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Biomedical subjects

T E Salt

Publications and source records attributed to T E Salt.

At least 55 records · Page 3Linked to original sources
PubMed1997

Modulation of sensory and excitatory amino acid responses by nitric oxide donors and glutathione in the ventrobasal thalamus of the rat.

Nitric oxide has been identified as having a role in synaptic transmission in the central nervous system. In the ventrobasal complex of the thalamus (VB), the precursor of nitric oxide synthesis, L-arginine, causes enhancement of excitatory amino acid responses and somatosensory transmission. In this study, the nitric oxide donors sodium nitroprusside, 3-morpholinosydnonimine and S-nitrosoglutathione were applied to VB relay neurons by iontophoresis and responses of single neurons were recorded extracellularly. Sodium nitroprusside caused selective inhibition of responses to NMDA, probably mediated by a by-product, ferrocyanide, as described in previous studies. 3-Morpholinosydnonimine and S-nitrosoglutathione, however, caused potentiation of responses to sensory stimuli and to excitatory amino acids. In contrast, glutathione in both its reduced and oxidized forms reduced such responses, and this suggests that the potentiating effect of S-nitrosoglutathione could be due to nitric oxide production. These results are consistent with the hypothesis that nitric oxide may have a local modulatory role in the thalamus. Data are presented which suggest that glutathione may have a negative modulatory influence on neurotransmission and excitatory amino acid responses in the ventrobasal thalamus.

Action Potentials↗
PubMed1996

Cellular localisation of metabotropic glutamate receptors in the mammalian optic nerve: a mechanism for axon-glia communication.

It has been proposed that neurotransmitter signalling can occur between axons and glia in the mammalian optic nerve in the absence of synaptic specialisations, and that this may be glutamate mediated. Here, the cellular distribution of five metabotropic glutamate receptors (mGluR's 1a, 1b, 1c, 2/3 and 5) have been assessed in the rat optic pathway using specific antibodies. Positive immunoreactivity is found for mGluR2/3 and 5. Both are found in axons, although only mGluR5 is present in the majority of these. Strong immunoreactivity for mGluR2/3 is found in cells in the optic pathway and thalamus. The cellular morphology and distribution is consistent with their being astrocytes. Examination of brain sections stained for mGluR2/3 is consistent with this notion, with many cells having end-feet processes terminating on blood vessels or the pial surface. The axonal immunoreactivity could represent the presence of these receptors on axons, but it is more probable that the receptor protein synthesised in the ganglion cell soma is being transported to the cell terminal in sufficient concentration to be revealed by immunohistochemistry. The reason for the axon-astrocyte signalling is unclear, and may be associated with metabolic coupling. In development, communication between axons and glia mediates a range of functions including pathway selection and myelination. It is probable that in the adult this form of signalling underpins a range of functions that have yet to be described.

Animals↗
PubMed1996

Antagonism of the presumed presynaptic action of L-AP4 on GABAergic transmission in the ventrobasal thalamus by the novel mGluR antagonist MPPG.

The metabotropic glutamate receptor (mGluR) agonists CCG-I and L-AP4, acting at Group II and Group III mGluRs respectively, can reduce GABAergic synaptic inhibition on single neurones in the rat thalamus in vivo via a presumed presynaptic mechanism. The actions of L-AP4 were antagonized by (+/-)-alpha-methyl-4-phosphonophenylglycine (MPPG), whereas CCG-I was significantly less affected. Thus MPPG may be a useful tool for detecting physiological roles for Group III mGluRs.

Alanine↗
PubMed1996

Characterization of the metabotropic glutamate receptors (mGluRs) which modulate GABA-mediated inhibition in the ventrobasal thalamus.

