismo , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Hongos/efectos de los fármacos , Hongos/enzimología , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Gramnegativas/enzimología , Bacterias Grampositivas/efectos de los fármacos , Bacterias Grampositivas/enzimología , Oligopéptidos/química , Oligopéptidos/farmacología , Compuestos Organofosforados/química , Compuestos Organofosforados/farmacología , Estereoisomerismo , Streptomyces/metabolismo
9.
J Neurosci ; 31(6): 2280-91, 2011 Feb 09.
Artículo en Inglés | MEDLINE | ID: mdl-21307264

RESUMEN

In the mammalian retina, excitatory and inhibitory circuitries enable retinal ganglion cells (RGCs) to signal the occurrence of visual features to higher brain areas. This functionality disappears in certain diseases of retinal degeneration because of the progressive loss of photoreceptors. Recent work in a mouse model of retinal degeneration (rd1) found that, although some intraretinal circuitry is preserved and RGCs maintain characteristic physiological properties, they exhibit increased and aberrant rhythmic activity. Here, extracellular recordings were made to assess the degree of aberrant activity in adult rd1 retinas and to investigate the mechanism underlying such behavior. A multi-transistor array with thousands of densely packed sensors allowed for simultaneous recordings of spiking activity in populations of RGCs and of local field potentials (LFPs). The majority of identified RGCs displayed rhythmic (7-10 Hz) but asynchronous activity. The spiking activity correlated with the LFPs, which reflect an average synchronized excitatory input to the RGCs. LFPs initiated from random positions and propagated across the retina. They disappeared when ionotrophic glutamate receptors or electrical synapses were blocked. They persisted in the presence of other pharmacological blockers, including TTX and inhibitory receptor antagonists. Our results suggest that excitation-transmitted laterally through a network of electrically coupled interneurons-leads to large-scale retinal network oscillations, reflected in the rhythmic spiking of most rd1 RGCs. This result may explain forms of photopsias reported by blind patients, while the mechanism involved should be considered in future treatment strategies targeting the disease of retinitis pigmentosa.


Asunto(s)
Potenciales Evocados Visuales/fisiología , Red Nerviosa/fisiopatología , Periodicidad , Degeneración Retiniana/patología , Células Fotorreceptoras Retinianas Bastones/fisiología , 2-Amino-5-fosfonovalerato/análogos & derivados , 2-Amino-5-fosfonovalerato/farmacología , Potenciales de Acción/efectos de los fármacos , Potenciales de Acción/fisiología , Factores de Edad , Animales , Carbenoxolona/farmacología , Inhibidores de la Ciclooxigenasa/farmacología , Modelos Animales de Enfermedad , Potenciales Evocados Visuales/efectos de los fármacos , Antagonistas de Aminoácidos Excitadores/farmacología , Antagonistas del GABA/farmacología , Uniones Comunicantes/efectos de los fármacos , Uniones Comunicantes/genética , Ácido Glutámico/farmacología , Glicina/farmacología , Técnicas In Vitro , Luz , Masculino , Ácido Meclofenámico/farmacología , Ratones , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Ratones Mutantes Neurológicos , Red Nerviosa/efectos de los fármacos , Inhibición Neural/efectos de los fármacos , Piridazinas/farmacología , Quinoxalinas/farmacología , Degeneración Retiniana/genética , Células Fotorreceptoras Retinianas Bastones/efectos de los fármacos , Bloqueadores de los Canales de Sodio/farmacología , Estadística como Asunto , Tetrodotoxina/farmacología , Ácido gamma-Aminobutírico/farmacología
10.
Hippocampus ; 22(11): 2157-70, 2012 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-22593084

RESUMEN

Our current understanding of brain mechanisms involved in learning and memory has been derived largely from studies using experimentally naïve animals. However, it is becoming increasingly clear that not all identified mechanisms may generalize to subsequent learning. For example, N-methyl-D-aspartate glutamate (NMDA) receptors in the dorsal hippocampus are required for contextual fear conditioning in naïve animals but not in animals previously trained in a similar task. Here we investigated how animals learn contextual fear conditioning for a second time-a response which is not due to habituation or generalization. We found that dorsal hippocampus infusions of voltage-dependent calcium channel blockers or the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) agonist impaired the first, not the second contextual learning. Only manipulations of the entire hippocampus led to an impairment in second learning. Specifically, inactivation of either the dorsal or ventral hippocampus caused the remaining portion of the hippocampus to acquire and consolidate the second learning. Thus, dorsal hippocampus seems necessary for initial contextual fear conditioning, but either the dorsal or ventral hippocampus is sufficient for subsequent conditioning in a different context. Together, these findings suggest that prior training experiences can change how the hippocampus processes subsequent similar learning.


