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PubMed2005

Sex differences in hippocampal estradiol-induced N-methyl-D-aspartic acid binding and ultrastructural localization of estrogen receptor-alpha.

Estradiol increases dendritic spine density and synaptogenesis in the CA1 region of the female hippocampus. This effect is specific to females, as estradiol-treated males fail to show increases in hippocampal spine density. Estradiol-induced spinogenesis in the female is dependent upon upregulation of the N-methyl-D-aspartic acid (NMDA) receptor as well as on non-nuclear estrogen receptors (ER), including those found in dendrites. Thus, in the male, the inability of estradiol to induce spinogenesis may be related to a failure of estradiol to increase hippocampal NMDA receptors as well as a paucity of dendritic ER. In the first experiment, we sought to investigate this possibility by assessing NMDA receptor binding, using [(3)H]-glutamate autoradiography, in estradiol-treated males and females. We found that while estradiol increases NMDA binding in gonadectomized females, estradiol fails to modulate NMDA binding in gonadectomized males. To further investigate sex differences in the hippocampus, we conducted a second separate, but related, ultrastructural study in which we quantified ERalpha-immunoreactivity (ERalpha-ir) in neuronal profiles in the CA1 region of the hippocampus in intact males and females in diestrus and proestrus. Consistent with previous reports in the female, we found ERalpha-ir in several extranuclear sites including dendrites, spines, terminals and axons. Statistical analyses revealed that females in proestrus had a 114.3% increase in ERalpha-labeled dendritic spines compared to females in diestrus and intact males. Taken together, these studies suggest that both the ability of estrogen to increase NMDA binding in the hippocampus and the presence of ERalpha in dendritic spines may contribute to the observed sex difference in estradiol-induced hippocampal spinogenesis.

Animals↗
PubMed2002

Participation of nitric oxide and N-methyl-D-aspartic acid receptors in the pressor response to intrathecal injected noradrenaline at the spinal cord of the rat.

In pentobarbital-anesthetized rats, intrathecal injection of noradrenaline (NA; 6, 18 and 60 nmol) induced a dose-dependent increase in the mean blood pressure. The pressor response to NA (18 nmol) was blocked by pretreatment with the selective antagonist for N-methyl-D-aspartic acid (NMDA) receptors, 2-amino-5-phosphonovaleric acid (30 nmol), but not by pretreatment with the selective antagonist for (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid/kainate receptors, 6,7-dinitroquinoxaline-2,3-dione (50 nmol). The pressor effect of NA was reduced after pretreatment with N(G)-nitro-L-arginine methyl ester (L-NAME, 1 micromol). The effect of L-NAME on the pressor response to NA was reverted by the precursor of nitric oxide (NO), L-arginine (5 micromol). The hypertension induced by NA was also reduced by the guanylate cyclase inhibitor methylene blue (0.3 micromol). These results suggest that spinal NMDA receptors and spinal NO are involved in the pressor response to NA.

Animals↗
PubMed1997

Comparison of the effects of N-methyl-DL-aspartic acid on gonadotropin and prolactin secretion in anestrous mares and mares exhibiting estrous cycles during anestrus.

This study investigated the hypothesis that for a subpopulation of horse mares continuation of estrous cycles during the nonbreeding season may be attributed to continued stimulatory glutamatergic activity on GnRH-secreting neurons. The gonadotropin response to the glutamatergic agonist N-methyl-DL-aspartic acid (NMA) was compared in cycling and anestrous mares during the nonbreeding season. It was anticipated that the gonadotropin response to NMA in cycling mares would be attenuated, compared with that of anestrous mares. The experiment used 16 anestrous mares and 15 mares that cycled during the nonbreeding season. The effect of NMA on prolactin secretion was also evaluated. In addition, the seasonal rhythm of prolactin secretion was compared in anestrous and cycling mares during October-April. In cycling mares, the response to NMA was dependent on the stage of the cycle, and a significantly (p < 0.05) larger proportion responded during the luteal phase (6 of 8), compared with the follicular phase (1 of 7 mares). The proportion of anestrous mares that responded to NMA was similar to that of cycling mares during the luteal phase, but larger than during the follicular phase. In anestrous and cycling mares, NMA suppressed prolactin secretion, and in both groups prolactin secretion decreased during the nonbreeding season. Thus, we conclude that differences in reproductive activity in mares during the nonbreeding season are unlikely to reflect a change in glutamatergic activity.

Anestrus↗
PubMed2001

Degradation of c-Fos protein expressed by N-methyl-D-aspartic acid in nuclear fractions of murine hippocampus.