The ventrobasal thalamus (VB) relays and processes somatosensory information ascending to the cerebral cortex. Several types of mGluR are known to be present in VB, and we have previously shown that Group II and Group III mGluR agonists can reduce inhibitory synaptic transmission by acting at presynaptic receptors on GABAergic terminals in this structure. We have tested the action of several antagonists against the disinhibitory action of the Group II agonist CCG-I [(2S,3S,4S)-alpha-(carboxycyclopropyl)-glycine] and the Group III agonist L-AP4 [L-2-amino-4-phosphonobutyrate] in the VB of anaesthetized rats using extracellular single-neurone recording techniques and iontophoretic applications of mGluR antagonists and agonists. The antagonists MAP4 [alpha-methyl-L-AP4] and MPPG [(+/-)-alpha-methyl-4-phosphonophenylglycine] reduced the disinhibitory actions of L-AP4 whilst having little effect on the disinhibitory action of CCG-I. In contrast, MCCG [alpha-methyl-CCG-I] and MCPG [(+)-alpha-methyl-4-carboxyphenylglycine] antagonized CCG-I, whilst having less effect against L-AP4 responses. These results support the hypothesis that GABAergic inhibitory transmission in VB can be modulated by at least two types of mGluR, belonging to Group II and Group III. Furthermore, the novel antagonists appear to be useful tools for the future study of the physiological role of these receptors in thalamic sensory processing.

Action Potentials↗
PubMed1996

Nitric oxide precursor arginine and S-nitrosoglutathione in synaptic and glial function.

In the last few years, there has been an important increase in interest in nitric oxide (NO) as an intercellular messenger, and its putative role in numerous CNS functions is being continually updated. Arginine, the nitric oxide precursor, has been found in our laboratory to be released following stimulation of the white matter in the cerebellum and of sensory afferents in the thalamus. Since arginine is localized in glial cells while the nitric oxide synthesizing enzyme is localized in different cells (predominantly in neurons), these findings may represent a transfer of arginine from glia to neurons in order to supply the nitric oxide synthase with its substrate. The mechanism underlying this glial-neuronal interaction seems to involve the activation of excitatory amino acid receptors present on glial cells. Our results speak for an intense crosstalk between neurons and glia (activation of glial receptors by neurotransmitter released from neurons) and between glia and neurons (supply of the nitric precursor arginine from glia to neurons). The form in which NO is released from cells has been much debated. The chemical identity of the endothelial-derived relaxing factor in particular is still a matter of dispute, the major contender being NO. and a S-nitrosothiol compound. Based on the strong reactivity of NO for thiols and on the presence of cysteine and glutathione at the mM level intracellularly and microM level extracellularly, we have investigated whether S-nitrosothiols, i.e. S-nitrosoglutathione, may be the potential "package" form in which NO could be stored. We demonstrated, with HPLC coupled to mass spectrometry techniques, the presence of endogenous nitrosoglutathione in rat brain tissue. This packaging of NO in the form of nitrosothiols might serve to facilitate its transfer, prolong its life, and target its delivery to specific effectors. That could confer a specificity of action to the widely diffusable messenger NO, may determine the range of effectiveness of NO and mitigate its adverse cytotoxic effects.

Animals↗
PubMed1996

Functions of ionotropic and metabotropic glutamate receptors in sensory transmission in the mammalian thalamus.

The thalamic relay nuclei play a pivotal role in gating and processing sensory information en route to the cerebral cortex. The major ascending sensory afferents and the descending cortico-fugal afferents to the thalamus almost certainly use the excitatory amino acid L-glutamate as their transmitter. This paper reviews the nature of this transmission in terms of the receptor types which may be used (NMDA, AMPA, kainate and metabotropic glutamate receptors), their electrophysiological and pharmacological properties, and their differential location in the thalamus on neurones, terminals and glial elements. Whilst AMPA receptors, probably of more than one variety, are likely to mediate fast transmission in the thalamus, the contributions of NMDA receptors and metabotropic glutamate receptors to sensory responses under different stimulus conditions may be more varied. This is discussed in the context of the possible functional significance of the interplay of L-glutamate-gated currents with intrinsic membrane currents of thalamic neurones. The interaction of L-glutamate transmission with other modulators (acetylcholine, noradrenaline, serotonin, glycine, D-serine, nitric oxide, arginine, redox agents) is considered.

