RESUMO
Impaired spatial learning is a prominent deficit in fragile X syndrome (FXS). Previous studies using the Fmr1 knockout (KO) mouse model of FXS have not consistently reported a deficit in spatial learning. Fmr1 KO mice bred onto an albino C57BL/6J-Tyr(c-Brd) background showed significant deficits in several primary measures of performance during place navigation and probe trials in the Morris water maze. Fmr1 KO mice were also impaired during a serial reversal version of the water maze task. We examined fear conditioning as an additional cognitive screen. Knockout mice exhibited contextual memory deficits when trained with unsignaled shocks; however, deficits were not found in a separate group of KO mice trained with signaled shocks. No potentially confounding genotypic differences in locomotor activity were observed. A decreased anxiety-like profile was apparent in the open field, as others have noted, and also in the platform test. Also as previously reported, startle reactivity to loud auditory stimuli was decreased, prepulse inhibition and social interaction increased in KO mice. Female Fmr1 KO mice were tested along with male KO mice in all assays, except for social interaction. The female and male KO exhibited very similar impairments indicating that sex does not generally drive the behavioral symptoms of the disorder. Our results suggest that procedural factors, such as the use of albino mice, may help to reliably detect spatial learning and memory impairments in both sexes of Fmr1 KO mice, making it more useful for understanding FXS and a platform for evaluating potential therapeutics.
Assuntos
Proteína do X Frágil da Deficiência Intelectual/genética , Síndrome do Cromossomo X Frágil/genética , Aprendizagem em Labirinto , Memória , Estimulação Acústica , Albinismo/genética , Animais , Ansiedade , Comportamento Animal , Condicionamento Psicológico , Modelos Animais de Doenças , Medo , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Atividade Motora , Fenótipo , Reflexo de SobressaltoRESUMO
Mice in which netrin-G2 has been genetically inhibited do not startle to an acoustic stimulus, but otherwise perform normally through a behavioral test battery. Light microscopic examination of the inner ear showed no obvious structural abnormalities. Brainstem responses to acoustic stimuli (auditory brainstem responses, ABR) were also present, confirming the lack of any overarching defects in the inner ear or auditory nerve. Genetic inhibition of netrin-G2 ligand produced a nearly identical phenotype, that is, no startle with ABR present, and otherwise normal. This similarity confirms that these two proteins act in the same biological pathway. We have also determined that the affinity between the two proteins is strong, around 2.5 nM, similar to that observed between netrin-G1 and netrin-G1 ligand - 2.3 nM in our hands. The combination of equivalent phenotypes when genetically inhibited coupled with evidence of a strong biochemical interaction supports the notion of a receptor-ligand interaction between these two proteins in vivo. This interaction is critical for auditory synaptic responsiveness in the brain.
Assuntos
Vias Auditivas/fisiopatologia , Proteínas do Tecido Nervoso/genética , Reflexo Anormal/genética , Reflexo de Sobressalto/genética , Estimulação Acústica , Animais , Audiometria , Vias Auditivas/crescimento & desenvolvimento , Comportamento Animal , Tronco Encefálico/crescimento & desenvolvimento , Tronco Encefálico/fisiopatologia , Potenciais Evocados Auditivos do Tronco Encefálico , Feminino , Regulação da Expressão Gênica no Desenvolvimento/genética , Ligantes , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Netrinas , Fenótipo , Ligação Proteica/genéticaRESUMO
The 5-hydroxytryptamine transporter (5-HTT) regulates 5-hydroxytryptamine (5-HT) neurotransmission by removing 5-HT from the synaptic cleft. Emerging evidence from clinical and genetic studies implicates the 5-HTT in various neuropsychiatric conditions, including anxiety and depression. Here we report that a 5-HTT null mutant mouse line was generated by gene trapping that disrupted the sequence encoding the C-terminus of 5-HTT. This mutation resulted in significant reduction of 5-HTT mRNA and loss of 5-HTT protein. Brain levels of 5-HT and its major metabolite, 5-hydroxyindoleacetic acid, were markedly decreased in C-terminus 5-HTT -/- mice, while 5-HT uptake or 5-HT content in platelets was absent. Behavioral phenotyping showed that C-terminus 5-HTT -/- mice were normal on a screen for gross behavioral, neurological, and sensory functions. In the tail suspension test for depression-related behavior, C-terminus 5-HTT -/- mice showed increased immobility relative to their +/+ controls. By comparison, a previously generated line of 5-HTT -/- mice lacking exon 2, encoding the N-terminus of the 5-HTT, showed abnormally high immobility in response to repeated, but not acute, exposure to the tail suspension test. In a novel, brightly-lit open field, both C-terminus 5-HTT -/- mice and N-terminus 5-HTT -/- mice displayed decreased center time and reduced locomotor activity compared with their +/+ controls. Both mutant lines buried significantly fewer marbles than their +/+ controls in the marble burying test. These findings further demonstrate the neurobiological functions of the 5-HTT and add to a growing literature linking genetic variation in 5-HTT function with emotional abnormalities.
