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/toxicidadRESUMEN
We tested whether N-methyl-D-aspartate (NMDA) receptors in the dorsal hippocampus (DH) are critical for the acquisition of trace fear conditioning using conditioned hypoalgesia (CHA), decrease in pain reactivity, as the conditioned response (CR) instead of commonly used freezing. Infusions of the NMDA receptor antagonist, DL-2-amino-5-phosphonovaleric acid (APV) into DH prior to conditioning resulted in impaired CHA, measured with the radiant heat tail flick test, only in the trace-conditioning group when they were tested during the trace interval. The same infusion had no effect on CHA in the delay-conditioned animals. The results support that NMDA receptors in DH are critically involved in associating the CS with the US across a temporal gap. In addition, temporal specificity of the CR was revealed as CHA was induced only in the temporal vicinity of the US used for the training.
Asunto(s)
Lesiones Encefálicas/fisiopatología , Condicionamiento Clásico/fisiología , Miedo/fisiología , Hipocampo/fisiopatología , Receptores de N-Metil-D-Aspartato/fisiología , 2-Amino-5-fosfonovalerato/administración & dosificación , 2-Amino-5-fosfonovalerato/toxicidad , Estimulación Acústica/métodos , Animales , Aprendizaje por Asociación/efectos de los fármacos , Aprendizaje por Asociación/fisiología , Conducta Animal , Lesiones Encefálicas/inducido químicamente , Condicionamiento Clásico/efectos de los fármacos , Antagonistas de Aminoácidos Excitadores/administración & dosificación , Antagonistas de Aminoácidos Excitadores/toxicidad , Miedo/efectos de los fármacos , Hipocampo/efectos de los fármacos , Hipocampo/patología , Masculino , Memoria/efectos de los fármacos , Memoria/fisiología , Microinyecciones , Ratas , Ratas Sprague-Dawley , Reflejo de Sobresalto/efectos de los fármacos , Reflejo de Sobresalto/fisiología , Factores de TiempoRESUMEN
Postnatal hypofunction of N-methyl-D-aspartate (NMDA) receptors leads to several behavioral deficits in adult rats resembling deficits typical of schizophrenia-like deficits of sensorimotor gating. Thus far, it is not known whether the above disruptions are sensitive to neuroleptic drugs. In order to verify the above model in pharmacological terms, we investigated whether deficits in the sensorimotor gating evoked by administration of NMDA receptor antagonists in the postnatal period is sensitive to neuroleptic drugs. We also investigated whether such treatment evoked alterations in the expression of dopamine D(1), D(2) and D(3) receptors in the nucleus accumbens, a key structure for dopamine-dependent alterations in sensorimotor gating. CGP 40116, a competitive antagonist of NMDA receptors was given in doses of 1.25 mg/kg on days 1, 3, 6 and 9; 2.5 mg/kg on days 12, 15 and 18; and 5 mg/kg on day 21 (all injections were sc). The efficacy of sensorimotor gating was tested on rats at the age of 60 days using a prepulse-induced inhibition of the startle reflex. In order to measure the expression of dopamine D(1), D(2) and D(3) receptors, we used quantitative autoradiography and tritiated ligands i.e. [(3)H]-SCH 23390, [(3)H]-Spiperone and [(3)H]-7-OH-DPAT, respectively. Haloperidol (0.1 mg/kg, sc), risperidone (1.0 mg/kg, sc) and clozapine (2.5 mg/kg, sc) reversed deficits of sensorimotor gating observed in adult rats evoked by the postnatal administration of CGP 40116. We also observed enhanced density of dopamine D(3), but not D(1) and D(2) receptors in the nucleus accumbens of CGP40116 treated rats. It is concluded that models of cognitive dysfunction, typical for schizophrenia based on postnatal administration of NMDA receptor antagonists, are sensitive to neuroleptic drugs and possibly not dependent on alteration in the density of dopaminergic receptors.
