Inhibition of serine esterases in different rat tissues following inhalation of soman.
Explore the source record for details and available documents.
Administration, Inhalation↗
Biomedical subjects
F Fonnum
Publications and source records attributed to F Fonnum.
Temporary impairment of Müller cell metabolism in the rat retina by intravitreal injection of fluorocitrate.
Fluorocitrate was injected in the vitreum of rats in order to define the experimental conditions for a temporary impairment of Müller cell metabolism in the retina. Injection of 16 nmol of fluorocitrate appeared to fulfil this requirement since this dose resulted in a large decrease in retinal endogenous glutamine and a smaller decrease in glutamate within 6 hr of administration. The reversible nature of the effect was attested by a substantial recovery of the retinal levels of the two amino acids within 24 hr of injection. In vitro experiments of carbon incorporation from different substrates, carried out with retinas dissected from eyes previously injected with fluorocitrate, were consistent with a metabolic impairment of glial cells, since carbon incorporation from [14C]acetate into glutamine was almost completely abolished in the fluorocitrate-treated retinas. Electron microscopic examination in fluorocitrate-poisoned retinas demonstrated essentially selective ultrastructural alterations of Müller cells at times corresponding to their maximal metabolic impairment. Since Müller cells are by far the largest glial population of the rat retina, common astrocytes being only scattered in the nerve fibre layer, the present experimental model may be used to study the role of Müller cells in the metabolism of retinal neurotransmitters.
Animals↗
Amino acids as modulators of cholinergic nerves in airways.
The bronchial smooth muscle of rat was examined for contractile responses to excitatory amino acids. The electrical field stimulation (EFS) which induces release of ACh, induced contraction which was enhanced by exogenous L-glutamate (L-glu). The ED50 of L-glu was 3.5 +/- 0.1 mM. Inhibition of the release by TTX or by HC-3 completely abolished the potentiation of the EFS-induced contraction by L-glu. The effect of L-glu is therefore probably a prejunctional effect. Concentrations of L-glu higher than 22 mM inhibited the EFS evoked contractions, and enhanced the tonus of the muscle by a postjunctional stimulation. The ED50 of ACh was not altered by L-glu. In contrast, an increase of the intrinsic activity (alpha) of ACh was seen, providing evidence for a postjunctional potentiation of ACh induced contraction. L-glu did not inhibit AChE-activity at concentrations up to 50 mM, indicating that the effect is not due to an accumulation of ACh. A relaxation of the EFS-induced bronchial smooth muscle contraction was seen with high concentrations of D-glu, L-asp, L-alpha-amino adipate and ibotenate. Neither L-GDEE nor DL-APV had any inhibitory effect on L-glu and L-asp induced alteration of EFS-evoked contraction or on the L-glu enhanced tonus of the bronchial smooth muscle. Kainate, NMDA and quisqualate had only minor transient potentiating effects on the EFS-induced contraction.(ABSTRACT TRUNCATED AT 250 WORDS)
Acetylcholine↗
Behavioural deficits and serotonin depletion in adult rats after transient infant nasal viral infection.
Dysfunction of subcortical serotoninergic neurons has been implicated in some behaviour disturbances. The serotoninergic neurons in the dorsal and median raphe project widely in the brain. They innervate the olfactory bulbs and can be targets for exogenous agents attacking the olfactory epithelium and bulbs. We report here an injury to the serotoninergic neurons after intranasal infection in 12-day-old rats with a temperature-sensitive mutant of vesicular stomatitis virus. The brain infection was focal and transient. Viral antigens could no longer be detected 13-15 days after infection. In spite of this the animals, as adults, had a severe serotonin depletion in the cerebral cortex and hippocampus, and showed abnormal locomotor and explorative behaviour as well as learning deficits. The neocortex was histologically intact and parameters related to other neurotransmitters such as dopamine, noradrenaline, GABA and acetylcholine showed no marked changes. A relatively selective damage to serotoninergic nuclei as a result of virus neuroinvasion through a natural portal of entry, may constitute a new pathogenetic mechanism for cortical dysfunction and behavioural deficits.
3,4-Dihydroxyphenylacetic Acid↗
Uptake of glycine into synaptic vesicles isolated from rat spinal cord.