Asunto(s)
Condicionamiento Clásico/fisiología , Miedo/fisiología , Hipocampo/fisiología , Retención en Psicología/fisiología , 2-Amino-5-fosfonovalerato/análogos & derivados , 2-Amino-5-fosfonovalerato/farmacología , 2-Amino-5-fosfonovalerato/toxicidad , Amnesia/inducido químicamente , Amnesia/fisiopatología , Animales , Anisomicina/farmacología , Anisomicina/toxicidad , Bloqueadores de los Canales de Calcio/farmacología , Bloqueadores de los Canales de Calcio/toxicidad , Condicionamiento Clásico/efectos de los fármacos , Electrochoque , Antagonistas de Aminoácidos Excitadores/farmacología , Antagonistas de Aminoácidos Excitadores/toxicidad , Reacción Cataléptica de Congelación/efectos de los fármacos , Reacción Cataléptica de Congelación/fisiología , Agonistas del GABA/farmacología , Agonistas del GABA/toxicidad , Hipocampo/efectos de los fármacos , Hipocampo/ultraestructura , Masculino , Modelos Neurológicos , Modelos Psicológicos , Muscimol/farmacología , Muscimol/toxicidad , Inhibidores de la Síntesis de la Proteína/farmacología , Inhibidores de la Síntesis de la Proteína/toxicidad , Ratas Sprague-Dawley , Retención en Psicología/efectos de los fármacos , Verapamilo/farmacología , Verapamilo/toxicidad
11.
J Neurosci ; 30(49): 16523-35, 2010 Dec 08.
Artículo en Inglés | MEDLINE | ID: mdl-21147992

RESUMEN

Mesial temporal lobe epilepsy (MTLE) is characterized by focal seizures, associated with hippocampal sclerosis, and often resistance to antiepileptic drugs. The parafascicular nucleus (PF) of the thalamus is involved in the generation of physiological oscillatory rhythms. It receives excitatory inputs from the cortex and inhibitory inputs from the basal ganglia, a system implicated in the control of epileptic seizures. The aim of this study was to examine the involvement of the PF in the occurrence of hippocampal paroxysmal discharges (HPDs) in a chronic animal model of MTLE in male mice. We recorded the local field potential (LFP) and the extracellular and intracellular activity of hippocampal and PF neurons during spontaneous HPDs in vivo. The end of the HPDs was concomitant with a slow repolarization in hippocampal neurons leading to an electrical silence. In contrast, it was associated in the PF with a transient increase in the power of the 10-20 Hz band in LFPs and a depolarization of PF neurons resulting in a sustained firing. We tested the role of the PF in the control of HPDs by single 130 Hz electrical stimulation of this nucleus and bilateral intra-PF injection of NMDA and GABA(A) antagonist and agonist. High-frequency PF stimulation interrupted ongoing HPDs at an intensity devoid of behavioral effects. NMDA antagonist and GABA(A) agonist suppressed hippocampal discharges in a dose-dependent way, whereas NMDA agonist and GABA(A) antagonist increased HPDs. Altogether, these data suggest that the PF nucleus plays a role in the modulation of MTLE seizures.


