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At least 19 recordsLinked to original sources
PubMed1988

Lateral hypothalamic feeding mechanisms: iontophoretic effects of kainic acid, ibotenic acid and 6-hydroxydopamine.

In order to study hunger motivated behavior kainic acid (KA), ibotenic acid (IB) and 6-hydroxydopamine (6-OHDA) were iontophoretically applied to the lateral hypothalamus of rats. Neurotoxins at concentrations between 20-120 mMol were applied with 5-20 microA current for 5-10 min. Tip diameter of glass micropipettes varied between 10-50 micron. Application of KA, IB and 6-OHDA caused temporary body weight loss, hypophagia and hypodipsia. Effects were dose dependent: correlation was found between current strength, tip diameter of pipettes, concentrations of neurotoxins and the extent of cellular damage. Aphagic and adipsic symptoms and the death of animals were only observed after extensive LH lesions. There was no significant difference in food consumption after 24 hr deprivation among groups. Water deprivation and extracellular or intracellular dehydration resulted in a considerable increase in water intake in all animals, however, consumption in lesioned rats was lower than that of controls. These water regulatory disturbances in 6-OHDA treated animals were somewhat less severe. Results show that the bilateral cellular microlesions of the LH and damage of dopaminergic (DA) elements with 6-OHDA both cause disturbances of feeding behavior. Although the severity of symptoms in some respects depends upon the nature of neurotoxic treatment, the basic consequences are essentially similar. It is suggested that the LH "feeding center" and the ascending DA pathways represent a single system involved in the organization of hunger motivated behavior.

Animals↗
PubMed2004

Mutation-induced quisqualic acid and ibotenic acid affinity at the metabotropic glutamate receptor subtype 4: ligand selectivity results from a synergy of several amino acid residues.

The metabotropic glutamate receptors (mGluRs) are key modulators of excitatory neurotransmission in the central nervous system. The eight mGluR subtypes are seven trans-membrane-spanning proteins that possess a large extracellular amino-terminal domain in which the endogenous ligand binding pocket resides. In this study, we have identified four non-conserved amino acid residues that are essential for differentiating mGluR1 from mGluR4. Our approach has been to increase the affinity of the classic mGluR1 agonists, quisqualic acid and ibotenic acid, at mGluR4 by making various point mutations that mimicked mGluR1 residues. Based on ligand docking to homology models, the non-conserved residues, Lys-74, Glu-287, Ser-313, and Lys-317, were chosen for the mutational studies and all of the mutations proved capable of partially or completely restoring the affinities of the ligands. In particular, the mutations K74Y and K317R induced dramatic triple-order-of-magnitude increases in the affinity of ibotenic acid at mGluR4, making the affinity equivalent to that of mGluR1. Furthermore, the affinity of quisqualic acid at mGluR4 was increased to the same level as mGluR1 by the two double mutations, K74Y/K317R and K74Y/E287G. Advanced analysis of ligand conformation and docking procedures were used for the interpretation of these results. The study shows that mGluR subtype selectivity results from a complex interplay of residues shaping the binding pocket, rather than being attributable to a single specific ligand-receptor interaction.

Cell Differentiation↗
PubMed1991

Behavioral impairments after lesions of the nucleus basalis by ibotenic acid and quisqualic acid.

Ibotenic acid (IBO) or quisqualic acid (QUIS) was infused into the region of the nucleus basalis magnocellularis (NBm) in F344 rats in order to behaviorally and biochemically characterize the effects of these two neurotoxins. QUIS infusion resulted in a slightly higher depletion of choline acetyltransferase (ChAT) activity in both anterior and posterior regions of cortex than did lesions caused by infusion of IBO. Both QUIS- and IBO-treated rats demonstrated significantly longer latencies than controls to find a hidden platform in a Morris water maze task. In addition, QUIS-treated rats performed significantly better than IBO-treated rats in the water maze. Analysis of swim speed and open field behavior did not show significant differences in general motor activity. Passive avoidance retention was unaffected by either neurotoxin. Cortical amino acid levels, [3H]neurotensin binding, dopamine, norepinephrine, and serotonin levels were unaffected by either neurotoxin. The levels of HVA and 5-HIAA in the IBO and QUIS groups were significantly reduced compared to controls, but were not significantly different from each other. Histological examination showed greater damage to non-NBm structures with IBO than with QUIS, including the basolateral nucleus of the amygdala and the reticular formation of the thalamus. The greater behavioral deficit seen after IBO lesions may be due to damage to other areas rather than differences in the extent of depletion of corticai ChAT, amino acids, catecholamines or indolamines.