Assuntos
Encéfalo/fisiologia , Emoções/fisiologia , Mutação , Proteínas da Membrana Plasmática de Transporte de Serotonina/deficiência , Serotonina/fisiologia , Análise de Variância , Animais , Comportamento Animal/fisiologia , Encéfalo/efeitos dos fármacos , Química Encefálica/genética , Citalopram/farmacocinética , Relação Dose-Resposta a Droga , Comportamento Exploratório/fisiologia , Elevação dos Membros Posteriores/métodos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Atividade Motora/genética , Fragmentos de Peptídeos/deficiência , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/genética , Serotonina/farmacocinética , Proteínas da Membrana Plasmática de Transporte de Serotonina/química , Inibidores Seletivos de Recaptação de Serotonina/farmacocinética , Trítio/farmacocinéticaRESUMO
BACKGROUND & AIMS: N-methyl-D-aspartate (NMDA) receptors are ligand-gated ion channels that have an important role in long-term potentiation and memory processing in the central nervous system. The aims in this study were to determine whether NMDA receptors are expressed in the peripheral nervous system and identify their role in mediating behavioral pain responses to colonic distention in the normal gut. METHODS AND RESULTS: Immunohistochemical localization of the NR1 subunit showed that NMDA receptors are expressed on the cell bodies and peripheral terminals of primary afferent nerves innervating the colon. Dorsal root ganglia neurons retrogradely labeled from the colon in short-term culture responded to addition of NMDA with increased intracellular [Ca2+]. Activation of peripheral NMDA receptors in colonic tissue sections caused Ca2+-dependent release of the proinflammatory neuropeptides, calcitonin gene-related peptide and substance P. Behavioral pain responses to noxious mechanical stimulation were inhibited in a reversible, dose-dependent manner by intravenous administration of memantine, a noncompetitive antagonist of the NMDA receptor. Single fiber recordings of decentralized pelvic nerves showed that colorectal distention responsive afferent nerve activity was inhibited by memantine. CONCLUSIONS: Peripheral NMDA receptors are important in normal visceral pain transmission, and may provide a novel mechanism for development of peripheral sensitization and visceral hyperalgesia.