Asunto(s)
Epilepsia del Lóbulo Temporal/patología , Núcleos Talámicos Intralaminares/patología , 2-Amino-5-fosfonovalerato/análogos & derivados , 2-Amino-5-fosfonovalerato/farmacología , Potenciales de Acción/efectos de los fármacos , Potenciales de Acción/fisiología , Animales , Fenómenos Biofísicos/efectos de los fármacos , Fenómenos Biofísicos/fisiología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Electroencefalografía/métodos , Epilepsia del Lóbulo Temporal/inducido químicamente , Epilepsia del Lóbulo Temporal/tratamiento farmacológico , Potenciales Evocados Somatosensoriales/efectos de los fármacos , Potenciales Evocados Somatosensoriales/fisiología , Antagonistas de Aminoácidos Excitadores/farmacología , Lateralidad Funcional/efectos de los fármacos , Lateralidad Funcional/fisiología , Agonistas de Receptores de GABA-A/farmacología , Hipocampo/efectos de los fármacos , Hipocampo/patología , Hipocampo/fisiología , Núcleos Talámicos Intralaminares/efectos de los fármacos , Núcleos Talámicos Intralaminares/fisiopatología , Ácido Kaínico , Masculino , Ratones , Ratones Endogámicos C57BL , Muscimol/farmacología , N-Metilaspartato/farmacología , Neuronas/fisiología , Estadísticas no Paramétricas , Factores de Tiempo , Vigilia
12.
J Pharmacol Exp Ther ; 332(3): 912-21, 2010 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-20008958

RESUMEN

Histamine potentiates activation of native and recombinant N-methyl-d-aspartate receptors (NMDARs), but its mechanisms of action and physiological functions in the brain remain controversial. Using four different models, we have further investigated the histamine-induced potentiation of various NMDAR-mediated responses. In single cultured hippocampal neurons, histamine potentiated NMDA currents. It also potentiated the NMDA-induced increase in intracellular calcium in the absence, as well as with saturating concentrations, of exogenous d-serine, indicating both glycine-dependent and glycine-independent components of its effect. In rat hippocampal synaptosomes, histamine strongly potentiated NMDA-induced [(3)H]noradrenaline release. The profile of this response contained several signatures of the histamine-mediated effect at neuronal or recombinant NMDARs. It was NR2B-selective, being sensitive to micromolar concentrations of ifenprodil. It was reproduced by tele-methylhistamine, the metabolite of histamine in brain, and it was antagonized by impromidine, an antagonist/inverse agonist of histamine on NMDA currents. Up to now, histamine was generally considered to interact with the polyamine site of the NMDAR. However, spermine did not enhance NMDA-induced [(3)H]noradrenaline release from synaptosomes, and the potentiation of the same response by tele-methylhistamine was not antagonized by the polyamine antagonist arcaine. In hippocampal membranes, like spermine, tele-methylhistamine enhanced [(3)H]dl-(E)-2-amino-4-propyl-5-phosphono-3-pentenoic acid (CGP39653) binding to the glutamate site. In contrast, spermine increased nonequilibrium [(3)H]5H-dibenzo[a,d]cyclohepten-5,10-imine (dizocilpine maleate; MK-801) binding, and suppressed [(3)H]ifenprodil binding, whereas histamine and tele-methylhistamine had no effect. In conclusion, the histamine-induced potentiation of NMDARs occurs in the brain under normal conditions. Histamine does not bind to the polyamine site, but to a distinct entity, the so-called histamine site of the NMDAR.


Asunto(s)
Histamina/farmacología , Poliaminas/metabolismo , Receptores de N-Metil-D-Aspartato/fisiología , 2-Amino-5-fosfonovalerato/análogos & derivados , 2-Amino-5-fosfonovalerato/farmacología , Sitio Alostérico , Animales , Sitios de Unión , Calcio/metabolismo , Maleato de Dizocilpina/farmacología , Sinergismo Farmacológico , Hipocampo/metabolismo , Técnicas In Vitro , Espacio Intracelular/metabolismo , Masculino , Metilhistaminas/farmacología , N-Metilaspartato/farmacología , Neuronas/metabolismo , Norepinefrina/metabolismo , Piperidinas/farmacología , Ensayo de Unión Radioligante , Ratas , Ratas Wistar , Espermina/farmacología , Sinaptosomas/metabolismo
13.
Behav Brain Res ; 378: 112312, 2020 01 27.
Artículo en Inglés | MEDLINE | ID: mdl-31629003