Amino Acids↗
PubMed1980

Two distinct inhibitory responses of cultured, mammalian spinal neurones to ibotenic acid.

Ibotenic acid, a structural analogue of glutamic acid, was applied to mouse spinal neurones grown in dissociated cultures. This amino acid evoked two inhibitory responses in addition to an excitatory response. Both inhibitory responses were manifested by membrane hyperpolarization and decreased input resistance. However, one was long-lasting (in excess of periods of 1 h) in comparison with the other. The latter response was likely a consequence of an increased chloride conductance and was sensitive to the gamma-aminobutyric acid antagonists bicuculline and picrotoxin whereas the former response was insensitive to these drugs. The ionic mechanism of this long-lasting response has yet to be elucidated.

Animals↗
PubMed1990

Regulation of neurotensin-containing neurons in the rat striatum. Effects of unilateral striatal lesions with quinolinic acid and ibotenic acid on neurotensin content and its binding site density.

Recently, we reported bilateral increases in striatal neurotensin (NT) levels following unilateral 6-hydroxydopamine lesion of the nigrostriatal dopaminergic pathway. In the present study, the effect of unilateral striatal lesions with quinolinic acid (QA, 300 nmol) or ibotenic acid (IBO, 130 nmol) on striatal NT levels and binding site densities were analyzed in order to investigate other possible regulations of NT systems. QA and IBO injection decreased gamma-aminobutyric acid (GABA) levels and [125I]iodosulpride (a specific D2 receptor antagonist) binding site densities in the lesioned striatum, indicating degeneration of striatal intrinsic neurons. Striatal dopaminergic terminals were not altered by QA as shown by the lack of changes in [3H]dihydrotetrabenazine [( 3H]TBZOH, a specific ligand of the vesicular monoamine transporter) binding site densities. Moreover, QA lesion induced an increase in NT levels and a decrease in NT binding sites in the lesioned striatum without any change in the contralateral structure. In contrast to QA, IBO might destroy a certain proportion of dopaminergic terminals in the lesioned striatum, as shown by a 54% decrease in [3H]TBZOH binding. Furthermore, IBO lesion enhanced striatal NT levels bilaterally, while NT binding sites decreased in the lesioned striatum and increased in the contralateral side. The present results suggest that not only dopaminergic neurons but also striatal intrinsic neurons may control NT systems in the striatum.

Animals↗
PubMed1985

Lateral hypothalamic self-stimulation persists in rats after destruction of lateral hypothalamic neurons by kainic acid or ibotenic acid.

Bilateral injections of 1 microgram/microliter of kainic or ibotenic acid into the lateral hypothalamus (LH) of rats destroyed most of the cells in the LH. This treatment did not prevent electrical self-stimulation from electrodes placed in the LH, indicating that intrinsic neurons of the LH alone are not crucial elements of the neural system that mediates reinforcing hypothalamic stimulation.

Animals↗
PubMed1977

Effects of ibotenic acid, quisqualic acid and their relatives on the excitability of an identifiable giant neurone of an African giant snail (Achatina fulica Férussac).

An identifiable giant neurone, PON (periodically oscillating neurone), of Achatina fulica Ferussac, inhibited by erythro-beta-hydroxy-L-glutamic acid, was also inhibited by 2 relatives of beta-hydroxy glutamic acid, ibotenic acid and quisqualic acid. These substances similarly showed the effect on the neurone even in the chloride-free medium.

Alanine↗
PubMed1986

Distant blood-brain barrier opening in subfields of the rat hippocampus after intrastriatal injections of kainic acid but not ibotenic acid.