Asunto(s)
2-Amino-5-fosfonovalerato/análogos & derivados , Antipsicóticos/farmacología , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Esquizofrenia/inducido químicamente , Filtrado Sensorial/efectos de los fármacos , 2-Amino-5-fosfonovalerato/toxicidad , Animales , Autorradiografía , Clozapina/farmacología , Modelos Animales de Enfermedad , Femenino , Masculino , Ratas , Ratas Wistar , Receptores Dopaminérgicos/análisis , Receptores Dopaminérgicos/clasificación , Risperidona/farmacología , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/metabolismoRESUMEN
The medial hypothalamus is proposed to play an important role in the modulation of defensive responses. Administration of a NMDA receptor antagonist (AP7) into the dorsomedial hypothalamic nucleus (DMH) of rats reduced exploratory behavior in the open field and elevated plus-maze (EPM), but failed to produce anxiolytic effects in the latter test. The objectives of the present work were to test the hypotheses that (i) AP7 injections into the DMH would also fail to induce anxiolytic effects in another model of anxiety, the Vogel's punished licking test; (ii) injection into the DMH of other glutamate ionotropic antagonists would also decreased exploratory behavior; and (iii) the decrease in exploratory activity found after AP7 administration into the DMH does not involve any gross locomotor impairment. Male Wistar rats (n=5-16/group) with cannulas aimed at the DMH were submitted to the following behavioral tests: EPM, Vogel, catalepsy and rota-rod. Diazepam (3 mg/kg) and haloperidol (2.5 mg/kg) were used as positive controls in the Vogel, rota-rod and catalepsy tests. AP7 failed to modify the number of punished licks in the Vogel test. It also did not induce any change on the rota-rod and catalepsy tests. Diazepam increased the number of punished licks and reduced the latency to fall in the rota-rod. Both 7-chlorokynurenic acid (4-8 nmol), an antagonist of the glycine competitive site in the NMDA receptor and 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo-[f]-quinoxaline-7-sulphonamide (NBQX, 1-10 nmol), a non-NMDA receptor antagonist, decreased the total distance moved in the EPM. The former compound also decreased open arm exploration at the dose of 4 nmol. The results suggest that the antagonism of ionotropic glutamate receptors in the DMH does not induce anxiolytic effects in the EPM or Vogel tests, but decreases exploratory behavior in a new environment.
Asunto(s)
2-Amino-5-fosfonovalerato/análogos & derivados , Ansiedad/psicología , Núcleo Hipotalámico Dorsomedial/fisiología , Actividad Motora/fisiología , Receptores de Glutamato/fisiología , 2-Amino-5-fosfonovalerato/farmacología , 2-Amino-5-fosfonovalerato/toxicidad , Animales , Ansiedad/inducido químicamente , Núcleo Hipotalámico Dorsomedial/efectos de los fármacos , Masculino , Actividad Motora/efectos de los fármacos , Quinoxalinas/farmacología , Ratas , Ratas WistarRESUMEN
The NMDA receptor has been widely investigated in recent years as a target for the pharmacological management of seizures, pain and a variety of neurological disorders. Its role in normal central nervous system (CNS) activity and development, as well as in the development of CNS abnormalities and neurodegeneration has also been of interest. The NMDA receptor is one of three pharmacologically distinct subtypes of ionotropic receptor channels that are sensitive to the endogenous excitatory amino acid, L-glutamate. The ontogeny of the NMDA receptor, a multiple tetrameric and heteromeric channel complex with at least six known subunits, is controlled by three gene families and varies in developmental profile with species and regional brain area. NMDA receptors play a role in excitatory synaptic transmission, in the activity-dependent synaptic plasticity underlying learning and memory, and in pre- and postnatal CNS development, including brain cell differentiation, axonal growth and degeneration of unused neurons. The results of recent studies suggest that sustained alteration of NMDA receptor activation during critical periods of development may have deleterious effects on normal CNS development and function. Neonatal rats administered the NMDA receptor antagonists 2-amino-5-phosphonovalerate (AP5) and MK-801 during the first two weeks of life develop abnormal axonal arborization in the retinal connections to the superior colliculus, interfering with normal visual responses. Results from monkey studies suggest that chronic developmental exposure to high doses of a NMDA antagonist, remacemide, has pronounced and long-lasting effects on learning. Recent findings indicate that if NMDA receptors are blocked during a specific period in neonatal life (first two weeks postnatally in the rat), massive apoptotic neurodegeneration results, due not to excitotoxic overstimulation of neurons but to deprivation of stimulation. These observations require further laboratory evidence and support in order to establish their relevance to drug-induced human neurodevelopmental concerns. It is necessary to investigate the relevance of these findings in other animal species in addition to the rat, most notably, nonhuman primates, where neuronal cytoarchitecture and development are significantly different than the rodent but more like the human.