Glycine was taken up by a synaptic vesicle fraction from spinal cord in a Mg-ATP-dependent manner. The accumulation of glycine was inhibited by carbonyl cyanide-m-chlorophenylhydrazone (CCCP) and nigericin, agents known to destroy the proton gradient across the vesicle membrane. Vesicular uptake of glycine was clearly different from synaptosomal uptake, with respect to both the affinity constant and the effect of Na+, ATP, CCCP, and temperature. Oligomycin and strychnine did not inhibit the vesicular uptake, showing that neither mitochondrial H(+)-ATPase nor binding to strychnine-sensitive glycine receptors was involved. It is suggested that the vesicular uptake of glycine is driven by a proton gradient generated by a Mg2(+)-ATPase. A low concentration of Cl- had little effect on the uptake of glycine, whereas the uptake of glutamate in the same experiment was highly stimulated. High concentrations of gamma-amino-n-butyric acid and beta-alanine inhibited vesicular glycine uptake, but glutamate did not. Accumulation of glycine was found to be fourfold higher in a spinal cord synaptic vesicle fraction than in a vesicle fraction from cerebral cortex.
Adenosine Triphosphate↗
Comparison of transmitter amino acid levels in rat globus pallidus and neostriatum during hypoglycemia or after treatment with methionine sulfoximine or gamma-vinyl gamma-aminobutyric acid.
The levels of amino acids in globus pallidus, a structure heavily innervated with gamma-aminobutyric acid (GABA)-ergic terminals but few glutamergic terminals, were compared with the levels in neostriatum, a structure richly innervated with glutamergic terminals but intermediate in GABAergic terminals. The level of glutamate in neostriatum was twice as high as in globus pallidus whereas the level of GABA in globus pallidus was three times higher than in neostriatum. The level of aspartate was similar in both regions whereas the level of glutamine was correlated with the level of glutamate. Methionine sulfoximine, a glutamine synthetase inhibitor, reduced the level of glutamine to 10-20% of control in both structures. This reduction was accompanied by the largest decrease in the level of glutamate in neostriatum, indicating that transmitter glutamate turns over more rapidly than other glutamate pools. Likewise, insulin decreased the levels of glutamate and glutamine more in neostriatum than in globus pallidus. gamma-Vinyl GABA increased the level of GABA in globus pallidus more than in neostriatum although the percent increase was largest in neostriatum. Treatment with gamma-vinyl GABA was accompanied by a large reduction in the level of GABA, indicating that a substantial proportion of the glutamine pool is linked to GABA metabolism.
Amino Acids↗
[Treatment of insecticide and nerve gas poisoning].
Organic phosphides such as insecticides and nerve gases are chemically and biologically akin. They have the same main structures and both act as cholinesterase inhibitors. The nerve gases are generally more reactively chemical and therefore far more toxic. Since both nerve gases and insecticides react to the same group of acetylcholinesterase the development of symptoms and the treatment of the intoxication are fairly similar. Intoxication may ensue from inhalation, from penetration of the skin, or from consumption of contaminated food or water. The latter mode of administration is the most common in cases of suicide.
Chemical Warfare Agents↗
Regional distribution of gamma-aminobutyrate and L-glutamate uptake into synaptic vesicles isolated from rat brain.
The ATP-dependent uptake of GABA and L-glutamate into synaptic vesicles isolated from 4 different regions of the rat brain was studied. The regional distribution of the vesicular uptake was related to the Na+-dependent synaptosomal uptake, which, as a first approximation, corresponds to the distribution of GABAergic and glutamatergic terminals. The ratio found between the vesicular GABA and L-glutamate uptake varied between 1.3 and 6.2. This indicates that GABA and L-glutamate are taken up into different vesicle populations.
Animals↗
Stimulation of peripheral cholinergic nerves by glutamate indicates a new peripheral glutamate receptor.