In both nuclear and cytosolic fractions of murine hippocampus, constitutive expression was seen with Fra-2 protein, but not with other Fos family members tested including c-Fos, Fos-B and Fra-1 proteins. Fos-B protein was only detected in nuclear fractions. The systemic administration of N-methyl-D-aspartic acid (NMDA) induced marked and transient expression of c-Fos protein, but not other family members, in both hippocampal fractions 2 h later. In vitro incubation at 30 degrees C led to more rapid degradation of inducible c-Fos protein than constitutive Fra-2 protein in nuclear fractions obtained 2 h after the administration of NMDA, without significantly affecting that of both member proteins in cytosolic fractions. The addition of phosphatase inhibitors significantly delayed the initial degradation rate of inducible c-Fos protein, with concomitant facilitation of that of constitutive Fra-2 protein, in nuclear fractions. The addition of protease inhibitors also delayed the initial degradation of constitutive Fra-2 protein, without markedly altering that of inducible c-Fos protein, in nuclear fractions. Immunoprecipitation analysis revealed that NMDA induced phosphorylation of c-Fos protein on tyrosine residues in nuclear fractions to a lesser extent than that on serine residues 2 h after administration. These results suggest that NMDA signals may be propagated to the nucleus to induce both expression and degradation of c-Fos protein through a molecular mechanism associated with phosphorylation on serine and/or tyrosine residues in murine hippocampus.

Animals↗
PubMed1999

Solute absorption from the airways of the isolated rat lung. V. Charge effects on the absorption of copolymers of N(2-hydroxyethyl)-DL-aspartamide with DL-aspartic acid or dimethylaminopropyl-DL-aspartamide.

PURPOSE: To determine the effects of ionized substituents upon the pulmonary absorption of 6-8 kDa synthetic, hydrophilic polypeptides. METHODS: Fluorophore-labeled poly (hydroxyethylaspartamide), F-PHEA (neutral at pH 7.4) and its copolymer derivatives poly (hydroxyethylaspartamide-co-dimethylaminopropylaspartamide), F-P(HEA-DMAPA) (positive at pH 7.4) and poly (hydroxyethylaspartamide-co-aspartic acid), F-P(HEA-AA) (negative at pH 7.4) were synthesized and administered in different concentrations to the airways of the isolated rat lung preparation. The time and molecular weight dependencies of polypeptide absorption into perfusate were determined at intervals by gel permeation chromatography. RESULTS: For all polypeptides, molecular weights in perfusate were about 1 kDa less than those which were administered, due to preferential absorption of smaller molecules. The absorption, up to 70% of the administered dose over 3 h, of the anionic F-P(HEA-AA), was significantly faster than that of the neutral F-PHEA or the polycationic F-P(HEA-DMAPA). The latter derivative produced greatest edema in the lung. Absorption showed both active [dose-dependent kinetics] and passive [diffusive] components for all three polymers. CONCLUSIONS: Pulmonary absorption of similarly sized macromolecular PHEA derivatives, either neutral, positively or negatively charged, occured via carrier-mediated and diffusive mechanisms. The highest rate of absorption was observed with the polyanionic derivative.

Absorption↗
PubMed1991

Enhancement of spinothalamic neuron responses to chemical and mechanical stimuli following combined micro-iontophoretic application of N-methyl-D-aspartic acid and substance P.

A role for sensitization of nociceptors in the generation of primary hyperalgesia is well documented. More recent work has begun to define a role of an increased excitability of neurons within the spinal cord in the generation of secondary hyperalgesia. The present study demonstrates increased responses of primate spinothalamic neurons following co-administration of N-methyl-D-aspartic acid (NMDA) and substance P (SP) by micro-iontophoresis. Wide dynamic range and high threshold STT neurons in laminae I-VI showed an increased frequency of discharges following application of NMDA which was characterized by a slow onset to peak discharge rate and a slow return to background levels of discharge. Combined application of NMDA with SP resulted in an enhancement of responses to NMDA that often long outlasted the administration of SP. This increase in response of the cells to NMDA was not produced by repeated application of NMDA alone or following combined application of NMDA with an SP analog. NMDA responses were reduced or prevented in all cases by co-application of an NMDA-receptor antagonist. Finally, long-lasting potentiation of NMDA responses by SP was paralleled by enhanced responses to mechanical stimulation of skin. It is proposed that a mechanism involving the combined synaptic release of excitatory amino acids and peptides leads to secondary hyperalgesia.

Animals↗
PubMed1999

Functional changes of N-methyl-D-aspartic acid and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate channels in gerbil hippocampal CA1, in relation to postischemic enhancement of glutamate receptor-mediated responses.