Blood-brain barrier (BBB) permeability towards proteins was determined in rats 4 h after intrastriatal kainic or ibotenic acid application, using Evans blue as indicator. Whereas, with the exception of the unspecific damage in cortex, after ibotenic acid BBB remained intact in deep brain areas. Evans blue leakage was found ipsilateral to the kainic acid injection, occasionally in striatum, thalamus and amygdala and regularly in hippocampus. There it was confined to the fimbria and the CA3 field. Only rarely a mirror focus-like staining was present in the contralateral hippocampus. The ultrastructural investigation revealed that BBB opening in CA3 is due to increased transendothelial pinocytosis; the tight junctions were intact. Thus, changes in the microenvironment around vessels, elicited by kainic acid and/or seizures, might be responsible for BBB opening.

Animals↗
PubMed1992

Amyloid beta-protein precursor deposition in rat hippocampus lesioned by ibotenic acid injection.

Ibotenic acid was injected into 3 parts of the lateral rat hippocampus. The animals were sacrificed 100 days after treatment, and studied immunohistochemically. The lesioned side of the hippocampus was highly atrophic with extensive neuronal loss and gliosis. Although silver staining revealed no particular structures such as neurofibrillary tangles or senile plaques, globular and granular depositions of amyloid beta-protein precursor (APP) immunoreactivity was observed by immunostaining in the lesion with the monoclonal antibody (clone 22C11). Increased immunoreactivities of glial fibrillary acidic protein (GFAP) and ubiquitin were found in the lesioned area, while the immunoreactivities of microtubule-associated protein 2 (MAP2) and 200 kDa neurofilament subunit protein (NF-H) were diminished. The results indicate that APP deposition is formed in the lesioned area where neuronal degeneration is produced by ibotenic acid in rat hippocampus.

Amyloid beta-Protein Precursor↗
PubMed1985

Synthesis and structure-activity studies on excitatory amino acids structurally related to ibotenic acid.

With use of ibotenic acid as a lead, analogues of (RS)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) and of (RS)-3-hydroxy-4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-7-carboxylic acid (7-HPCA) were synthesized and tested as excitants of neurons in the cat spinal cord by using microelectrophoretic techniques and as inhibitors of the binding of kainic acid in vitro. Like AMPA and 7-HPCA, (RS)-3-hydroxy-4,5,6,7-tetrahydroisoxazolo[5,4-c]-pyridine-5-carboxylic acid (10, 5-HPCA) and (RS)-3-hydroxy-5-(bromomethyl)isoxazole-4-propionic acid (11, ABPA) proved to interact potently and selectively with central quisqualic acid receptors, assumed to represent physiological glutamic acid receptors. Analogues of 7-HPCA or 10, in which one or both of the acid groups were masked, were very weak or inactive as neuronal excitants and had no antagonistic effects at excitatory amino acid receptors. The structure of 7-HPCA in the crystalline state was established by X-ray analyses. The preferred conformation of 10 in aqueous solution was determined by 1H NMR spectroscopy. On the basis of these studies, 7-HPCA as well as 10 were shown to adopt preferentially conformations with the carboxylate groups in equatorial positions. It is suggested that AMPA, 7-HPCA, and 10 interact with quisqualic acid receptors in conformations essentially reflecting active conformation(s) of glutamic acid at these receptors.

Amino Acids↗
PubMed1985

Excitatory amino acids: studies on the biochemical and chemical stability of ibotenic acid and related compounds.