The bronchial smooth muscle of the rat was examined for contractile responses to excitatory amino acids. The nerve-mediated contraction induced by electrical field stimulation was enhanced by exogenous L-glutamate (L-Glu). The apparent affinity (ED50) of L-Glu was 3.5 +/- 0.1 mM. Both tetrodotoxin and hemicholinium-3 completely abolished the electrical field-induced contraction and therefore the potentiation by L-Glu, which indicates that L-Glu has a prejunctional effect. Concentrations of L-Glu higher than 22 mM inhibited the electrical field-induced contractions and enhanced the tonus of the smooth muscle by postjunctional stimulation. The ED50 of exogenous ACh was not altered by L-Glu. High concentrations (62 mM) of L-Glu increased the intrinsic activity (alpha) of ACh, indicating a postjunctional potentiation of ACh-induced contractions. L-Glu did not inhibit the activity of acetylcholinesterase, therefore the postjunctional potentiation was not due to ACh accumulation. Inhibition of the electrical field-induced contraction was seen with high concentrations of D-Glu, L-aspartate (L-Asp), L-alpha-amino adipate and ibotenate. Neither glutamate diethyl ester nor 2-amino-5-phosphonovalerate had any inhibitory effects on the L-Glu- and L-Asp-induced alterations of the electrical field-stimulated contraction or on the L-Glu-enhanced tonus of the bronchial smooth muscle. Kainate, N-methyl-D-aspartate, quisqualate and N-acetyl-aspartyl-glutamate had only minor transient potentiating effects on the electrical field-induced contraction. The results provide evidence for a L-Glu receptor in rat bronchi that has a different specificity for glutamate agonists and antagonists than the L-Glu receptor described in the CNS. The receptor seems to be located prejunctionally and enhances nerve-mediated responses and thereby stimulates the bronchial smooth muscle to contract. The possible involvement of this type of receptor in the 'Chinese restaurant syndrome' is discussed.
Amino Acids↗
Impaired reference memory and reduced glutamergic activity in rats with temporo-entorhinal connections disrupted.
The purpose of the present study was to investigate whether effects of temporo-entorhinal disconnections on acquisition and retention of a visual discrimination task might be associated with neurochemical dysfunctions. The results revealed that the present lesions impaired both acquisition and retention of the discrimination task. This impairment was accompanied by decreased glutamergic activity in both temporal and entorhinal cortices. No changes were seen in levels of acetylcholine or GABA. Further, the distribution of glutamate/aspartate was related to both regional and hemispheric differences. The results are discussed in terms of a highly integrative role of the lateral entorhinal cortex and in terms of other putative neurotransmitter systems involved in the function of memory.
Animals↗
L-[3H]glutamate binding to a membrane preparation from crayfish muscle.
The binding of L-[3H]glutamate to an isolated membrane preparation from crayfish tail muscle has been studied. The muscle homogenate was osmotically shocked, frozen and thawed, and thoroughly washed before incubation with L-[3H]glutamate. The preparation showed high specific binding of L-glutamate with a KD of 0.12 microM and Bmax of 4.7 pmol/mg protein measured in Tris/HCl pH 7.3 and at 4 degrees C. Nonspecific binding was 5-10% of total binding. The glutamate binding was highly stereospecific [K0.5 (D-glutamate), 270 microM] and showed a high degree of discrimination between L-glutamate and L-aspartate [K0.5 (L-aspartate), 54 microM]. In mammalian CNS preparations potent agonists of L-glutamate such as kainate and N-methyl-D-aspartate had no effect at 1 mM, and quisqualate was a weak inhibitor of L-glutamate binding [K0.5 (quisqualate), 162 microM]. Ibotenate was the most potent inhibitor [K0.5 (ibotenate), 0.27 microM], and various esters of L-glutamate were of intermediate potency as displacers of L-[3H]glutamate binding (K0.5 values from 6 to 60 microM). The glutamate binding site from crayfish muscle is clearly different from any of the subclasses of glutamate receptors in mammalian CNS. A possible physiological function of the binding site is a postsynaptic receptor for glutamate, either an extra-junctional or a junctional receptor.
Animals↗
Comparison of the properties of gamma-aminobutyric acid and L-glutamate uptake into synaptic vesicles isolated from rat brain.
Rat brain synaptic vesicles exhibit ATP-dependent uptake of gamma-[3H]amino-n-butyric acid ([3H]GABA) and L-[3H]glutamate. After hypotonic shock, the highest specific activities of uptake of both L-glutamate and GABA were recovered in the 0.4 M fraction of a sucrose gradient. The uptakes of L-glutamate and GABA were inhibited by similar, but not identical, concentrations of the mitochondrial uncoupler carbonyl cyanide m-chlorophenylhydrazone and the ionophores nigericin and gramicidin, but they were not inhibited by the K+ carrier valinomycin. N,N'-Dicyclohexyl-carbodiimide and N-ethylmaleimide, Mg2+-ATPase inhibitors, inhibited the GABA and L-glutamate uptakes similarly. Low concentrations of Cl- stimulated the vesicular uptake of L-glutamate but not that of GABA. The uptakes of both L-glutamate and GABA were inhibited by high concentrations of Cl-. These results indicate that the vesicular GABA and L-glutamate uptakes are driven by an electrochemical proton gradient generated by a similar Mg2+-ATPase. The vesicular uptake mechanisms are discussed in relation to other vesicle uptake systems.