Glutamate receptor-mediated responses have been reported to be enhanced in the postischemic CA1 pyramidal neurons before the appearance of delayed neuronal death, and the enhancement has been thought to be one of crucial factors leading postischemic CA1 pyramidal neurons to irreversible neuronal injury. In the present study, we examined what changes in functional properties of N-methyl-D-aspartic acid (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) channels are responsible for the enhanced postischemic glutamate receptor-mediated responses. Gerbils were subjected to 5-min ischemia to induce the enhancement of glutamate receptor-mediated responses and the hippocampal slices were prepared 3 h after ischemia. Single channel activities evoked by NMDA and AMPA were recorded from outside-out patches excised from the postischemic CA1 pyramidal neurons. The main conductance levels of NMDA and AMPA channels in the postischemic CA1 pyramidal neurons were not significantly different from those in control CA1 pyramidal neurons. The mean open time and the open-state probability of NMDA and AMPA channels significantly increased in the postischemic CA1 pyramidal neurons (NMDA channels: mean open time, 1.4-fold increase; open-state probability, 1.5-fold increase) (AMPA channels: mean open time, 1.3-fold increase; open-state probability, 1.8-fold increase). These findings indicate that the increases in the mean open time and the open-state probability of NMDA and AMPA channels are responsible for the enhancement of postischemic NMDA and non-NMDA receptor-mediated responses.

Animals↗
PubMed1989

Selective inhibition of excitatory amino acids by divalent cations. A novel means for distinguishing N-methyl-D-aspartic acid-, kainate- and quisqualate-mediated actions in the mouse spinal cord.

Biting and scratching behaviors produced by intrathecal injection of excitatory amino acid (EAA) agonists were examined to determine whether the biting and scratching behavioral effects produced by these compounds are altered selectively in vivo by coadministration with divalent cations. N-methyl-D-aspartate (NMDA)-induced behavior was inhibited by both magnesium and calcium but not by zinc. Kainic acid (KA)-induced behavioral activity was also inhibited by coadministration with calcium but not by magnesium or zinc. In contrast to both NMDA and KA, calcium, magnesium and zinc failed to alter the intensity of quisqualic acid (Quis)-induced biting and scratching behaviors. Based on this selective inhibition of the three EAA subtypes by divalent cations, we examined the behavioral responses produced by Glu and Asp in combination with calcium or magnesium to identify the receptor population involved in these motor effects. Calcium antagonized the biting and scratching behavior produced by i.t. injected Glu in contrast with Asp which was inhibited significantly by magnesium. Our results support the concept that Glu and Asp produce biting and scratching behaviors by an interaction with distinct receptor populations in the spinal cord. To date, there are no selective antagonists at the KA or Quis receptors. Thus, a systematic examination of the selective inhibition of EAA activity by divalent cations in addition to currently available pharmacologic antagonists may prove to be a useful approach to the identification of NMDA, KA and Quis receptor interactions.

Animals↗
PubMedDate not supplied

Metaphit-induced audiogenic seizures in mice: II. Studies on N-methyl-D-aspartic acid, GABA, and sodium channel receptors and on the disposition of metaphit in the brain.

We previously demonstrated that metaphit (a phencyclidine analogue with an acylating isothiocyanate group) induces occurrence of audiogenic seizures in mice exposed to audio stimulation 24 h after metaphit administration. We have studied various receptor systems associated with excitatory and inhibitory networks: sites for competitive and noncompetitive antagonists of the N-methyl D-aspartic acid (NMDA) receptor complex, for [3H]muscimol on the gamma-aminobutyric acid (GABA) receptor complex, and for [3H]batrachotoxinin A20-alpha-benzoate on the voltage-dependent sodium channel. Mice were examined for neurochemical changes at 24 h after pretreatment with metaphit, when susceptibility to audiogenic seizures is greatest. Ex vivo receptor binding studies detected no changes; in vivo labeling of the phencyclidine site in the NMDA receptor complex was reduced by 20% in cortical and midbrain regions. A separate group of experiments was aimed at measuring brain levels of metaphit. One minute after retroorbital administration of [3H]metaphit at a dose sufficient to produce susceptibility to audiogenic seizures 24 h later, the brain level of [3H]metaphit (determined by high-performance liquid chromatography, HPLC) was 49 pmol/mg tissue; at 1, 4, and 24 h, the level was 12, 6, and 1.4 pmol/mg tissue or microM if metaphit was evenly distributed throughout the brain. Although the observed metaphit concentrations during the first 4 h are high enough to acylate receptors, no firm evidence for acylation was found for most of the examined receptors. Finally, the time course of the brain level of metaphit showing a continuous decrease is entirely different from that of development of the seizure susceptibility, which peaks at 18-24 h.

Acoustic Stimulation↗
PubMed2004

Organization of single components of defensive behaviors within distinct columns of periaqueductal gray matter of the rat: role of N-methyl-D-aspartic acid glutamate receptors.