Asunto(s)
Sistema Nervioso Central/embriología , Sistema Nervioso Central/crecimiento & desarrollo , Síndromes de Neurotoxicidad/embriología , Receptores de N-Metil-D-Aspartato/metabolismo , 2-Amino-5-fosfonovalerato/toxicidad , Acetamidas/toxicidad , Animales , Animales Recién Nacidos , Apoptosis/efectos de los fármacos , Conducta Animal/efectos de los fármacos , Sistema Nervioso Central/efectos de los fármacos , Condicionamiento Operante/efectos de los fármacos , Maleato de Dizocilpina/toxicidad , Relación Dosis-Respuesta a Droga , Antagonistas de Aminoácidos Excitadores/toxicidad , Síndromes de Neurotoxicidad/etiología , Ratas , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidoresRESUMEN
PURPOSE: The NMDA (N-methyl-D-aspartate) receptor antagonists and the NMDA glycine site antagonists given alone have minimal effects on acute nociception. In contrast, the AMPA (alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) receptor antagonists have a major role in acute nociception. We investigated the interactions among these three antagonists in acute nociception. METHODS: Sprague-Dawley rats (250-300 g) were implanted with chronic lumbar intrathecal catheters and were tested for their thermal withdrawal response using the hot plate test after intrathecal administration of AP-5 (NMDA receptor antagonist), ACEA 1021 (NMDA glycine site antagonist), or ACEA 2085 (AMPA receptor antagonist). The combinations of these three agents were also tested. RESULTS: Intrathecal administration of ACEA 2085 had a dose dependent analgesic effect while intrathecal AP-5 or ACEA 1021 could not induce dose dependent effect. Co-administration of AP-5 10 microg and ACEA 2085 intrathecally showed no changes in the thermal response latency compared with ACEA 2085 alone. ACEA 1021, 12 microg, and AP-5 showed left-ward shift of the dose effect curve only with small doses of AP-5 (1 microg, 3 microg). Only the smallest dose of ACEA 2085 (0.1 ng) with ACEA 1021 12 microg induced antinociception compared with that of ACEA 2085 alone. CONCLUSIONS: The combination of the NMDA glycine site antagonist and low doses of the NMDA receptor antagonist or the AMPA receptor antagonist increased the analgesic effect on acute thermal nociception with increased side effects, while the NMDA receptor antagonist and the AMPA receptor antagonist had no such interaction.
Asunto(s)
2-Amino-5-fosfonovalerato/análogos & derivados , Antagonistas de Aminoácidos Excitadores/farmacología , Nociceptores/efectos de los fármacos , Receptores AMPA/antagonistas & inhibidores , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Médula Espinal/efectos de los fármacos , 2-Amino-5-fosfonovalerato/farmacología , 2-Amino-5-fosfonovalerato/toxicidad , Analgesia , Animales , Conducta Animal/efectos de los fármacos , Sitios de Unión , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Antagonistas de Aminoácidos Excitadores/toxicidad , Glicina/metabolismo , Inyecciones Espinales , Actividad Motora/efectos de los fármacos , Dimensión del Dolor/efectos de los fármacos , Quinoxalinas/farmacología , Quinoxalinas/toxicidad , Ratas , Médula Espinal/fisiologíaRESUMEN
While the principal components of the brain reward system, the nucleus accumbens septi and the ventral tegmental area have received much attention, their efferent and afferent structures have not been investigated to the same degree. One major input to this system originates from the medial prefrontal cortex (mPFC) which is not a homogenous structure but can be divided into different subareas that can be distinguished on anatomical and possibly functional grounds. We examined the effects of discrete bilateral quinolinic acid lesions (45 nmol/0.5 micro(L)) of each of the mPFC subareas, the infralimbic (il), prelimbic (pl) and the anterior cingulate (cg) mPFC, on the conditioned place preference (CPP) and psychomotor activation induced by several drugs. Lesions of the il mPFC blocked CPP induced by morphine (10 mg/kg) and CGP37849 [DL-(E)-2-amino-4-methyl-5-phosphono-3-pentic acid, a competitive N-methyl-D-aspartate receptor antagonist; 10 mg/kg]. Lesions of the pl mPFC blocked CPP induced by cocaine (15 mg/kg) and CGP37849, and lesions of the cg mPFC only blocked CGP37849-induced CPP. Lesions of the whole mPFC blocked morphine-, cocaine- and CGP37849-induced CPP. None of the lesions affected DL-amphetamine (4 mg/kg)-induced CPP. During the conditioning period, none of the lesions affected amphetamine-induced psychomotor activation and sensitization, whereas both phenomena were attenuated by pl and whole mPFC lesions in the case of cocaine, and by il and whole mPFC lesions in the case of morphine. These results show that the different mPFC subregions have distinct functional roles in the generation of behavioural effects produced by different classes of drugs. This heterogeneity should be taken into account in future studies addressing the role of the mPFC in drug reward and sensitization.