Assuntos
Colo/fisiopatologia , Dor/fisiopatologia , Receptores de N-Metil-D-Aspartato/fisiologia , Sequência de Aminoácidos , Animais , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Cálcio/metabolismo , Antagonistas de Aminoácidos Excitatórios/farmacologia , Gânglios Espinais/química , Imuno-Histoquímica , Masculino , Dados de Sequência Molecular , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/análise , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Substância P/metabolismoRESUMO
Differences in the degree of trapping of initial block by N-methyl-D-aspartate (NMDA) receptor antagonists may affect their safety and, hence, suitability for clinical trials. In this comparative study, 23 compounds structurally related to the low-affinity, use-dependent NMDA receptor antagonist (S)-alpha-phenyl-2-pyridineethanamine dihydrochloride (AR-R15896AR) were examined to determine the degree of trapping block they exhibit. Compounds were tested at concentrations that produced a comparable initial 80% block of NMDA-mediated whole-cell current in rat cortical cultures. A wide range of values of trapping block was found, indicating that trapping is not an all-or-none event. Fifteen of the compounds trapped significantly more than the 54 +/- 3% of initial block trapped by AR-R15896AR. The off-rates of these compounds were slower than that of AR-R15896AR. Only 2 of the 23 compounds trapped significantly less than AR-R15896AR. AR-R15808, the piperidine analog of AR-R15896AR, appeared to trap only 8 +/- 3% of its initial block, although its fast off-rate confounded accurate quantification of trapping. AR-R26952, which, like AR-R15896AR, contains a pyridine in place of a phenyl group, trapped 40 +/- 5% of its initial block and exhibited kinetics comparable with AR-R15896AR. Structure-activity analysis suggested that the presence of two basic nitrogen atoms and decreased hydrophobicity led to decreased trapping. There was no correlation between trapping and lipophilicity as would be expected if closed-channel egress was due to escape through the lipid bilayer. However, there was a positive correlation between off-rate and degree of trapping. Models that can account for partial trapping are presented.
Assuntos
Antagonistas de Aminoácidos Excitatórios/química , Antagonistas de Aminoácidos Excitatórios/farmacologia , Neurônios/metabolismo , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Animais , Células Cultivadas , Relação Dose-Resposta a Droga , Potenciais Evocados/efeitos dos fármacos , Ativação do Canal Iônico/efeitos dos fármacos , N-Metilaspartato/farmacologia , Neurônios/citologia , Neurônios/efeitos dos fármacos , Técnicas de Patch-Clamp , Piridinas/química , Piridinas/farmacologia , Ratos , Relação Estrutura-AtividadeRESUMO
The 5-HT3 receptor antagonist tropisetron (ICS 205-930) was found to be a potent and selective partial agonist at alpha7 nicotinic receptors. Two other 5-HT3 receptor antagonists, ondansetron and LY-278,584, were found to lack high affinity at the alpha7 nicotinic receptor. Quinuclidine analogues (1 and 2) of tropisetron were also found to be potent and selective partial agonists at alpha7 nicotinic receptors.
Assuntos
Indóis/farmacologia , Agonistas Nicotínicos/farmacologia , Receptores Nicotínicos/efeitos dos fármacos , Antagonistas da Serotonina/farmacologia , Animais , Membrana Celular/química , Hipocampo/ultraestrutura , Concentração Inibidora 50 , Intestino Delgado/ultraestrutura , Ligantes , Potenciais da Membrana/efeitos dos fármacos , Camundongos , Oócitos/efeitos dos fármacos , Oócitos/fisiologia , Ligação Proteica , Ratos , Receptores Nicotínicos/metabolismo , Relação Estrutura-Atividade , Tropizetrona , Xenopus , Receptor Nicotínico de Acetilcolina alfa7RESUMO
NMDA antagonists like AR-R15896 have been selected on the basis of their good therapeutic indices. As Dr. Rogawski has pointed out, there may be a number of molecular factors which can improve the therapeutic index of NMDA antagonists. In this paper we will consider three factors; use-dependence, low affinity/fast kinetics, and partial trapping.
Assuntos
Antagonistas de Aminoácidos Excitatórios/farmacologia , Piridinas/farmacologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidoresRESUMO
Rat dorsal root ganglion neurons can be classified into at least three distinct groups based on cell size, afferent fiber diameter, electrophysiological properties, sensitivity to vanilloid agonists such as capsaicin, and function. In the present study, ATP-activated current in these neurons was characterized using whole-cell patch-clamp recording. Small diameter (<30 microm) cells had high capsaicin sensitivity, high affinity for ATP, and rapidly desensitizing ATP-activated current. Medium diameter (30-50 microm) cells had no capsaicin sensitivity, lower affinity for ATP and slowly desensitizing ATP-activated current. Large diameter (>50 microm) cells were insensitive to both capsaicin and ATP. These findings suggest that distinct types of ATP receptor-ion channels are expressed in different types of dorsal root ganglion neurons, and may contribute to the functional differences among these types of neurons.