Animals↗
PubMed1996

Role of N-methyl-D-aspartate and metabotropic glutamate receptors in corticothalamic excitatory postsynaptic potentials in vivo.

The ventrobasal thalamus is the principal somatosensory thalamic relay nucleus, and it receives two major sources of excitatory input: firstly an input from ascending sensory afferents, and secondly a descending projection from the primary somatosensory cortex. There is considerable anatomical evidence to suggest that both of these projections utilise the excitatory amino acid L-glutamate as their neurotransmitter. Previous work from this laboratory has shown that the sensory input to the rat ventrobasal thalamus in vivo is mediated by ionotropic excitatory amino acid receptors of both the N-methyl-D-aspartate and non-N-methyl-D-aspartate type. These findings are consistent with data from other studies in various thalamic relay nuclei. In contrast, there are considerably less data available concerning the synaptic pharmacology of the corticothalamic projection although there have been both speculation and studies concerning the functional significance of this pathway. There is some evidence to suggest an involvement of N-methyl-D-aspartate receptors and metabotropic glutamate receptors. The aim of this study was to determine which excitatory amino acid receptors might mediate cortically-elicited excitatory postsynaptic potential in the ventrobasal thalamus in vivo. Intracellular recordings were made, and neurotransmitter antagonists were applied on to rat ventrobasal thalamus neurons by microiontophoresis. Cortically-elicited excitatory postsynaptic potentials were reduced by the N-methyl-D-aspartate antagonist 3-[(+/-)-2-carboxy-piperazin-4-yl]-propyl-1-phosphonate, or the Group I metabotropic antagonist (S)-4-carboxyphenylglycine. These data indicate that both N-methyl-D-aspartate receptors and Group I (possibly metabotropic glutamate receptors type I) metabotropic receptors are involved in the mediation of corticothalamic transmission. Such a transmitter mechanism would allow a modulatory system that could selectively enhance other excitatory inputs. Some of these data have been reported in abstract form.

Animals↗
PubMed1996

Importance of NMDA receptors for multimodal integration in the deep layers of the cat superior colliculus.

1. Many sensory events contain multimodal information, yet most sensory nuclei are devoted to the analysis of single-modality information. In the deep superior colliculus (DSC), visual, auditory, and somatosensory information converges on individual multimodal neurons. The responses of multimodal neurons are determined by the temporal and spatial correspondence properties of the converging inputs such that stimuli arising from the same event elicit a facilitated multimodal response. 2. N-methyl-D-aspartate (NMDA) receptors may underlie the detection of spatial and temporal coincidence and could be involved in the generation of multimodal facilitatory responses because of the nonlinear properties of NMDA-receptor-mediated events. To assess the role of NMDA receptors in multimodal integration, we made extracellular recordings from single multisensory neurons in the DSC of the cat. 3. The responses to visual, auditory, and somatosensory stimuli alone and to multimodal combinations of stimuli were challenged with iontophoretically applied D-2-amino-5-phosphonovalerate (AP5), an NMDA receptor antagonist. All responses to visual stimuli presented alone (n = 9) were greatly reduced. Somatosensory responses (n = 25) were usually decreased. In contrast, the responses to auditory stimulation were decreased (n = 9), unaffected (n = 3), or enhanced (n = 5). 4. Responses to multimodal stimulus presentations were consistently reduced during iontophoretic application of AP5, irrespective of the modalities that made up the stimulus. The reductions of multimodal responses were significantly greater than the sum of the reductions of responses to single-modality stimuli. 5. The data suggest that for unimodal stimuli, the importance of NMDA receptors in synaptic transmission of sensory responses in DSC may be dependent on the stimulus modality. Furthermore, NMDA receptors are of major importance in the integration of input from different modalities for the generation of multimodal responses.