Asunto(s)
2-Amino-5-fosfonovalerato/análogos & derivados , Anfetamina/farmacología , Conducta de Elección/fisiología , Condicionamiento Operante/fisiología , Morfina/farmacología , Corteza Prefrontal/fisiología , Ácido Quinolínico/toxicidad , 2-Amino-5-fosfonovalerato/toxicidad , Animales , Conducta de Elección/efectos de los fármacos , Cocaína/farmacología , Condicionamiento Operante/efectos de los fármacos , Antagonistas de Aminoácidos Excitadores/toxicidad , Lateralidad Funcional , Masculino , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Corteza Prefrontal/efectos de los fármacos , Desempeño Psicomotor/efectos de los fármacos , Desempeño Psicomotor/fisiología , Ratas , Ratas Sprague-Dawley , Recompensa , Conducta Estereotipada/efectos de los fármacos , Conducta Estereotipada/fisiología , Factores de TiempoRESUMEN
Sustained (20 h) exposure to the glycine partial agonist 1-aminocyclopropanecarboxylic acid (ACPC) significantly reduced N-methyl-D-aspartate (NMDA)-induced neurotoxicity in cultured spinal cord neurons when the NMDA (25 and 100 microM) was added to the cultures 30 min after removal of the ACPC (1 mM). In contrast, ACPC preexposure failed to protect against kainate-induced neuronal injury. The magnitude of neuronal protection against NMDA (100 microM) was further enhanced if the neurons pretreated with ACPC were reexposed to this drug during the NMDA challenge. In addition, the potencies of both the competitive NMDA antagonist AP5 and the noncompetitive antagonist dizocilpine to block NMDA toxicity were significantly increased following ACPC preexposure, while the potency of the competitive glycine receptor antagonist 7-chlorokynurenate (7-CK) was unchanged. Analysis of Northern blots suggest that ACPC-induced changes in NMDA receptor function were not associated with alterations in the levels of the mRNAs encoding the NMDAR-1, -2A, -2B, or -2C subunits. These results indicate that sustained exposure to ACPC modifies NMDA receptors in a manner that diminishes NMDA receptor-mediated neurotoxicity while selectively enhancing the potencies of several NMDA receptor antagonists. These effects do not appear to be related to changes in expression of specific NMDA receptor subunits, and may instead involve a post-translational modification of one or more subunit proteins.
Asunto(s)
Cicloleucina/farmacología , Agonistas de Aminoácidos Excitadores/toxicidad , N-Metilaspartato/toxicidad , Neuronas/efectos de los fármacos , Receptores de N-Metil-D-Aspartato/efectos de los fármacos , Médula Espinal/efectos de los fármacos , 2-Amino-5-fosfonovalerato/toxicidad , Animales , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Maleato de Dizocilpina/farmacología , Embrión de Mamíferos/efectos de los fármacos , Expresión Génica/efectos de los fármacos , N-Metilaspartato/antagonistas & inhibidores , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores de N-Metil-D-Aspartato/agonistas , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Receptores de N-Metil-D-Aspartato/genéticaRESUMEN
In the adult mammalian cochlea, the ability of nerve fibres to regenerate has been observed following disruption of the organ of Corti by various means, or transsection of the cochlear nerve in the internal auditory meatus. Based upon the implication of glutamate as a neurotransmitter at synapses between sensory hair cells and terminal dendrites of the auditory nerve in the mammalian cochlea, we have developed, in a previous study, an in vivo model of neural regeneration and formation of synapses after the destruction of the afferent nerve endings by local application of the glutamate agonist alpha-amino-3-hydroxy-5-methyl-isoxazol-propionic acid (AMPA). In situ hybridization experiments performed during the re-innervation process revealed an overexpression of mRNA coding for NR1 subunit of N-methyl-D-aspartate (NMDA) receptors in the spiral ganglion neurons, suggesting that these receptors are implicated in neural regenerative processes. The present study has been designed to study the functional implication of NMDA receptors in the regrowth and synaptic repair of auditory dendrites in the guinea pig cochlea, by blocking the NMDA receptors during the period of normal functional recovery. In a first set of experiments, we recorded compound action potential after acute perilymphatic perfusion of cumulative doses (0.03-10mM) of DL 2-amino-5-phosphonovalerate (D-AP5), a NMDA antagonist, to determine the efficiency of the drug. In a second set of experiments, the auditory dendrites were destroyed by local application of the glutamate agonist AMPA. The blockage of NMDA by the antagonist D-AP5 applied with an osmotic micropump delayed the functional recovery and the regrowth of auditory dendrites. The findings of our study support the hypothesis that, in addition to acting as a fast transmitter, glutamate has a neurotrophic role via the activation of NMDA receptors.