Assuntos
Trifosfato de Adenosina/farmacologia , Gânglios Espinais/fisiologia , Neurônios/fisiologia , Trifosfato de Adenosina/análogos & derivados , Trifosfato de Adenosina/fisiologia , Animais , Capsaicina/farmacologia , Tamanho Celular , Gânglios Espinais/citologia , Técnicas In Vitro , Masculino , Potenciais da Membrana/efeitos dos fármacos , Potenciais da Membrana/fisiologia , Fibras Nervosas/ultraestrutura , Neurônios/classificação , Neurônios/citologia , Técnicas de Patch-Clamp , Ratos , Ratos Sprague-Dawley , Tionucleotídeos/farmacologiaRESUMO
This study characterizes the trapping of block of N-methyl-D-aspartic acid (NMDA)-induced currents by three structurally distinct, use-dependent NMDA receptor antagonists with similar rapid on-off rates. The antagonism of whole-cell currents in cultured rat cortical neurons by AR-R15896AR, ketamine, and memantine was examined. All three compounds produced a steady-state block after a 30-s coapplication, which was fully relieved after 50 s of NMDA exposure. The amplitudes of block caused by 50 microM AR-R15896AR, 10 microM ketamine, or 10 microM memantine were not significantly different, being 82 +/- 1%, 80 +/- 2%, and 81 +/- 2%, respectively. All three NMDA receptor antagonists exhibited trapping of block that was not significantly increased by extending the agonist/antagonist coapplication beyond 30 s. Although the initial blocks were similar, after 120 s of washout without agonist present, there were significant differences in trapping of block between antagonists, as only 54 +/- 3% of the AR-R15896AR block, 86 +/- 1% of the ketamine block, and 71 +/- 4% of the memantine block remained trapped. The lack of complete trapping is consistent with closed-channel egress by these compounds. Higher antagonist concentrations produced larger initial blocks, but the degree of trapping block was not significantly different from that at lower antagonist concentrations. The results demonstrate that differences in the degree of trapping exist among use-dependent NMDA receptor antagonists even when on and off rates are similar. These differences are correlated with measures of therapeutic index.
Assuntos
N-Metilaspartato/metabolismo , Neurônios/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Animais , Células Cultivadas , Antagonistas de Aminoácidos Excitatórios/farmacologia , Ketamina/farmacologia , Cinética , Memantina/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Neurônios/efeitos dos fármacos , Ratos , Receptores de N-Metil-D-Aspartato/antagonistas & inibidoresRESUMO
The 5-HT3 receptor (5-HT3R) is part of a superfamily of ligand-gated ion channels which includes nicotinic acetylcholine receptors (nAChR). cRNA derived from the long isoform cloned mouse 5-HT3R was used to drive expression of 5-HT3Rs in Xenopus oocytes. 5-HT-induced currents were monitored using two-electrode voltage-clamp. Eight nicotinic agonists, including ACh and nicotine, but not alpha-anatoxin, were found to antagonize 5-HT-induced currents. With the exception of 3-(2,4)-dimethoxybenzylidene-anabaseine (DMXB-anabaseine; GTS-21) this antagonism appeared to be competitive since it could be overcome by increasing concentrations of 5-HT. Potency of 5-HT3 antagonism was comparable to reported values for nAChR alpha7 activation. These results confirm the notion of families of receptors and further indicate that strong similarities can exist in some critical binding domains.