2-Amino-5-phosphonovalerate↗
PubMed1995

Modulation of sensory neurone excitatory and inhibitory responses in the ventrobasal thalamus by activation of metabotropic excitatory amino acid receptors.

Several different types of metabotropic excitatory amino acid receptors (mGluRs) are present in the thalamus. We have previously shown that the agonists L-AP4 and CCG-I can have apparently presynaptic effects on GABAergic inhibitory transmission in the thalamus. In this study we attempted to characterize the different receptor types which may mediate these effects and the known post-synaptic excitatory actions of 1S,3R-ACPD in the ventrobasal thalamus, by using a number of agonists with different spectra of activity at the various mGluRs. Inhibitory responses in ventrobasal thalamic neurones of urethane-anaesthetized rats were evoked by air-jet stimuli to the vibrissae and extracellular recording methods were used to reveal inhibitory responses as an inhibition of excitatory responses in a condition-test paradigm. The Group II and Group III mGluR agonists L-AP4, CCG-I, DCG-IV, 1S,3R-ACPD and S-4C3HPG, applied in the vicinity of the recording site by iontophoresis, were found to reduce inhibitions revealed by the condition-test paradigm (by 67, 75, 50, 43 and 77% from control inhibitions, respectively). The endogenous mGluR agonist L-serine-O-phosphate (L-SOP) was found to have similar, although weaker, actions (31% reduction of inhibition), while the Group I agonist 3,5-DHPG had little effect in this test (9% reduction of inhibition). In contrast, both 3,5-DHPG and 1S,3R-ACPD had direct excitatory actions on VB neurones, and these could be antagonized by 4CPG. The effects of CCG-I in the condition-test paradigm could be antagonized by the antagonists MCCG, MCPG, but not MAP4.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Thalamocortical and corticocortical excitatory postsynaptic potentials mediated by excitatory amino acid receptors in the cat motor cortex in vivo.

Intracellular recordings were made from neurons in the motor cortex of an anaesthetized cat, together with iontophoretic application of excitatory amino acid receptor agonists and antagonists, in order to evaluate the role of such receptors in excitatory postsynaptic potentials evoked from stimulation of afferent and recurrent pathways in vivo. Excitatory postsynaptic potentials which were evoked by stimulation of the ventrolateral thalamus were found to be largely insensitive to antagonism by N-methyl-D-aspartate receptor antagonists, although they were susceptible to blockade by the non-N-methyl-D-aspartate receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione. Increasing the ventrolateral thalamus stimulation frequency from 0.5 or 1 to 5 Hz caused an increase of evoked excitatory postsynaptic potential amplitudes and number of action potentials. These augmented excitatory postsynaptic potentials remained insensitive to application of N-methyl-D-aspartate antagonists. In contrast, recurrent excitatory postsynaptic potentials evoked by stimulation of the pyramidal tract were found to be sensitive to N-methyl-D-aspartate receptor antagonists and/or non-N-methyl-D-aspartate receptor antagonists in some neurons. These results demonstrate the involvement of both N-methyl-D-aspartate- and non-N-methyl-D-aspartate receptors in synaptic responses of cat motor cortex neurons in vivo, and that the synaptic pharmacology of the thalamic input may differ from that of the local recurrent pathways.

2-Amino-5-phosphonovalerate↗
PubMed1995

Distinct presynaptic metabotropic receptors for L-AP4 and CCG1 on GABAergic terminals: pharmacological evidence using novel alpha-methyl derivative mGluR antagonists, MAP4 and MCCG, in the rat thalamus in vivo.