Asunto(s)
Cóclea/patología , Aminoácidos Excitadores/toxicidad , Regeneración Nerviosa/fisiología , Receptores de N-Metil-D-Aspartato/fisiología , Sinapsis/fisiología , 2-Amino-5-fosfonovalerato/toxicidad , Potenciales de Acción/efectos de los fármacos , Potenciales de Acción/fisiología , Animales , Cóclea/metabolismo , Electrofisiología , Agonistas de Aminoácidos Excitadores/toxicidad , Antagonistas de Aminoácidos Excitadores/toxicidad , Femenino , Cobayas , Hibridación in Situ , Masculino , Microscopía Electrónica , Perfusión , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiónico/toxicidadRESUMEN
We have compared the effects of parallel fiber stimuli on extracellularly recorded neurons showing regular or bursting spontaneous activity patterns in the dorsal cochlear nucleus of rat brainstem slices. Ninety percent of regular neurons failed to respond to stimulus currents (1.4 +/- 0.28 mA, mean +/- SEM) significantly greater than those (0.4 +/- 0.07 mA) that elicited responses from 96% of bursting neurons. Responses of bursting neurons were elicited from widely separated loci along the molecular layer. Kynurenic acid and CNQX or DNQX blocked both spontaneous firing and responses to parallel fiber stimuli of bursting neurons. The same agents also blocked responses of regular neurons but had little or no effect on their spontaneous firing rates. AP-5 caused small decreases in spontaneous rates of both bursting and regular neurons but did not appear to affect responses to stimuli. The data support the hypothesis that the responses of both regular and bursting neurons to parallel fiber stimulation are mediated by glutamate, acting mainly through non-NMDA receptors. Spontaneous activity of bursting, but not regular, neurons also requires non-NMDA glutamatergic transmission, suggesting that the spontaneous firing of bursting neurons, consisting largely of cartwheel cells, may depend upon granule cell activity.
Asunto(s)
Cóclea/inervación , Núcleo Coclear/fisiología , Fibras Nerviosas/fisiología , 2-Amino-5-fosfonovalerato/toxicidad , 6-Ciano 7-nitroquinoxalina 2,3-diona/toxicidad , Animales , Tronco Encefálico/fisiología , Cóclea/efectos de los fármacos , Núcleo Coclear/efectos de los fármacos , Estimulación Eléctrica , Antagonistas de Aminoácidos Excitadores/toxicidad , Femenino , Ácido Quinurénico/toxicidad , Masculino , Fibras Nerviosas/efectos de los fármacos , Quinoxalinas/toxicidad , Ratas , Ratas Sprague-DawleyRESUMEN
The cerebroprotective properties of the competitive N-methyl-D-aspartate (NMDA) antagonist CGP 40116 were evaluated in a rat model of excitotoxicity-induced brain damage using direct intrastriatal injection of quinolinic acid and subsequent (5 or 45 min later) i.p. administration of the drug. Diffusion-weighted magnetic resonance imaging (DWI) was used to follow the temporal lesion growth during the acute phase (4 h) and T2-weighted MRI (T2WI) to quantify vasogenic edema extent 2 days later. For control animals, we found a rapid increase in lesion volume during the first hour followed by a moderate growth over the following hours. The DWI-visible hyperintensity was partially reversible after treatment with CGP 40116. The onset of action of CGP 40116 was immediate. The final outcome (63% reduction of lesion volume within 2-4 h post-surgery) was independent of the time of drug administration. DWI data after 4 h correlated well with those obtained by T2WI 2 days later. DWI is a valuable method for early prediction of the outcome of therapeutic interventions of excitotoxic insults.