Assuntos
Agonistas Nicotínicos/farmacologia , Receptores de Serotonina/efeitos dos fármacos , Antagonistas da Serotonina/farmacologia , Acetilcolina/farmacologia , Animais , Toxinas Bacterianas/farmacologia , Compostos de Benzilideno/farmacologia , Sítios de Ligação , Ligação Competitiva , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Colina/farmacologia , Toxinas de Cianobactérias , DNA Complementar/genética , Iodeto de Dimetilfenilpiperazina/farmacologia , Feminino , Toxinas Marinhas/farmacologia , Camundongos , Microcistinas , Família Multigênica , Nicotina/farmacologia , Oócitos , Técnicas de Patch-Clamp , Piridinas/farmacologia , Receptores Nicotínicos/química , Receptores de Serotonina/química , Receptores de Serotonina/genética , Receptores 5-HT3 de Serotonina , Proteínas Recombinantes de Fusão/antagonistas & inibidores , Relação Estrutura-Atividade , Xenopus laevisRESUMO
The purpose of this study was to characterize the kinetics and voltage-dependence of the block of N-methyl-D-aspartate (NMDA)-induced currents in primary cultures of rat cortical neurons by the neuroprotective, low-affinity, NMDA antagonist ARL 15896AR, using whole-cell voltage-clamp techniques. ARL 15896AR caused rapid and reversible inhibition of NMDA (50 microM)-evoked currents from neurons held at -60 mV, with an IC50 of 9.8 microM. The EC50 for NMDA was not significantly affected by 10 microM ARL 15896AR (P > .05), consistent with a noncompetitive mechanism of block. ARL 15896AR antagonism was use-dependent, because application of the drug 60 sec before NMDA did not attenuate the initial NMDA-evoked current, although the block developed rapidly thereafter. Once bound, ARL 15896AR remained trapped upon removal of NMDA until subsequent NMDA re-exposure, whereupon currents recovered rapidly. The forward and reverse binding rate constants were estimated to be 2.406 x 10(4) M(-1) sec(-1) and 0.722 sec(-1), respectively. Antagonism was strongly voltage-dependent; the K(D) values at 0 and -60 mV were 60 and 11 microM, respectively. Additionally, there was a component of the block by ARL 15896AR that was voltage-insensitive. This component of the block did not act at the ligand binding site, because it was not influenced by NMDA concentration, or at the polyamine site, because it was not affected by spermine. However, there was an interaction of ARL 15896AR with the glycine regulatory site. In contrast to many uncompetitive NMDA antagonists, like MK-801, ARL 15896AR exhibited rapid kinetics. This property may result in a large margin of safety while maintaining the efficacy associated with use-dependent NMDA antagonists, making this compound an excellent candidate for clinical trials.
Assuntos
Córtex Cerebral/efeitos dos fármacos , Antagonistas de Aminoácidos Excitatórios/farmacologia , Piridinas/farmacologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Animais , Células Cultivadas , Córtex Cerebral/fisiologia , Relação Dose-Resposta a Droga , Feminino , Gravidez , Ratos , Ratos Sprague-DawleyRESUMO
NMDA receptor antagonists reduced NMDA-triggered increases in [Ca2+]i measured by fura-2 and showed qualitative differences in the potency and kinetics of block. High potency antagonists produced a slow block which allowed an initial increase in [Ca2+]i that was greater than the steady-state level, while compounds with moderate to low potency produced a rapid block that was at steady-state from the first measurement. The more potent antagonists showed the slowest unblocking rates. Using this simple method, novel NMDA antagonists can be screened to ascertain potency, kinetics of block and relative toxicity, prior to animal testing.