RESUMEN

Chemical inhibition and nitrergic stimulation of the left and right medial prefrontal cortex (L and RmPFC), respectively, provoke anxiety in mice. Moreover, LmPFC inhibition immediately followed by a single social defeat stress (SDS) led to anxiogenesis in mice exposed to the elevated plus maze (EPM) 24 h later. Given that glutamate NMDA (N-methyl-D-aspartate) receptors are densely present in the mPFC, we investigated (i) the time course of LmPFC inhibition + SDS-induced anxiogenesis and (ii) the effects of intra-RmPFC injection of AP-7 (a NMDA receptor antagonist) on this long-lasting anxiety. Male Swiss mice received intra-LmPFC injection of CoCl2 (1 mM) and 10 min later were subjected to a single SDS episode and then (i) exposed to the EPM 2, 5, or 10 days later or (ii) 2 days later, received intra-RmPFC injection of AP-7 (0.05 nmol) and were exposed to the EPM to observe the percentage of open arm entries and time (%OE; %OT) and frequency of closed arm entries (CE). Dorsal but not ventral LmPFC inhibition + SDS reduced open arm exploration 2, 5, and 10 days later relative to that of saline-treated or non-defeated mice. Moreover, this effect is not due to locomotor impairment as assessed using the general activity. Intra-RmPFC AP-7 injection 2 days after LmPFC inhibition + SDS prevented this type of anxiogenesis. These results suggest that the integrity of the LmPFC is important for mice to properly cope with SDS, and that NMDA receptor blockade in the RmPFC facilitates resilience to SDS-induced anxiogenesis in mice.


Asunto(s)
Ansiedad , Conducta Animal , Antagonistas de Aminoácidos Excitadores/farmacología , Aprendizaje por Laberinto , Corteza Prefrontal/efectos de los fármacos , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Derrota Social , Estrés Psicológico/complicaciones , 2-Amino-5-fosfonovalerato/análogos & derivados , 2-Amino-5-fosfonovalerato/farmacocinética , Adaptación Psicológica/efectos de los fármacos , Adaptación Psicológica/fisiología , Animales , Ansiedad/etiología , Ansiedad/fisiopatología , Ansiedad/prevención & control , Conducta Animal/efectos de los fármacos , Conducta Animal/fisiología , Antagonistas de Aminoácidos Excitadores/farmacocinética , Lateralidad Funcional/fisiología , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Aprendizaje por Laberinto/fisiología , Ratones
14.
Psychopharmacology (Berl) ; 237(1): 231-248, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31654083

RESUMEN

RATIONALE: Several findings indicate that early-life dysfunction of N-methyl-D-aspartate (NMDA) receptors might cause schizophrenia-like abnormalities in adulthood that might be induced by impairments in epigenetic regulation. OBJECTIVES: In the present study, we investigated whether postnatal blockade of NMDA receptors (within the first 3 weeks of life) by the competitive antagonist CGP 37849 (CGP) might affect some epigenetic markers in the adult medial prefrontal cortex (mPFC). METHODS: Histone H3 phosphorylation at serine 10 (H3S10ph), histone H3 acetylation at lysine 9 or 14 (H3K9ac or H3K14ac, respectively), or expression of histone deacetylase (HDAC) 2, HDAC5, myocyte enhancer factor (MEF) 2D and activity-regulated cytoskeleton-associated protein (Arc) were analysed. Moreover, we also evaluated whether the deacetylase inhibitor sodium butyrate (SB; 1.2 mg/kg, ip) could prevent behavioural and neurochemical changes in the mPFC induced by CGP during memory retrieval in the trace fear conditioning paradigm. RESULTS: The results showed that CGP administration increased the number of H3S10ph nuclei but did not affect H3K9ac and H3K14ac or HDAC2 protein levels. However, CGP administration altered the HDAC5 mRNA and protein levels and increased the mRNA and protein levels of MEF2D. CGP also increased Arc mRNA, which was correlated with an increase in the amount of Arc DNA bound to MEF2D. SB given 2 h after training prevented impairment of the freezing response and disruption of epigenetic markers (H3S10ph, HDAC5, MEF2D) and Arc expression during memory retrieval induced by CGP administration. CONCLUSIONS: The early-life blockade of NMDA receptors impairs some epigenetic regulatory processes in the mPFC that are involved in fear memory formation.