Asunto(s)
2-Amino-5-fosfonovalerato/análogos & derivados , Química Encefálica/efectos de los fármacos , Antagonistas de Aminoácidos Excitadores/toxicidad , Neurotoxinas/toxicidad , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , 2-Amino-5-fosfonovalerato/toxicidad , Animales , Edema/fisiopatología , Estudios Longitudinales , Imagen por Resonancia Magnética , Masculino , Ácido Quinolínico/farmacología , Ratas , Ratas Endogámicas , Lóbulo Temporal/fisiopatología , Factores de TiempoRESUMEN
CGP 37849 (1 mg/kg i.p.) enhanced the protective action of carbamazepine, diphenylhydantoin and phenobarbital against maximal electroshock-induced convulsions in mice. At 0.25 mg/kg CGP 37849 was inactive and at 0.5 mg/kg it potentiated the anticonvulsive activity of phenobarbital. CGP 39551 (5 mg/kg i.p.) reduced the ED50 values of diphenylhydantoin and phenobarbital, being without influence on carbamazepine. In the dose of 1.25 mg/kg, CGP 39551 potentiated the antielectroshock action of diphenylhydantoin and at 2.5 mg/kg that of phenobarbital. Neither NMDA receptor antagonist elevated the total plasma levels of antiepileptic drugs. Consequently, a pharmacokinetic interaction (in terms of total plasma levels at least) seems unlikely to be responsible for the observed potentiation of the antiepileptic drugs' activity. Combinations of CGP 37849 with either carbamazepine or phenobarbital resulted in a motor and memory impairment quantified by the chimney test and passive avoidance task, respectively. Moreover, combined treatment with phenobarbital and CGP 39551 caused a memory deficit. In contrast, diphenylhydantoin combined with either CGP 37849 or 39551 was devoid of adverse effects. It may be concluded that NMDA receptor blockade results in enhanced anticonvulsive action of common antiepileptics against maximal electroshock-induced seizures.
Asunto(s)
2-Amino-5-fosfonovalerato/análogos & derivados , Anticonvulsivantes/farmacología , Conducta Animal/efectos de los fármacos , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Convulsiones/tratamiento farmacológico , 2-Amino-5-fosfonovalerato/farmacología , 2-Amino-5-fosfonovalerato/uso terapéutico , 2-Amino-5-fosfonovalerato/toxicidad , Animales , Anticonvulsivantes/toxicidad , Reacción de Prevención/efectos de los fármacos , Carbamazepina/farmacología , Carbamazepina/uso terapéutico , Sinergismo Farmacológico , Electrochoque , Masculino , Memoria/efectos de los fármacos , Ratones , Actividad Motora/efectos de los fármacos , Fenobarbital/farmacología , Fenobarbital/uso terapéutico , Fenitoína/farmacología , Fenitoína/uso terapéuticoRESUMEN
In this report, a novel bioisostere of the alpha-amino acid, 3,4-diamino-3-cyclobutene-1,2-dione, has been incorporated into a series of compounds which are NMDA antagonists. These compounds, which are achiral and easily prepared, demonstrated good affinity at the NMDA receptor by their ability to displace [3H]CPP binding in vitro. In particular, the phosphonic acid 24 provided protection against NMDA-induced lethality in mice equivalent to 2-amino-7-phosphonoheptanoic acid (5). This was considered an encouraging result in lieu of the fact that 24, like 5, lacks the conformational rigidity of the more potent NMDA antagonists. In addition, analogs that incorporate the 1,2,4-oxadiazolidine-3,5-dione heterocycle of quisqualic acid and the unsaturation of kainic acid were prepared to explore selectivity at the non-NMDA receptor subtypes.