Assuntos
Quelantes , Antagonistas de Aminoácidos Excitatórios/farmacologia , Fura-2 , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Animais , Cálcio/metabolismo , Células Cultivadas , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Indicadores e Reagentes , Cinética , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , RatosRESUMO
The anticonvulsant phenytoin has been reported to block anoxia-induced losses of synaptic activity in the rat hippocampal slice and experimental ischemia-induced losses of synaptic activity in the guinea pig hippocampal slice. We examined phenytoin in our rat hippocampal slice model of experimental ischemia (anoxia +2 mM D-glucose). In this model, ischemic depolarization (ID) occurs 4-5 min after the introduction of anoxic medium, and oxygen and D-glucose are restored 1 min after the onset of ID. In control slices, synaptic recovery is never observed following ID in 2 mM D-glucose. Phenytoin (30,100 and 300 microM), perfused for 20 min prior to, and for 10 min following anoxia, did not allow for synaptic recovery following ID. At the higher concentrations, however, it did increase the latency to ID. In addition, the presynaptic volley (PV), which normally disappears at the time of ID, was lost substantially earlier in the presence of phenytoin. These findings suggest that the anti-ischemic effects of phenytoin reported by others are due to delay of ID. This may suggest that phenytoin will be effective in preventing global ischemia-induced damage only when the ischemic insult is of short duration.
Assuntos
Isquemia Encefálica , Hipocampo/efeitos dos fármacos , Fenitoína/farmacologia , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Glucose/metabolismo , Hipóxia , Masculino , Potenciais da Membrana/efeitos dos fármacos , Ratos , Ratos Sprague-DawleyRESUMO
Hippocampal slices maintained in an oxygen-rich static interface chamber remained viable, as determined by the mitochondrial marker 2,3,5-triphenyltetrazolium chloride (TTC), for over 20 h in vitro. By contrast, slices exposed, after 1 h in vitro, to an anoxic environment for 25 min and then allowed to recover for 1-18 h, showed an initial slight decrease in TTC staining followed by a dramatic decrease at time points greater than 6.5 h after anoxia. These data are suggestive of delayed neuronal death. Furthermore, the decreases in TTC staining induced by anoxia could be prevented by conditions known to prevent cell death either in vitro or in vivo. For example, pretreatment of the slices with the N-methyl-D-aspartate antagonist 3-((RS)-2-carboxy-piperazin-4-yl)-propyl-1- phosphonic acid dose-dependently prevented the loss of TTC staining induced by 25 min anoxia. In addition, high-intensity TTC staining correlated with normal CA1 synaptic activity, even after more than 20 h in vitro, suggesting that TTC staining reflects functional neuronal activity. These data suggest that the use of TTC staining of in vitro hippocampal slices may represent a novel and convenient screen for anti-ischemic compounds.
Assuntos
Hipocampo/metabolismo , Hipóxia Encefálica/metabolismo , Coloração e Rotulagem , Sais de Tetrazólio , Animais , Câmaras de Exposição Atmosférica , Eletrofisiologia , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Hipóxia Encefálica/patologia , Hipóxia Encefálica/fisiopatologia , Técnicas In Vitro , Masculino , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/antagonistas & inibidoresRESUMO
The present study utilized in vitro gerbil and rat hippocampal slices to compare responses to experimental ischemia without species differences in the cerebrovasculature as a variable. Ischemic depolarization occurred faster in the gerbil (2.53 +/- 0.05 min) than in the rat (4.59 +/- 1.1 min). These results indicate that the gerbil's greater propensity to neuronal damage following short ischemic periods may be due to greater sensitivity of the gerbil brain itself.
Assuntos
Isquemia Encefálica/fisiopatologia , Hipocampo/fisiopatologia , Neurônios/fisiologia , Animais , Isquemia Encefálica/patologia , Gerbillinae , Hipocampo/patologia , Hipóxia Encefálica/fisiopatologia , Técnicas In Vitro , Masculino , Potenciais da Membrana , RatosRESUMO
The memory-enhancing potential of D-cycloserine (cycloserine) a partial agonist at the glycine recognition site on the NMDA receptor, was evaluated in mice using a thirst-motivated linear maze learning task. Immediate acute post-training injections (10, 20 and 80 mg/kg) significantly improved retention relative to vehicle-injected controls. Retention was also facilitated if cycloserine (3 and 10 mg/kg but not 20 or 40 mg/kg) was administered 20 min before the retention test. Acquisition of the habit was accelerated if cycloserine (3 mg/kg) was injected 20 min before the training session. Acute post-training injections failed to facilitate retention if mice were pretreated with cycloserine (3 mg/kg) b.i.d. for 15 days before training on the maze. These results indicate that acute cycloserine administration can enhance consolidation and retrieval of memory but that desensitization may occur with chronic exposure to the drug.