The complex pharmacological profile (excitation/inhibition) of ibotenic acid on single neurons in the mammalian CNS prompted studies on the stability of ibotenic acid and a number of structurally related excitatory amino acids under different in vitro conditions in the presence or absence of enzymes. Ibotenic acid, (RS)-3-hydroxy-4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-7-carboxylic acid (7-HPCA), (RS)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and (RS)-alpha-amino-3-hydroxy-4-bromo-5-isoxazolepropionic acid (4-Br-homoibotenic acid) were all inhibitors of (S)-glutamic acid decarboxylase (GAD) in mouse brain homogenates, but only ibotenic acid was shown to undergo decarboxylation during incubation with brain homogenates. The formation of the decarboxylated product, muscimol, which primarily occurred in a synaptosomal fraction, was dependent on the presence of pyridoxal-5-phosphate (PALP) and was inhibited by (S)-glutamic acid, 3-mercaptopropionic acid (3MPA), aminooxyacetic acid (AOAA), and allyglycine, suggesting that ibotenic acid is a substrate for GAD. The overall decomposition rate for ibotenic acid (8.7 nmol min-1 mg-1 of protein), which apparently embraces other reactions in addition to decarboxylation to muscimol, was higher than the rate of decarboxylation of (S)-glutamic acid (3.2 nmol min-1 mg-1 of protein). At pH 7.4 and 37 degrees C, but in the absence of enzymes, none of the excitatory amino acids under study underwent any detectable decomposition, whereas ibotenic acid and 7-HPCA, but not AMPA and 4-Br-homoibotenic acid, decomposed, partially by decarboxylation, at 100 degrees C in a pH-dependent manner. In the presence of liver homogenates, ibotenic acid was also shown to decompose.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

A simplified approach to retrograde/anterograde axonal labeling using combined injections of horseradish peroxidase and ibotenic acid.

Combined injections of ibotenic acid and horseradish peroxidase (HRP) were made into the region of the mouse ventrobasal thalamus that is related to the large mystacial vibrissae. Examination 4 and 5 days later of the corresponding area of the primary somatosensory cortex (i.e., barrel cortex), in thick and in thin sections, showed it to contain numerous corticothalamic projection cells the somata, dendrites and axons of which were densely labeled by the retrograde transport of HRP. Analysis of serial thin sections showed that thalamocortical axon terminals, which had degenerated in response to the injection of ibotenic acid, formed approximately 20% of the asymmetrical synapses in barrel cortex. The fine structure and distribution in cortex of degenerating thalamocortical axon terminals and of intrinsic HRP-labeled corticothalamic axon terminals were identical to those reported in previous studies in which the injection of HRP into the thalamus was combined with the making of electrolytic lesions. This indicates that injecting ibotenic acid is an effective replacement for electrolytic lesioning of the thalamus. The combined injection of ibotenic acid and HRP represents a new and efficient approach for studying reciprocal projection pathways.

Animals↗
PubMed1987

Open field activity and passive avoidance responses in rats after lesion of the central amygdaloid nucleus by electrocoagulation and ibotenic acid.

The effect of two types of bilateral lesion of the central amygdaloid nucleus on open field activity and on the acquisition of a passive avoidance conditioning in a run way was studied in male Wistar rats. The animals were divided into three groups: sham-operated, a group with lesions caused by electrocoagulation, and a third group lesioned by local application of ibotenic acid. Ibotenic acid is a neurotoxin which damages the neurons but spares the passing fibres. The results indicate that lesion by electrocoagulation leads to a significant increase in the number of rearing responses in the open field. Moreover, lesion by electrocoagulation, but not by ibotenic acid, leads to a deficit in the acquisition of passive avoidance conditioning. This latter result suggests that the deficit is caused by lesion of the fibres crossing the central amygdaloid nucleus and not by the intrinsic elements of the nucleus.

Amygdala↗
PubMed1994

Hippocampal theta rhythm in behaving rats following ibotenic acid lesion of the septum.

The effects of ibotenic acid lesion of the septum were studied in rats implanted with chronically indwelling electrodes and septal cannula. Each rat served as its own control and the properties of the hippocampal theta rhythm were studied before and after ibotenic acid and control saline infusion into the medial septal area. Ibotenic acid preferentially killed neurons in the lateral septum, and significantly attenuated the hippocampal theta rhythm about 50% bilaterally, at both surface and deep electrodes. The coherence and the phase of the theta rhythm at the CA1 apical dendrites, with respect to a superficial electrode, also declined significantly after ibotenic acid lesion. Pilocarpine (25 mg/kg i.p.) induced a theta rhythm of 7-9 Hz during immobility in the lesioned rats that was significantly higher in frequency than that induced in intact rats (4-6 Hz). In lesioned rats, the theta rhythm during tail pinch under urethane anesthesia was largely abolished, and the theta during walking was attenuated by atropine sulfate (50 mg/kg i.p.). Phencyclidine (10 mg/kg i.p.) or parachlorophenylalanine (PCPA) alone, which was inferred to abolish an atropine-resistant theta input, did not affect the power of the walking theta rhythm in either the lesioned or the normal rat. It was concluded that the theta in the behaving rats after ibotenic acid lesion in the septum has a strong atropine-sensitive component, and that it is not predominantly atropine-resistant, as suggested previously. The lack of PCPA effect on the theta phase in intact and lesioned rats also suggested a different view of the atropine-resistant theta in hippocampal region CA1. One possible mechanism of the atropine-resistant theta at the distal dendrites of pyramidal cells may result from rhythmic inhibition by stratum lacunosum-moleculare interneurons which may be activated by either serotonergic or cholinergic inputs.