Asunto(s)
2-Amino-5-fosfonovalerato/análogos & derivados , Ácidos Carboxílicos/síntesis química , N-Metilaspartato/antagonistas & inhibidores , 2-Amino-5-fosfonovalerato/química , 2-Amino-5-fosfonovalerato/toxicidad , Animales , Sitios de Unión/efectos de los fármacos , Ácidos Carboxílicos/química , Ácidos Carboxílicos/toxicidad , Masculino , Ratones , Receptores de Glutamato/efectos de los fármacos , Receptores de Glutamato/metabolismo , Receptores de Ácido Kaínico , Receptores de N-Metil-D-Aspartato/efectos de los fármacos , Receptores de N-Metil-D-Aspartato/metabolismo , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
The anticonvulsant and behavioural actions of CGP 37849 and CGP 39551, two novel competitive NMDA receptor antagonists, were examined in fully amygdala kindled rats following systemic administration. Only weak anticonvulsant effects were observed following either i.p. or i.v. injection of the antagonists. Moreover, behavioural abnormalities (ataxia, hyperactivity, muscular hypotonia) were apparent at all anticonvulsant doses. These results suggest that CGP 37849 and CGP 39551 may be of limited therapeutic usefulness against complex partial seizures in man, the seizure type showing greatest refractoriness to presently available medication.
Asunto(s)
2-Amino-5-fosfonovalerato/análogos & derivados , Excitación Neurológica/efectos de los fármacos , Convulsiones/tratamiento farmacológico , 2-Amino-5-fosfonovalerato/administración & dosificación , 2-Amino-5-fosfonovalerato/farmacología , 2-Amino-5-fosfonovalerato/toxicidad , Animales , Anticonvulsivantes/farmacología , Inyecciones Intraperitoneales , Inyecciones Intravenosas , Masculino , Actividad Motora/efectos de los fármacos , Ratas , Ratas Endogámicas , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Convulsiones/etiologíaRESUMEN
Supernatants (SN) of brain macrophages in culture induce death of cerebellar granule cells in vitro, while those of astrocytes and endothelial cells do not. This toxicity can be prevented by N-methyl-D-aspartate (NMDA) receptor antagonists. Macrophage SN contain high concentrations of glutamate. Reducing the glutamate level of macrophage SN, either by exposure to astrocytes or by enzymatic degradation abolished the toxic effect. Thus, macrophage neurotoxicity is mediated by glutamate acting on NMDA receptors, and might play a role in vivo in traumatic and cerebrovascular brain lesions.
Asunto(s)
Encéfalo/fisiología , Glutamatos/metabolismo , Macrófagos/fisiología , Neuroglía/fisiología , Neuronas/citología , Neurotoxinas/metabolismo , Receptores de N-Metil-D-Aspartato/fisiología , 2-Amino-5-fosfonovalerato/toxicidad , 6-Ciano 7-nitroquinoxalina 2,3-diona , Animales , Animales Recién Nacidos , Astrocitos/fisiología , Encéfalo/citología , Células Cultivadas , Maleato de Dizocilpina/toxicidad , Ácido Glutámico , Ratones , Ratones Endogámicos ICR , Neuronas/efectos de los fármacos , Neurotoxinas/toxicidad , Quinoxalinas/toxicidadRESUMEN
The neurodegenerative action of the excitatory amino acid neurotransmitter (glutamate) and its exogenous (N-methyl-D-aspartate, kainate) or endogenous (quinolinate) analogues were studied on cultures of dissociated nerve cells from the embryonal mouse hippocampus. The exposure of primary cultures for 3-6 h to these excitotoxins showed that neurons were vulnerable to both glutamate and all tested agonists which induced the swelling and vacuolization of neuronal bodies accompanied by degeneration of their dendrites. This process terminated by complete cell destruction. The neurotoxic effect of glutamate (1 mM) was not suppressed by a competitive NMDA receptor antagonist (D, L-2-amino-5-phosphonovalerate, 0.3 mM) and was only slightly prevented by gamma-D-glutamylglycine (3mM). The protective action of the latter was more evident in the presence of lower glutamate concentration (0.5 mM). The excitotoxic effect of N-methyl-D-aspartate (0.1 mM) or quinolinate (0.5mM) was almost completely blocked by both antagonists. In contrast, D, L-2-amino-5-phosphonovalerate failed to protect hippocampal neurons from damage induced by kainate while partial antagonism of kainate neurotoxicity was observed with gamma-D-glutamylglycine. These finding suggest that glutamate neurotoxicity may be derived, mainly, from the non-NMDA type(s) of glutamate receptor present on hippocampal cell membranes with a low effectiveness to suppress this effect by selective competitive NMDA antagonist. Possible involvement of glutamate receptor(s) in the early dendritic outgrowth of hippocampal neurons and in the process of neuronal "cell death" is discussed.