Asunto(s)
Epigénesis Genética/efectos de los fármacos , Antagonistas de Aminoácidos Excitadores/farmacología , Miedo/efectos de los fármacos , Corteza Prefrontal/efectos de los fármacos , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , 2-Amino-5-fosfonovalerato/análogos & derivados , 2-Amino-5-fosfonovalerato/farmacología , Acetilación/efectos de los fármacos , Animales , Conducta Animal/efectos de los fármacos , Condicionamiento Psicológico/efectos de los fármacos , Miedo/fisiología , Histonas/metabolismo , Masculino , Memoria/fisiología , Corteza Prefrontal/metabolismo , Ratas , Esquizofrenia/metabolismo
15.
J Neurosci Res ; 87(11): 2418-29, 2009 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-19360885

RESUMEN

Innate fear stimulus induces activation of neurons containing the neuronal nitric oxide synthase enzyme (nNOS) in defensive-related brain regions such as the dorsolateral periaqueductal gray (dlPAG). Intra-dlPAG administration of nitric oxide synthase (NOS) inhibitors and glutamate antagonists induce anxiolytic-like responses. We investigated the involvement of nitric oxide (NO) and glutamate neurotransmission in defensive reactions modulated by dlPAG. We tested if intra-dlPAG injections of the selective nNOS inhibitor, N-propyl-L-arginine (NP), or the glutamate antagonist, AP7 (2-amino-7-phosphonoheptanoic acid), would attenuate behavioral responses and cellular activation induced by predator exposure (cat). Fos-like immunoreactivity (FLI) was used as a marker of neuronal functional activation, whereas nNOS immunohistochemistry was used to identify NOS neurons. Cat exposure induced fear responses and an increase of FLI in the dlPAG and dorsal premammillary nucleus (PMd). NP and AP7 attenuated the cat-induced behavioral responses. Whereas NP tended to attenuate FLI in the dlPAG, AP7 induced a significant reduction in cellular activation of this region. The latter drug, however, increased FLI and double-labeled cells in the PMd. Cellular activation of this region was significantly correlated with time spent near the cat (r = 0.7597 and 0.6057 for FLI and double-labeled cells). These results suggest that glutamate/NO-mediated neurotransmission in the dlPAG plays an important role in responses elicit by predator exposure. Blocking these neurotransmitter systems in this brain area impairs defensive responses. The longer time spent near the predator that follows AP7 effect could lead to an increased cellular activation of the PMd, a more rostral brain area that has also been related to defensive responses.


Asunto(s)
Miedo/efectos de los fármacos , Óxido Nítrico Sintasa de Tipo I/antagonistas & inhibidores , Sustancia Gris Periacueductal/efectos de los fármacos , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , 2-Amino-5-fosfonovalerato/análogos & derivados , 2-Amino-5-fosfonovalerato/farmacología , Animales , Arginina/análogos & derivados , Arginina/farmacología , Conducta Animal/efectos de los fármacos , Conducta Animal/fisiología , Inhibidores Enzimáticos/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Miedo/fisiología , Masculino , Óxido Nítrico/metabolismo , Proteínas Proto-Oncogénicas c-fos/metabolismo , Ratas , Ratas Wistar , Transmisión Sináptica/efectos de los fármacos , Transmisión Sináptica/fisiología , Factores de Tiempo
16.
Behav Neurosci ; 123(1): 145-55, 2009 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-19170439

RESUMEN

The tegmental pedunculopontine nucleus (TPP) of the midbrain is critical in mediating the acute rewarding effects of opiates. However, the circuitry and neurochemistry underlying this effect has not been determined. Here we identify TPP receptors and cell types involved in systemic morphine reward and suggest an anatomical and neurochemical model for reward in the TPP. Simple hypothetical anatomical models for serial cell arrangements and receptors in the TPP were proposed and predictions of behavioral outcome (reward or no reward) then were made, based on the administration of agonists and antagonists directly into the TPP of rats. We report that TPP-administered NMDA produced rewarding effects, although GABA agonists and antagonists had no motivational effects on their own. However, the NMDA receptor antagonist AP-7 and the GABA-B receptor antagonist saclofen, while having no motivational effects on their own, blocked systemic morphine reward as measured by conditioned place preference. These results provide positive evidence for GABA-B and glutamate synapses in the TPP, which mediates systemic morphine reward and suggest that a serial pathway for morphine reward in the TPP is unlikely.