Animals↗
PubMed1979

Intrahippocampal injections of ibotenic acid provide histological evidence for a neurotoxic mechanism different from kainic acid.

Stereotaxic injections of ibotenic acid (IBO) and kainic acid (KA) into either the dorsal hippocampus or the lateral cerebroventricle were performed in order to determine the relative potencies of the drugs and the vulnerability of different hippocampal cell types to their neurotoxic action, IBO was found to be approximately five times less potent than KA in causing degeneration of hippocampal neuronal cell bodies. Unlike KA (0.5 and 1.0 microgram), IBO (5.0 micrograms) caused few signs of intrahippocampal bleeding or necrosis of non-neuronal elements. Pyramidal cells of the CA3 and CA4 regions were the most sensitive and dentate granule cells the least sensitive to KA. In contrast, IBO cused degeneration of granule cells and CA3/CA4 pyramids to an equal extent.

Animals↗
PubMed1990

Calcium deposits develop in rat substantia nigra but not striatum several weeks after local ibotenic acid injection.

The excitotoxin ibotenic acid (IBO) was used to place local circumscript lesions in rat substantia nigra (SN). Four to six months after the injection we found in the neuron depleted SN basophilic deposits resembling calcium concretion. Additional experiments revealed that calcium deposits, as verified with the alizarin red stain, were first detectable after a delay of 4 weeks. They increased in number, size and extent over the following 12 weeks, but remained confined to the boundaries of SN. Injection of at least 3.5 micrograms IBO was necessary for induction of deposits. In striatum, 14 micrograms IBO did not cause clearly identifiable concretions. Thus, IBO-induced lesions are not stationary but mature, and the long-term effects can be different in different brain regions. These observations may have some relevance for considerations on the cause of the idiopathic nonarteriosclerotic calcifications.

Animals↗
PubMed1989

Comparative effects of kainic, quisqualic, and ibotenic acids on phenylethanolamine-N-methyltransferase-containing cells of rat retina.

Phenylethanolamine-N-methyltransferase (PNMT) activity is located in a subpopulation of amacrine cells in the inner nuclear layer of the rat retina. Kainic, quisqualic, and ibotenic acids, all of which are analogues of glutamic acid, were injected intravitreally to the right and saline to the contralateral left eyes of adult male rats in order to determine the effect of these agents upon retinal PNMT activity. Animals were sacrificed 1 week later for tissue removal. The effect of these agents was measured by radiometric assay for PNMT. The fall in PNMT activity was used to measure the sensitivity of the PNMT-containing cells to these agents. Kainic acid was the most potent, producing the greatest reduction in PNMT activity in the smallest doses. Quisqualic acid was intermediate in potency to that of kainic and ibotenic acids. Ibotenic acid reduced PNMT activity only in extremely high doses. The PNMT-containing cells are sensitive to the toxic actions of kainic and quisqualic acids, but relatively insensitive to the actions of ibotenic acid.

Animals↗
PubMed1981

No detectable remote lesions following massive intrastriatal injections of ibotenic acid.

Behavioral and anatomical consequences of particularly large intrastriatal injections of ibotenic acid are described. Only in the rat with the largest injection, which encompassed almost the entire frontal lobe, were enduring aphagia and adipsia observed; epileptic attacks were, however, not detectable in this or in any other of the rats. In spite of the massiveness of the lesion, neither remote lesions nor damage to passing fibers was observed. It is therefore suggested to substitute kainic acid by ibotenic acid for the production of local, discrete brain lesions.

Animals↗