Adenosine Triphosphate↗
Role of glial cells for the basal and Ca2+-dependent K+-evoked release of transmitter amino acids investigated by microdialysis.
The role of glial cells for the inactivation and synthesis of precursors for amino acid transmitters was studied in the brains of anesthetized rats in vivo using the microdialysis technique. The dialysis probes were inserted stereotactically into each neostriatum. One neostriatum was treated with the gliotoxin fluorocitrate, whereas the contralateral side served as a control. The basal efflux of amino acids, reflecting the extracellular level, was measured as well as the efflux during depolarization with 100 mM K+ in the dialysis stream. The potassium-evoked efflux of transmitter amino acids was calcium dependent and thus considered to reflect release from the transmitter pool. gamma-Aminobutyric acid (GABA) and glutamate release from the treated side was higher than the control value during the first 2-3 h, a result indicating an important role of glial cells in the inactivation of released transmitter. After 6-7 h with fluorocitrate, the release of glutamate was lower than the control value, a result indicating an important role of glial cells in the synthesis of precursors for the releasable pool of glutamate. The role of glutamine for the production of transmitter glutamate and GABA in vivo was further investigated by inhibiting glutamine synthetase with intrastriatally administered methionine sulfoximine. The release of gluatamate into the dialysis probe decreased to 54% of the control value, whereas the release of GABA decreased to 22% of the control value, a result indicating that glutamine may be more important for transmitter GABA than for transmitter glutamate.
Amino Acids↗
Postnatal development of glutamatergic, GABAergic, and cholinergic neurotransmitter phenotypes in the visual cortex, lateral geniculate nucleus, pulvinar, and superior colliculus in cats.
We have analyzed the postnatal development of glutamatergic/aspartergic, GABAergic, and cholinergic neurotransmitter systems in the visual cortical Areas 17 and 18, lateral geniculate nucleus (LGN), pulvinar, and the visual and non-visual parts of superior colliculus (SC) in kittens. High-affinity uptake of D-aspartate (HA D-Asp), glutamate decarboxylase (GAD), and choline acetyltransferase (ChAT) activities were measured as a means of probing the development of the respective transmitter systems. HA D-Asp exceeded the adult level several-fold in all areas during the postnatal period which corresponded with the period of maximal dendritic/axonal branching patterns and synapse densities in the respective regions. GAD exhibited a gradual increase towards adult levels during the first month. The adult level was reached during postnatal week (PNW) 5-6 in Areas 17 and 18, during PNW3 within LGN, pulvinar, and the visual part of SC. In the nonvisual part of SC, the adult GAD level was reached as early as PNW2. ChAT exhibited biphasic developmental profiles in Areas 17 and 18. An initial peak of near adultlike activity in PNW2 was followed by a decline and subsequently by a slow increase towards adult levels during PNW5-17. ChAT developed very slowly in LGN and pulvinar, and in the latter structure only approximately 70% of the adult activity had been attained by PNW17. In both subdivisions of SC, ChAT had reached adult levels during PNW3-5. Dark-rearing from birth until PNW6 moderately attenuated GAD development in all areas and increased ChAT activity in Areas 17 and 18 but did not affect development of HA D-Asp in any part of the kitten visual system. Our neurochemical findings in the developing cat visual system are consistent with available evidence regarding localization of neurotransmitter systems, as well as postnatal changes in terms of cytoarchitectonics, synaptogenesis, functional development, and susceptibility to neonatal dark-rearing in visual pathways.
Animals↗
The effect of acetylcholinesterase-inhibition on the tonus of guinea-pig bronchial smooth muscle.