A variety of metabotropic excitatory amino acid receptors are present in the thalamus. We have investigated the possibility that some of these receptors may have presynaptic effects on GABAergic inhibitory transmission in the thalamus. Inhibitory responses in ventrobasal thalamic neurons of urethane-anaesthetized rats were evoked by either air-jet stimuli to the vibrissae or by electrical stimulation of the somatosensory cortex. Both intracellular and extracellular recording methods were used to reveal inhibitory responses, either as inhibitory postsynaptic potentials or inhibition of excitatory responses in a condition-test paradigm. The metabotropic glutamate receptor agonists (S)-2-amino-4-phosphonobutyrate (L-AP4) and (2S,3S,4S)-alpha-(carboxycyclopropyl)-glycine (CCG1), applied in the vicinity of the recording site by iontophoresis, were found to reduce the amplitudes of inhibitory postsynaptic potentials (to 76% and 63% of control amplitudes, respectively) and inhibitions revealed by the condition-test paradigm (to 33% and 28% of control inhibitions, respectively). As the inhibitory responses arise from the neurons of the nucleus reticularis thalami, some distance away from the site of recording and iontophoretic drug application, it is likely that the reduction of inhibition seen with L-AP4 and CCG1 is due to an action of these agonists on the terminals or axons of these inhibitory neurons. The novel antagonists of L-AP4 and CCG1, alpha-methyl-L-AP4 and alpha-methyl-CCG1, were found to block the disinhibitory actions of the agonists in a differential manner when applied iontophoretically. This suggests that there may be at least two types of receptor mediating the disinhibitory effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Excitatory amino acid receptors participate in synaptic transmission of visual responses in the superficial layers of the cat superior colliculus.

The contribution of NMDA and non-NMDA receptors to visual synaptic transmission in the superficial layers of the superior colliculus of the cat has been studied using extracellular recording and iontophoretic techniques. Neuronal responses to natural visual stimulation and the ejection of NMDA and AMPA were observed in the absence and presence of the antagonists CNQX, CPP and AP5. CNQX routinely reduced the responses to visual stimulation at ejection currents which selectively blocked the responses to AMPA but not those to NMDA. Agonist selective ejection currents of CPP and AP5 also reduced visual responses of most SC neurons, but there was a substantial majority whose visual responses were resistant to these antagonists. Neurons with CPP/AP5 resistant visual responses were more commonly found 750-1000 microns from the dorsal surface of the SC. The data indicate that, while non-NMDA receptors are heavily involved in visual synaptic transmission in the superficial SC, the involvement of NMDA receptors varies with recording depth.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed1994

The function of metabotropic excitatory amino acid receptors in synaptic transmission in the thalamus: studies with novel phenylglycine antagonists.

The phenylglycines 3-hydroxyphenylglycine, 4-carboxy-3-hydroxy-phenylglycine (4C3HPG), 4-carboxyphenylglycine (4CPG) and alpha-methyl-4-carboxyphenylglycine (MCPG) were evaluated as putative selective antagonists of metabotropic glutamate receptors on single neurones of the ventrobasal thalamus of rats, with a view to using these compounds as tools to elucidate synaptic mechanisms in this brain area. The S-isomers of the latter three compounds were found to reduce excitations evoked by iontophoretically applied 1S,3R-ACPD, but not those evoked by ionotropic excitatory amino receptor agonists. When the antagonists were tested against sensory synaptic responses of ventrobasal neurones, it was found that responses evoked by noxious thermal stimulation of the peripheral receptive field were reduced in parallel with responses to 1S,3R-ACPD. In contrast, responses of neurones evoked by non-noxious (air-jet) stimuli were not reduced by the phenylglycine antagonists and 4C3HPG was found to enhance such responses, possibly by a presynaptic action mediated via mGluR2 receptors. The reductions of nociceptive responses are discussed in the context of antagonism of mGluR1 receptors, which are known to be numerous in the thalamus and located on post-synaptic dendrites. The involvement of such receptors in the nociceptive responses of thalamic neurones may be of considerable functional significance.