The periaqueductal gray matter (PAG) is functionally organized in longitudinal columns arranged along the aqueduct. Stimulation of lateral and dorsal columns produces a complex set of unconditioned behaviors named the 'defense reaction.' Overt responses in rats comprise a tense immobile display, fully opened eyes (herein named exophthalmus), trotting, galloping, jumping, micturition and defecation. Besides, the PAG is rich in glutamate and respective receptors, including the N-methyl-d-aspartic acid (NMDA) type. Therefore, the present study employed regression analysis to map out electrically and NMDA-induced single components of defensive behaviors produced by stepwise increasing stimulation of PAG. Data confirmed the defensive nature of PAG-evoked responses. Neither the appetitive, nor offensive, mouse-killing or male reproductive behaviors were produced by stimulation of PAG in presence of appropriate targets. Threshold and dose-response logistic analyses largely corroborated the columnar organization of PAG-evoked responses. Thus, whereas the defecation was restricted to PAG lateral column, exophthalmus, micturition and somatic defensive responses were similarly organized in dorsolateral and lateral, but not in the ventrolateral column. Moreover, thresholds of dorsolateral and lateral repertoires were strictly hierarchical, with exophthalmus, immobility, trotting, galloping and jumping appearing in this very order. However, the defensive responses of PAG dorsolateral column required NMDA doses significantly lower than those of lateral PAG. Accordingly, NMDA receptors within the dorsolateral PAG are likely to play a major role in the initiation of PAG-evoked defensive responses. In contrast, the present data do not support the organization of unconditioned defensive behaviors in ventrolateral PAG. The neuroanatomical substrate of each response and the role of PAG and NMDA receptors are discussed in relation to the present data. Further, this is the first report on PAG columnar organization of single components of defensive behaviors.

Animals↗
PubMed1995

Modulation of N-methyl-D-aspartic acid receptors by extracellular calcium in immature and adult hippocampal slices: whole cell recordings in CA3 pyramidal cells.

Lowering extracellular calcium concentration [Ca2+]o in rat hippocampal slices can lead to an induction of epileptiform activity. It has been shown that this effect is more pronounced in slices of neonatal rats (postnatal day, PND 8-19) than in mature slices (> PND 40) and it has been suggested that unique N-methyl-D-aspartic acid (NMDA) receptor properties of immature rat hippocampal pyramidal cells contribute to this developmental effect. In a voltage clamp experiment we tested NMDA receptor properties in hippocampal pyramidal cells by measuring NMDA receptor mediated currents evoked by iontophoretic applied NMDA in the basal dendrites of CA3 pyramidal neurons. We found that lowering extracellular calcium from 2 to 1 mM, increases NMDA evoked inward current in pyramidal cells around the resting membrane potential. However, this effect is observed in slices of neonatal as well as in slices of mature rats, suggesting that there is no difference in NMDA receptor sensitivity to extracellular Ca2+ between these two age groups. The modulation of the NMDA receptor by extracellular calcium at physiological concentrations can have important consequences in pathological conditions during which extracellular calcium reaches low levels. Because this 'hypocalcemic' condition induces a larger current influx via the NMDA receptor channel at resting membrane potentials, it can further enhance cellular excitability and contribute to sustain epileptiform activity.

Age Factors↗
PubMed1995

Experimental neuronal injury in the newborn lamb: a comparison of N-methyl-D-aspartic acid receptor blockade and nitric oxide synthesis inhibition on lesion size and cerebral hyperemia.

The purpose of this study was to compare the effects of dizocilipine maleate (MK-801) and NG-nitro-L-arginine methyl ester (L-NAME) on focal excitotoxic brain injury and associated hemodynamic response in the newborn lamb. A 27 gauge needle was placed into the right striatum in 28 anesthetized newborn lambs. Seven animals were placed in each group. A negative control group received 0.2 mL of buffered saline, a positive control group received 5 mumol of N-methyl-D-aspartic acid (NMDA) alone, and two groups received NMDA and pretreatment with L-NAME. Ultrasound images and cerebral blood flow determinations (microspheres) were obtained before, and at 20, 40, and 60 min after, intrastrial injection. Three animals in each group underwent histopathologic evaluation. Sonographic lesions were visible immediately after intracerebral injection. Saline injection resulted in small lesions (mean volume; 13.6 +/- 5 mm3) without hyperemia. NMDA alone resulted in larger lesions (92.9 +/- 24 mm3) and hyperemia to both hemispheres, whereas pretreatment with MK-801 reduced lesion size (11.7 +/- 6 mm3) and completely ablated cerebral hyperemia. Pretreatment with L-NAME showed no effect on lesion size (69.9 +/- 20 mm3) and hyperemia only in the ipsilateral hemisphere. Sonographic lesions correlated well with gross and histopathologic appearance. We concluded that NMDA-induced focal brain injury and associated hyperemia in the newborn lamb appear to be specific NMDA receptor-mediated events. NO production probably does not play a major part in NMDA-induced neonatal neuronal injury, and may be only partly responsible for regional hyperemia during NMDA injection.

Animals↗