The irreversible acetylcholinesterase inhibitor soman (O-[1,2,2-trimethylpropyl]-methyl-phosphonofluoridate) induced contraction of guinea-pig primary bronchial smooth muscle. The apparent affinity (ED50) of acetylcholine (ACh) was altered from control value of 12 microM to 0.3 microM following exposure of the bronchial smooth muscle to 14 microM soman for 15 min in vitro. The ED50 of the cholinergic agonist carbachol was not changed even when the acetylcholinesterase (AChE) activity was inhibited completely. The intrinsic activity (alpha) of ACh and carbachol was not significantly changed after exposure to soman for 15 min. The results demonstrate that the effect of soman is only due to its anticholinesterase activity. Furthermore, the contraction induced by histamine was not altered by concentrations of soman which increase the cholinergic stimulation. This indicates that histamine does not induce contraction of bronchial smooth muscle in guinea pig through the release of ACh or by modulation of muscarinic receptors. Furthermore, soman also inhibited the carboxylesterase activity in the primary bronchi. In respiratory tissue this group of enzymes may have a major protective function, due to their ability to bind several organophosphorus compounds. Compared to studies performed on other species, this study shows that guinea-pig bronchi are very sensitive to the AChE-inhibitor soman. Therefore, exposure to very low concentrations of AChE-inhibitors may induce contraction of bronchial smooth muscle.
Acetylcholinesterase↗
Metabolism of T-2 toxin by blood cell carboxylesterases.
Human and rat blood hydrolysed T-2 toxin along two different pathways giving HT-2 toxin and neosolaniol as primary metabolites, respectively. Neosolaniol represents a metabolic pathway different from that obtained by liver. Rat erythrocytes formed neosolaniol as a primary metabolite whereas white blood cells hydrolysed T-2 toxin to HT-2 toxin. Human erythrocytes formed both HT-2 toxin and neosolaniol whereas all human white cells produced only HT-2 as the primary metabolite. The enzymes responsible for hydrolysis of T-2 toxin to HT-2 toxin in white blood cells and T-2 toxin to neosolaniol in red blood cells were all identified as carboxylesterases by use of specific inhibitors. The ratio between trichothecene hydrolysis and 4-nitrophenyl butyrate hydrolysis varied among the different cell fractions indicating that specific isoenzymes are involved.
Animals↗
The effect of fluorocitrate on transmitter amino acid release from rat striatal slices.
In order to study the role of glutamine from glial cells for the synthesis of transmitter amino acids, the effect of the gliotoxic-substance fluorocitrate on amino acid release from slices was investigated. In vivo treatment with 1 nmol fluorocitrate reduced the Ca2+ dependent K+ evoked release of endogenous glutamate and GABA from the slices, whereas the glutamine efflux decreased and alanine efflux increased. The K+ evoked release of [3H]D-aspartate increased during fluorocitrate treatment. The latter is consistent with an inhibited uptake of D-aspartate into glial cells. Incubation of striatal slices with fluorocitrate (0.1 mM) decreased the glutamine efflux and increased the alanine efflux. Similar to the in vivo condition, fluorocitrate increased the K+ evoked [3H]D-aspartate release, but the K+ evoked release of endogenous glutamate and GABA increased rather than decreased. The ratio between the K+ evoked release of exogenous D-aspartate to endogenous glutamate increased in both cases. The results suggest an important role of glial cells in the synthesis and inactivation of transmitter amino acids.
Amino Acids↗
Importance of glutamine for gamma-aminobutyric acid synthesis in rat neostriatum in vivo.
This work was carried out to evaluate the importance of glial cells in providing precursors for the in vivo synthesis of gamma-aminobutyric acid (GABA). Fluorocitrate, which selectively inhibits the tricarboxylic acid cycle in glial cells, was administered locally in rat neostriatum. Inhibition of the glial cell tricarboxylic acid cycle led to a decrease both in glutamine level and in gamma-vinyl GABA (GVG)-induced GABA accumulation, an observation indicating reduced GABA synthesis. The role of glutamine, which is synthesized in glial cells as a precursor for GABA, was further investigated by inhibition of glutamine synthetase with intrastriatally administered methionine sulfoximine. In this case, the glutamine level was reduced to near zero values, and the GVG-induced GABA accumulation was only half that of normal. The results show that glutamine is an important precursor for GABA synthesis, but it cannot be the sole precursor because it was not possible to depress the GVG-induced GABA accumulation completely.
Aminocaproates↗