Action Potentials↗
PubMed1994

Release of the nitric oxide precursor, arginine, from the thalamus upon sensory afferent stimulation, and its effect on thalamic neurons in vivo.

The neurophysiology and neuroanatomy of the thalamus have been extensively studied in a variety of species and sensory systems. The identity of the neurotransmitter(s) which mediate the excitation from ascending sensory afferents on to thalamic relay neurons is, however, still unclear, although it appears to be a substance which is a ligand for excitatory amino acid receptors, as the responses of ventrobasal thalamus neurons to natural stimulation of somatosensory afferents arising from the mustachial vibrissae of the rat are mediated by ionotropic excitatory amino acid receptors, when stimulation is performed using an air-jet directed at the vibrissa receptor field. In an effort to determine the transmitter of these sensory afferents, we have attempted to detect the release of amino acids in the ventrobasal thalamus in vivo upon such stimuli. We have thus used a similar natural stimulation protocol, together with push-pull perfusion and recording in the ventrobasal thalamus, and we describe the release of the amino acid, arginine, in this brain area following physiological stimulation of afferents. Furthermore, we show that application of L-arginine on to thalamic relay neurons can facilitate sensory synaptic transmission, possibly via the synthesis of the diffusable messenger, free radical gas, nitric oxide. This may represent a novel, local positive-feedback, modulatory system which could enhance the responsiveness of thalamic neurons to sensory input.

Afferent Pathways↗
PubMed1993

Mediation of thalamic sensory responses in vivo by ACPD-activated excitatory amino acid receptors.

The existence of the so-called metabotropic excitatory amino acid receptor has been known for some years. Various functions have been suggested for this receptor, but the lack of selective antagonists for (IS, 3R)-aminocyclopentane dicarboxylic acid (ACPD) has precluded the direct demonstration of a functional role for this receptor in synaptic processes. We describe here a specific antagonism of the excitatory responses of thalamic neurons to ACPD by two novel antagonists, and a parallel antagonism by these compounds of sensory synaptic responses to noxious stimuli of the same neurons. This provides the first direct pharmacological evidence for a functional role of ACPD-sensitive receptors in central neurotransmission, and indicates that these receptors may play an important part in central sensory processes.

Animals↗
PubMed1993

Competitive antagonism at metabotropic glutamate receptors by (S)-4-carboxyphenylglycine and (RS)-alpha-methyl-4-carboxyphenylglycine.

Two phenylglycine derivates, (S)-4-carboxyphenylglycine and (RS)-alpha-methyl-4-carboxyphenylglycine, competitively antagonised (1S,3R)-1-aminocyclopentane-1,3-dicarboxylate (ACPD)-stimulated phosphoinositide hydrolysis in rat cerebral cortical slices. The same phenylglycine derivatives selectively antagonized ACPD-induced depolarization in neonatal rat spinal motoneurones and rate thalamic neurones relative to depolarization or excitation induced by N-methyl-D-aspartate (NMDA) or alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA). Both phenylglycine derivatives also selectively depressed synaptic excitation in thalamic neurones evoked by noxious thermal stimuli, without affecting the synaptic stimulation of the same cells by non-noxious stimuli.

Animals↗
PubMed1993

Stereospecific antagonism by (+)-alpha-methyl-4-carboxyphenylglycine (MCPG) of (1S,3R)-ACPD-induced effects in neonatal rat motoneurones and rat thalamic neurones.

The (+)-enantiomer of alpha-methyl-4-carboxyphenylglycine (MCPG) stereoslectively antagonized the depolarization of neonatal rat motoneurones and the excitation of rat thalamic neurons induced by the specific metabotropic glutamate receptor agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylate (ACPD). (+)-MCPG preferentially reduced (1S,3R)-ACPD-induced responses relative to responses induced by (S)-alpha-amino-3-hydorxy-5-methylisoxazole-4-propionic acid (AMPA) and N-methyl-D-aspartate (NMDA).

Animals↗