Assuntos
Ciclosserina/farmacologia , Aprendizagem/efeitos dos fármacos , Memória/efeitos dos fármacos , Receptores de Glicina/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Análise de Variância , Animais , Comportamento Animal/efeitos dos fármacos , Ciclosserina/administração & dosagem , Esquema de Medicação , Masculino , Camundongos , Receptores de Glicina/efeitos dos fármacosRESUMO
D-cycloserine, a partial agonist of the NMDA receptor-associated glycine site, can enhance cognition. The present experiment examines the behavioral effects of D-cycloserine on cognitive deficits in male Fischer-344 rats, 24 months old. Rats 24 months old (n = 42) received either vehicle or one of 3 doses of D-cycloserine prior to testing. Young rats, 4 months old (n = 13), received vehicle prior to testing. Place discrimination and repeated acquisition were tested in the water maze and a variety of sensorimotor tasks were given. Aging impaired performance in all tasks. D-cycloserine improved performance in place discrimination and repeated acquisition. No doses affected sensorimotor function. These results support the hypothesis that D-cycloserine has cognition enhancing properties and that it may be useful in treating disorders involving cognitive impairment.
Assuntos
Envelhecimento/psicologia , Cognição/efeitos dos fármacos , Ciclosserina/farmacologia , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Percepção Espacial/efeitos dos fármacos , Animais , Aprendizagem por Discriminação/efeitos dos fármacos , Masculino , Desempenho Psicomotor/efeitos dos fármacos , Ratos , Ratos Endogâmicos F344RESUMO
The Mongolian gerbil displays spontaneous seizures and is used as a model for global ischemia. This study investigated the electrophysiological events associated with 0-Mg(2+)-induced seizures in gerbil hippocampal slices. In the rat hippocampal slice, 0-Mg2+ medium leads to rapid extracellular epileptic depolarization (ED) accompanied by long-term synaptic failure. Both evoked and spontaneous epileptiform activity was observed in the gerbil hippocampal slice after the introduction of the 0-Mg2+ aCSF. However, unlike the rat, ED was rarely observed in the gerbil hippocampal slice (2/17). When ED occurred, synaptic responses recovered (75%) within 20 min. This resistance to epileptic depolarization did not generalize to experimental ischemia-induced depolarization. Anoxia in 2 mM D-glucose produced anoxic depolarization in all gerbil hippocampal slices tested (6/6).
Assuntos
Epilepsia/fisiopatologia , Hipocampo/fisiologia , Magnésio/toxicidade , Animais , Hipóxia Celular , Potenciais Evocados/efeitos dos fármacos , Gerbillinae , Glucose/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/fisiopatologia , Técnicas In Vitro , Masculino , Potenciais da Membrana/efeitos dos fármacos , Potenciais da Membrana/fisiologia , Ratos , Convulsões/induzido quimicamente , Convulsões/fisiopatologia , Fatores de TempoRESUMO
D-Cycloserine can enhance activation of the NMDA receptor complex and could enhance the induction of long-term potentiation (LTP). In animals and humans, D-cycloserine can enhance performance in learning and memory tasks. This enhancing effect can disappear during repeated administration. The enhancing effects are also lost when higher doses are used, and replaced by behavioral and biochemical effects like those produced by NMDA antagonists. It has been reported that NMDA agonists, applied before or after tetanic stimulation, can block the induction of LTP. This may be the result of feedback inhibition of second messenger pathways stimulated by receptor activation. This may explain the antagonist-like effects of glycine partial agonists like D-cycloserine. In clinical trials of D-cycloserine in age-associated memory impairment (AAMI) and Alzheimer's disease, chronic treatment provided few positive effects on learning and memory. This may be due to inhibition of second messenger pathways following chronic stimulation of the receptor complex.