Asunto(s)
Morfina/administración & dosificación , Narcóticos/administración & dosificación , Núcleo Tegmental Pedunculopontino/metabolismo , Receptores de GABA-B/metabolismo , Receptores de Glutamato/metabolismo , Recompensa , 2-Amino-5-fosfonovalerato/análogos & derivados , 2-Amino-5-fosfonovalerato/farmacología , Análisis de Varianza , Animales , Baclofeno/análogos & derivados , Baclofeno/farmacología , Conducta Animal , Bicuculina/farmacología , Condicionamiento Operante/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Agonistas de Aminoácidos Excitadores/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Agonistas del GABA/farmacología , Antagonistas del GABA/farmacología , Masculino , N-Metilaspartato/farmacología , Núcleo Tegmental Pedunculopontino/citología , Núcleo Tegmental Pedunculopontino/efectos de los fármacos , Ratas , Ratas Wistar
17.
Synapse ; 63(10): 836-46, 2009 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-19533626

RESUMEN

A hypofunction of the N-methyl-D-aspartate (NMDA) receptor has been implicated in the pathophysiology of schizophrenia. Compelling evidence of altered NMDA receptor subunit expression in the schizophrenic brain has not, however, so far emerged. Rats reared in isolation exhibit several characteristics, including disturbed sensory gating, which resemble those seen in schizophrenia. To explore the possibility that NMDA receptor dysfunction may contribute to the behavioral and neurochemical consequences of rearing rats in isolation, we compared NMDA receptor subunit expression in brains of rats which were housed in isolation and which displayed a deficit in prepulse inhibition of the acoustic startle response with that of socially housed controls. An initial microarray analysis revealed a 1.26-fold increase in NR2A transcript in the prefrontal cortex, but not in the nucleus accumbens, of rats reared in isolation compared with those housed socially. In contrast, NR1, NR2B, NR2C, NR2D, NR3A, and NR3B subunit expression was unchanged in either brain area. In a second cohort of animals, in situ hybridization revealed increased NR2A mRNA expression in the medial prefrontal cortex, an observation that was substantiated by increased [(3)H]CGP39653 binding suggesting that NR2A receptor subunit protein expression was also elevated in the medial prefrontal cortex of the same animals. No changes in expression of NR1 or NR2B subunits were observed at both mRNA and protein level. Altered NR2A subunit expression in the medial prefrontal cortex of rats reared in isolation suggests that NMDA receptor dysfunction may contribute to the underlying pathophysiology of this preclinical model of aspects of schizophrenia.


Asunto(s)
Regulación de la Expresión Génica/fisiología , Corteza Prefrontal/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Aislamiento Social , 2-Amino-5-fosfonovalerato/análogos & derivados , 2-Amino-5-fosfonovalerato/metabolismo , Estimulación Acústica/efectos adversos , Animales , Animales Recién Nacidos , Perfilación de la Expresión Génica/métodos , Indoles/metabolismo , Masculino , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , Unión Proteica/fisiología , Ensayo de Unión Radioligante/métodos , Ratas , Receptores de N-Metil-D-Aspartato/genética , Reflejo de Sobresalto/fisiología , Tritio/metabolismo
18.
Science ; 226(4676): 850-2, 1984 Nov 16.
Artículo en Inglés | MEDLINE | ID: mdl-6093256

RESUMEN

In rats ischemia of the forebrain induced by a 30-minute occlusion of the carotid artery, followed by 120 minutes of arterial reperfusion, produced ischemic lesions of selectively vulnerable pyramidal cells in both hippocampi. Focal microinfusion into the dorsal hippocampus of 2-amino-7-phosphonoheptanoic acid, an antagonist of excitation at the N-methyl-D-aspartate-preferring receptor, before ischemia was induced protected against the development of ischemic damage. It is proposed that excitatory neurotransmission plays an important role in selective neuronal loss due to cerebral ischemia.


Asunto(s)
2-Amino-5-fosfonovalerato/análogos & derivados , Isquemia Encefálica/prevención & control , Receptores de Neurotransmisores/fisiología , Aminoácidos/farmacología , Animales , Isquemia Encefálica/patología , Hipocampo/efectos de los fármacos , Hipocampo/patología , Ratas , Receptores de N-Metil-D-Aspartato , Receptores de Neurotransmisores/efectos de los fármacos , Transmisión Sináptica/efectos de los fármacos
19.
Science ; 230(4726): 681-3, 1985 Nov 08.
Artículo en Inglés | MEDLINE | ID: mdl-2996146

RESUMEN

The possibility that neuronal damage due to hypoglycemia is induced by agonists acting on the N-methyl-D-aspartate (NMDA) receptor was investigated in the rat caudate nucleus. Local injections of an NMDA receptor antagonist, 2-amino-7-phosphonoheptanoic acid, were performed before induction of 30 minutes of reversible, insulin-induced, hypoglycemic coma. Neuronal necrosis in these animals after 1 week of recovery was reduced 90 percent compared to that in saline-injected animals. The results suggest that hypoglycemic neuronal damage is induced by NMDA receptor agonists, such as the excitatory amino acids or related compounds.


Asunto(s)
2-Amino-5-fosfonovalerato/análogos & derivados , Aminoácidos/farmacología , Ácido Aspártico/análogos & derivados , Hipoglucemia/metabolismo , Neuronas/efectos de los fármacos , Animales , Ácido Aspártico/antagonistas & inhibidores , Núcleo Caudado/citología , Electroencefalografía , Hipoglucemia/patología , Masculino , N-Metilaspartato , Necrosis , Neuronas/metabolismo , Neuronas/patología , Ratas , Ratas Endogámicas , Receptores de N-Metil-D-Aspartato , Receptores de Neurotransmisores/metabolismo
20.
ACS Chem Biol ; 14(4): 742-750, 2019 04 19.
Artículo en Inglés | MEDLINE | ID: mdl-30830751

RESUMEN

Rhizocticins are phosphono-oligopeptide antibiotics that contain a toxic C-terminal ( Z) -l -2-amino-5-phosphono-3-pentenoic acid (APPA) moiety. APPA is an irreversible inhibitor of threonine synthase (ThrC), a pyridoxal 5'-phosphate (PLP)-dependent enzyme that catalyzes the conversion of O-phospho-l-homoserine to l-threonine. ThrCs are essential for the viability of bacteria, plants, and fungi and are a target for antibiotic development, as de novo threonine biosynthetic pathway is not found in humans. Given the ability of APPA to interfere in threonine metabolism, it is unclear how the producing strain B. subtilis ATCC 6633 circumvents APPA toxicity. Notably, in addition to the housekeeping APPA-sensitive ThrC ( BsThrC), B. subtilis encodes a second threonine synthase (RhiB) encoded within the rhizocticin biosynthetic gene cluster. Kinetic and spectroscopic analyses show that PLP-dependent RhiB is an authentic threonine synthase, converting O-phospho-l-homoserine to threonine with a catalytic efficiency comparable to BsThrC. To understand the structural basis of inhibition, we determined the crystal structure of APPA bound to the housekeeping BsThrC, revealing a covalent complex between the inhibitor and PLP. Structure-based sequence analyses reveal structural determinants within the RhiB active site that contribute to rendering this ThrC homologue resistant to APPA. Together, this work establishes the self-resistance mechanism utilized by B. subtilis ATCC 6633 against APPA exemplifying one of many ways by which bacteria can overcome phosphonate toxicity.


Asunto(s)
2-Amino-5-fosfonovalerato/análogos & derivados , Antibacterianos/metabolismo , Bacillus subtilis/metabolismo , Farmacorresistencia Microbiana , Oligopéptidos/metabolismo , 2-Amino-5-fosfonovalerato/metabolismo , 2-Amino-5-fosfonovalerato/farmacología , Antibacterianos/farmacología , Liasas de Carbono-Oxígeno/antagonistas & inhibidores , Liasas de Carbono-Oxígeno/metabolismo , Conformación Proteica
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA