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To investigate the role of excitatory amino acid neurotransmission within the rostral raphe pallidus area (RPa) in thermogenic and cardiovascular responses, changes in sympathetic nerve activity to brown adipose tissue (BAT), BAT temperature, expired CO(2), arterial pressure, and heart rate were recorded after microinjection of excitatory amino acid (EAA) receptor agonists into the RPa in urethan-chloralose-anesthetized, ventilated rats. To determine whether EAA neurotransmission within the RPa is necessary for the responses evoked by disinhibition of the RPa or by prostaglandin E(2) acting within the medial preoptic area, BAT sympathetic nerve activity, BAT temperature, expired CO(2), arterial pressure, and heart rate were measured during these treatments both before and after blockade of EAA receptors within the RPa. Microinjection of EAA receptor agonists into the RPa resulted in significant increases in all measured variables; these increases were attenuated by prior microinjection of the respective EAA receptor antagonists into the RPa. Microinjection of prostaglandin E(2) into the medial preoptic area or microinjection of bicuculline into the RPa resulted in respective significant increases in BAT sympathetic nerve activity (+approximately 190% and +approximately 235% of resting levels), in BAT temperature (approximately 1.8 degrees C and approximately 2 degrees C), in expired CO(2) (approximately 1.1% and approximately 1.1%), and in heart rate (approximately 97 beats per minute (bpm) and approximately 100 bpm). Blockade of ionotropic EAA receptors within the RPa by microinjection of kynurenate completely reversed the prostaglandin E(2) or bicuculline-evoked increases in all of the measured variables. Blockade of either N-methyl-D-aspartate (NMDA) receptors or non-NMDA receptors alone resulted in marked attenuations of the prostaglandin E(2)-evoked effects on all of the measured variables. These data demonstrate that activation of an EAA input to the RPa is necessary for the BAT thermogenic and the cardiovascular effects resulting from the actions of prostaglandin E(2) within the medial preoptic area or from the disinhibition of local neurons in the RPa.
1. The effects of the active metabolite of chloral derivative sedative-hypnotic agents, 2,2,2-trichloroethanol (trichloroethanol), and its analog 2,2,2-trifluoroethanol (trifluoroethanol), were studied on ion current activated by the excitatory amino acids N-methyl-D-aspartate (NMDA) and kainate in mouse hippocampal neurones in culture using whole-cell patch-clamp recording. 2. Both trichloroethanol and trifluoroethanol inhibited excitatory amino acid-activated currents in a concentration-dependent manner. Trichloroethanol inhibited NMDA- and kainate-activated currents with IC50 values of 6.4 and 12 mM, respectively, while trifluoroethanol inhibited NMDA- and kainate-activated currents with IC50 values of 28 and 35 mM, respectively. 3. Both trichloroethanol and trifluoroethanol appeared to be able to inhibit excitatory amino acid-activated currents by 100 per cent. 4.Concentration-response analysis of NMDA- and kainate-activated current revealed that trichloroethanol decreased the maximal response to both agonists without significantly affecting their EC50 values. 5. Both trichloroethanol and trifluoroethanol inhibited excitatory amino acid-activated currents more potently than did ethanol. The inhibitory potency of trichloroethanol and trifluoroethanol appears to be associated with their increased hydrophobicity. 6. The observation that trichloroethanol inhibits excitatory amino acid-activated currents at anaesthetic concentrations suggests that inhibition of excitatory amino acid receptors may contribute to the CNS depressant effects of chloral derivative sedative-hypnotic agents.
Glioma cells release glutamate through expression of system xc-, which exchanges intracellular glutamate for extracellular cysteine. Lack of the excitatory amino acid transporter 2 (EAAT2) expression maintains high extracellular glutamate levels in the glioma microenvironment, causing excitotoxicity to surrounding parenchyma. Not only does this contribute to the survival and proliferation of glioma cells, but is involved in the pathophysiology of tumour-associated epilepsy (TAE). We investigated the role of the peroxisome proliferator activated receptor gamma (PPARγ) agonist pioglitazone in modulating EAAT2 expression in glioma cells. We found that EAAT2 expression was increased in a dose dependent manner in both U87MG and U251MG glioma cells. Extracellular glutamate levels were reduced with the addition of pioglitazone, where statistical significance was reached in both U87MG and U251MG cells at a concentration of ≥ 30 μM pioglitazone (p < 0.05). The PPARγ antagonist GW9662 inhibited the effect of pioglitazone on extracellular glutamate levels, indicating PPARγ dependence. In addition, pioglitazone significantly reduced cell viability of U87MG and U251MG cells at ≥ 30 μM and 100 μM (p < 0.05) respectively. GW9662 also significantly reduced viability of U87MG and U251MG cells with 10 μM and 30 μM (p < 0.05) respectively. The effect on viability was partially dependent on PPARγ activation in U87MG cells but not U251MG cells, whereby PPARγ blockade with GW9662 had a synergistic effect. We conclude that PPARγ agonists may be therapeutically beneficial in the treatment of gliomas and furthermore suggest a novel role for these agents in the treatment of tumour associated seizures through the reduction in extracellular glutamate.
1. The interactions between 5-hydroxytryptaminergic neurones and excitatory amino acid utilizing neurones were studied in the locus coeruleus of conscious, freely moving rats. The locus coeruleus was superfused with artificial cerebrospinal fluid through a push-pull cannula and 5-hydroxytryptamine (5-HT) was determined in the superfusate that was continuously collected in time periods of 10 min. 2. Superfusion of the locus coeruleus with the NMDA receptor antagonist AP5 (10 microM), kynurenic acid (1 mM), or the AMPA/kainate receptor antagonist DNQX (10 microM) reduced the 5-HT release in the locus coeruleus. 3. Superfusion with the agonists NMDA (50 microM), kainic acid (50 microM) or AMPA (10 microM) enhanced the release rate of 5-HT. AP5 (10 microM) blocked the stimulant effect of NMDA, while tetrodotoxin (1 microM) failed to influence the NMDA-induced release of 5-HT. In the presence of 10 microM DNQX, the releasing effect of 50 microM kainic acid was abolished. 4. Pain elicited by tail pinch, as well as noise-induced stress, increased the release of 5-HT. Superfusion of the locus coeruleus with 10 microM AP5 reduced the tail pinch-induced 5-HT release. AP5 (10 microM) did not affect the noise-induced release of 5-HT which was reduced, when the locus coeruleus was superfused simultaneously with this concentration of AP5 and 1 microM kynurenic acid. DNQX (10 mM) failed to influence the release of 5-HT induced by tail pinch or noise. 5. The findings suggest that 5-hydroxytryptaminergic neurones of the locus coeruleus are tonically modulated by excitatory amino acids via NMDA and AMPA/kainate receptors. The release of 5-HT elicited by tail pinch and noise is mediated to a considerable extent through endogenous excitatory amino acids acting on NMDA receptors, while AMPA/kainate receptors are not involved in this process.
The present study sought to determine whether cannabinoids inhibit glutamatergic and GABAergic synaptic input onto neurons of the hypothalamic arcuate nucleus (ARC), and whether estrogen modulates this process. Whole-cell patch clamp recordings were performed in hypothalamic slices prepared from ovariectomized female guinea pigs. CB1 receptor activation reduced the amplitude of excitatory postsynaptic currents (EPSCs) evoked by electrical stimulation that were sensitive to ionotropic glutamate receptor antagonists. The CB1 receptor antagonist AM251 increased evoked EPSC (eEPSC) amplitude, and reversed the agonist-induced decrease. CB1 receptor activation similarly decreased the amplitude of evoked inhibitory postsynaptic currents (eIPSCs). The cannabinoid-induced reduction in eEPSC and eIPSC amplitude correlated with a decrease in the frequency of miniature EPSCs (mEPSCs) and IPSCs (mIPSCs) that were abolished by ionotropic glutamate and GABA(A) receptor antagonists, respectively. AM251 increased mEPSC frequency, and antagonized the agonist-induced decrease. Compared to neurons obtained from vehicle-treated controls, estradiol benzoate (25 mug; s.c.) given 24 h prior to experimentation increased mEPSC frequency, and markedly decreased the potency of CB1 receptor agonists to decrease mEPSC frequency. Conversely, the steroid potentiated the cannabinoid-induced decrease in mIPSC frequency. These effects were observed in neurons subsequently identified as proopiomelanocortin (POMC) neurons. These data reveal that ARC neurons, including POMC neurons, receive glutamatergic and GABAergic synaptic inputs that are presynaptically inhibited by cannabinoids, and differentially modulated by estrogen. These opposing effects of estrogen on the cannabinoid regulation of amino acid neurotransmission excite POMC neurons, and lend additional insight into the mechanisms underlying estrogen-induced anorexia and negative feedback of the reproductive axis.
The insect repellent methyl salicylate elicits excitatory responses upon interaction with CquiOR32, an odorant receptor (OR) from the southern house mosquito, Culex quinquefasciatus. By contrast, eucalyptol binds to CquiOR32 to generate electrophysiological and behavioral inhibitory responses. In an attempt to identify CquiOR32 variants displaying more robust inhibitory responses for more accurate current-voltage analysis, we sequenced 31 CquiOR32 clones. In the Xenopus oocyte recording system, CquiOR32V2/CquiOrco-expressing oocytes yielded eucalyptol-elicited outward (inhibitory) currents relatively larger than methyl salicylate-generated inward (excitatory) currents. Rescuing experiments showed that two of the amino acid substitutions in CquiOR32V2 located in a predicted transmembrane helix of the receptor are determinants of the outward/inward ratios. These findings, along with co-stimulus assays, suggest that odorant and inhibitor may bind to the same binding pocket. Current-voltage relationships obtained with standard perfusion buffer and those devoid of Na+ or Cl- indicated that both excitatory and inhibitory currents are mediated, at least in part, by cation. We then concluded that eucalyptol is an inverse agonist, which shifts the open ⇔ closed equilibrium of the receptor toward the closed conformation, thus reducing the spontaneous activity. By contrast, the binding of methyl salicylate shifts the equilibrium towards the open conformation and, consequently, leads to an increase in cation influx.
The activity of bulbospinal (presympathetic) vasomotor neurons of the rostral ventrolateral medulla is modulated pre- and postsynaptically by exogenously applied opioid agonists. To determine whether these neurons receive direct opioid inputs, we examined the relationship between bulbospinal barosensitive neurons and nerve terminals immunoreactive for enkephalin in the rostral ventrolateral medulla of rats. By light microscopy, we mapped the distribution of close appositions by enkephalin-immunoreactive varicosities on 10 bulbospinal barosensitive neurons labelled in vivo with biotinamide. We also examined four labelled neurons ultrastructurally for synapses by enkephalin-immunoreactive terminals and determined with post-embedding immunogold labelling whether these enkephalin-positive terminals contained amino acids. Enkephalin-immunoreactive varicosities closely apposed all bulbospinal barosensitive neurons. Maps of the dendritic distribution of appositions indicated that fast-conducting bulbospinal barosensitive neurons with myelinated axons (conduction velocity >3 m/s; n=3) received many appositions (up to 470/neuron); and slowly conducting neurons with unmyelinated axons (conduction velocity <0.90 m/s; n=3), substantially fewer. Ultrastructural analysis of three fast- and one slowly conducting bulbospinal barosensitive neurons revealed numerous synapses from enkephalin-immunoreactive terminals on cell bodies and dendrites. Enkephalin-positive terminals synapsing on bulbospinal barosensitive neurons contained one or more amino acid: GABA+glycine, glutamate alone or GABA+glutamate. Enkephalin-immunoreactive terminals located near biotinamide-labelled cells contained a similar variety of amino acids. In summary, enkephalin-immunoreactive terminals in the rostral ventrolateral medulla densely innervate lightly myelinated presympathetic neurons and more sparsely those with unmyelinated axons. Enkephalin is present in both excitatory (glutamate-immunoreactive) and inhibitory (GABA- and/or glycine-immunoreactive) terminals. The data suggest that endogenous enkephalin inhibits amino acid release from terminals that innervate bulbospinal barosensitive neurons of the rostral ventrolateral medulla.
The overstimulation of excitatory glutamatergic neurotransmission and the inhibition of Na(+),K(+)-ATPase enzymatic activity have both been implicated in neurotoxicity and are possibly related to the pathogenesis of epilepsy and neurodegenerative disorders. In the present study, we investigated whether glutamatergic stimulation by the glutamatergic agonists glutamate, α-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid (AMPA), kainate and N-methyl-d-aspartate (NMDA) modulates the Na(+),K(+)-ATPase and the K(+)-p-nitrophenylphosphatase activities in the crude synaptosomal fraction of the hippocampus and the frontal cortex of rats.
In view of the widespread use of non-steroidal anti-inflammatory drugs for treatment of inflammatory pain, we determined the effects of the non-steroidal anti-inflammatory drug, indomethacin, on dorsal horn neurons in the rat spinal cord in vivo. At 2.0-12.0 mg/kg (i.v.), indomethacin depressed the responses of spinal dorsal horn neurons to the effects of iontophoretic application of substance P, N-methyl-D-aspartate, quisqualate and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate. As indomethacin inhibits cyclo-oxygenase, these are the first data linking prostanoids and possibly arachidonic acid and other eicosanoids to the effects of substance P and glutamate in the spinal dorsal horn. As responses to iontophoretic application can be assumed to have been postsynaptic and as indomethacin had an effect generalized to all excitatory responses, we suggest a postsynaptic site for cyclo-oxygenase. We also suggest that elements in the cyclo-oxygenase signal transduction pathway may thus mediate at least some of the effects of substance P and glutamate receptor activation. Activation of the cyclo-oxygenase pathway in CNS neurons is Ca2- dependent, and activation of both N-methyl-D-aspartate and substance P receptors increases intracellular Ca2+. This led to the expectation that indomethacin would have a greater effect on responses to N-methyl-D-aspartate than to alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate, but the reverse was observed. Thus, in addition to a mediator role, we hypothesize that an element(s) of the cyclo-oxygenase pathway may regulate the efficacy of excitation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptors and perhaps other membrane-bound receptors. The cyclo-oxygenase signal transduction pathway thus appears to play at least two major roles in regulation of sensory processing in the spinal cord. Therefore, non-steroidal anti-inflammatory drugs, via cyclo-oxygenase inhibition, may have multiple actions in control of spinal sensory mechanisms.
The structure of the brain is dramatically altered during the critical period. Physiological substances (neurotransmitters, hormones, etc.) in the body fluctuate significantly before and after sexual maturation. Therefore, the effect of chemical exposure on the central nervous system often differs depending on the developmental stage and sex. We aimed to compare the behavioural effects that emerged from the administration of chemicals to mice of different life stages (immature or mature) and different sex (male or female). We administered mice with domoic acid (DA), a marine poison, and ibotenic acid (IA), found in poisonous mushrooms. These excitatory amino acids act as agonists for glutamate and are potent neurotoxins. Interestingly, the behavioural effects of these chemicals were completely different. Following DA administration, we observed memory deficits only in groups of male mice treated at maturity. Following IA administration, we observed deviations in emotional behaviour in groups of male mice treated at both immaturity and maturity. In contrast, few characteristic changes were detected in all groups of females. Our results support the theory that the behavioural effects of chemical administration vary considerably with developmental stages and sex. In conclusion, our findings promote better understanding of individual differences in excitatory chemical-induced neurotoxicity and provide evidence for future risk strategies and treatments.
Glucocorticoids were long believed to primarily function through cytosolic glucocorticoid receptor (GR) activation and subsequent classical genomic pathways. Recently, however, evidence has emerged that suggests the presence of rapid non-genomic GR-dependent signaling pathways within the brain, though their existence in spinal and peripheral nociceptive neurons remains elusive. In this paper, we aim to systemically identify GR within the spinal cord and periphery, to verify their putative membrane location and to characterize possible G protein coupling and pain modulating properties. Double immunofluorescence confocal microscopy revealed that GR predominantly localized in peripheral peptidergic and non-peptidergic nociceptive C- and Aδ-neurons and existed only marginally in myelinated mechanoreceptive and proprioreceptive neurons. Within the spinal cord, GR predominantly localized in incoming presynaptic nociceptive neurons, in pre- and postsynaptic structures of the dorsal horn, as well as in microglia. GR saturation binding revealed that these receptors are linked to the cell membrane of sensory neurons and, upon activation, they trigger membrane targeted [35S]GTPγS binding, indicating G protein coupling to a putative receptor. Importantly, subcutaneous dexamethasone immediately and dose-dependently attenuated acute nociceptive behavior elicited in an animal model of formalin-induced pain hypersensitivity compared to naive rats. Overall, this study provides firm evidence for a novel neuronal mechanism of GR agonists that is rapid, non-genomic, dependent on membrane binding and G protein coupling, and acutely modulates nociceptive behavior, thus unraveling a yet unconsidered mechanism of pain relief.
Glutamate is a classic excitatory neurotransmitter in the central nervous system (CNS), but despite several studies reporting the expression of glutamate together with its various receptors and transporters within the enteric nervous system (ENS), its role in the gut remains elusive. In this study, we characterized the expression of the vesicular glutamate transporter, vGluT2, and examined the function of glutamate in the myenteric plexus of the distal colon by employing calcium (Ca2+)-imaging on Wnt1-Cre; R26R-GCaMP3 mice which express a genetically encoded fluorescent Ca2+ indicator in all enteric neurons and glia. Most vGluT2 labeled varicosities contained the synaptic vesicle release protein, synaptophysin, but not vesicular acetylcholine transporter, vAChT, which labels vesicles containing acetylcholine, the primary excitatory neurotransmitter in the ENS. The somata of all calbindin (calb) immunoreactive neurons examined received close contacts from vGluT2 varicosities, which were more numerous than those contacting nitrergic neurons. Exogenous application of L-glutamic acid (L-Glu) and N-methyl-D-aspartate (NMDA) transiently increased the intracellular Ca2+ concentration [Ca2+]i in about 25% of myenteric neurons. Most L-Glu responsive neurons were calb immunoreactive. Blockade of NMDA receptors with APV significantly reduced the number of neurons responsive to L-Glu and NMDA, thus showing functional expression of NMDA receptors on enteric neurons. However, APV resistant responses to L-Glu and NMDA suggest that other glutamate receptors were present. APV did not affect [Ca2+]i transients evoked by electrical stimulation of interganglionic nerve fiber tracts, which suggests that NMDA receptors are not involved in synaptic transmission. The group I metabotropic glutamate receptor (mGluR) antagonist, PHCCC, significantly reduced the amplitude of [Ca2+]i transients evoked by a 20 pulse (20 Hz) train of electrical stimuli in L-Glu responsive neurons. This stimulus is known to induce slow synaptic depolarizations. Further, some neurons that had PHCCC sensitive [Ca2+]i transients were calb immunoreactive and received vGluT2 varicosities. Overall, we conclude that electrically evoked release of endogenous glutamate mediates slow synaptic transmission via activation of group I mGluRs expressed by myenteric neurons, particularly those immunoreactive for calb.
Serotonin (1-40 microM) reduced input resistance by 20.6 +/- 6% and hyperpolarized stellate and pyramidal neurons of layers two and three of the lateral entorhinal cortex. 5-Carboxamidotryptamine, a 5-HT1 agonist, and the selective 5-HT1A agonist 8-hydroxy-dipropylaminotetralin mimicked the action of serotonin. The reversal potential of 5-HT-mediated hyperpolarizations was sensitive to the extracellular K+ concentration, indicating a potassium conductance change. Serotonin treatment suppressed excitatory amino acid-mediated synaptic potentials (by 48%, Kd = 6.9 microM) and responses to exogenously applied glutamate (70.1 +/- 17% of control, n = 7), but did not alter paired-pulse facilitation, indicating a postsynaptic site of action. Intracellular application of QX-314, a blocker of potassium conductance, significantly reduced depression of synaptic potentials by 5-HT agonists. In cells filled with QX-314, responses to exogenously applied glutamate were not reduced by serotonin or 5-carboxamidotryptamine application. These results indicate that the observed conductance increase associated with 5-HT application accounts for most if not all of the observed depressant effects of 5-HT1A agonists on excitatory amino acid-mediated neurotransmission.
Glycine and related endogenous compounds (d-serine, d-alanine, sarcosine) serve critical roles in both excitatory and inhibitory neurotransmission and are influenced by a multitude of enzymes and transporters, including glycine transporter 1 and 2 (GlyT1 and GlyT2), d-amino acid oxidase (DAAO), serine racemase (SRR), alanine-serine-cysteine transporter 1 (Asc-1), and kynurenine aminotransferase (KAT). MEDLINE, Web of Science, and PsychINFO were searched for relevant human trials of compounds. Many studies utilizing exogenous administration of small molecule agonists of the glycineB site of n-methyl-d-aspartate receptor have been studied as have a growing number of glycine transporter type 1 (GlyT1) inhibitors. The clinical effects of these compounds are reviewed as are the potential effects of newer novel compounds.
A culture system was developed whereby murine cerebellar granule cells were grown under serum-free conditions in chemically defined B27-supplemented neurobasal medium plus depolarizing K+ levels, to allow the investigation of the role of agonists at the kainate and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors in glutamate-mediated neurotoxicity. Neurones were killed in a concentration-dependent manner by L-glutamate, kainate and its analogues, domoate and 4-(2-methoxyphenyl)-2-carboxy-3-pyrrolidineacetic acid, but not by (S)-AMPA or (S)-5-fluorowillardiine. Kainate (60% maximal cell death at 1mM) was markedly more toxic than NMDA (40% maximal cell death at 1mM) and was shown to be the predominant cause of excitatory amino acid-induced toxicity in these cells as the neuronal death induced by KA was attenuated by the non-NMDA antagonist CNQX, but not the AMPA antagonist LY293558. This study suggests that serum-free cultures of cerebellar granule cells in B27-supplemented neurobasal medium provide a valuable model system for investigations of the role of the kainate receptor in excitatory amino acid-induced neurodegeneration.
This study aimed at analyzing the involvement of (RS)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainate (AMPA/kainate) receptors in the survival of cultured rat embryonic brainstem cells, dissociated on embryonic day 14. The cell number was estimated after pharmacological manipulation of the receptors by exposure to agonists or antagonists. The developmental stage at the moment of drug application was critical for cell survival. We observed after 8 days in vitro a much stronger decrease in the number of gamma-enolase-positive cells when the cultures were treated for 3 days with the antagonist 6,7-dinitroquinoxaline-2,3-dione (DNQX) starting on the day of plating than when DNQX was added after 5 days in vitro. Conversely, exposure to the agonists (RS)-2-amino-3-(3-hydroxy-5-tri-fluoromethyl-4-isoxazolyl)-propion ic acid (T-AMPA) or kainate for 3 days significantly reduced cell survival only when the treatment was initiated after 5 days in vitro. Survival of S-100-positive cells was not affected after exposure to either agonists or antagonists. Neither agonist nor antagonist treatment modified cell proliferation, as assessed by 5-bromo-2'-deoxyuridine (BrdU) staining, suggesting that the decrease in the number of gamma-enolase-positive cells is essentially due to cell death. If some of the processes we observed in vitro correspond to analogous events in vivo, then exposure to excitatory amino acid receptor agonists or antagonists at critical stages of embryogenesis may alter the development of the central nervous system.
Although GABA (gamma-aminobutyric acid) is the major inhibitory neurotransmitter in the brain, intense activation of GABA receptors can cause excitation under certain conditions. In the superficial layers of the guinea-pig superior colliculus (SC) slice the excitatory action of GABA (< or = 3 mM) is dominant and sufficient to induce a robust and novel form of long-term potentiation, termed LTPG, of evoked field excitatory postsynaptic potentials (fEPSPs). This action of GABA could neither be mimicked by GABA-A nor -B agonists which were found to suppress synaptic transmission. Additionally, LTPG was not inhibited by the GABA-A receptor antagonist bicuculline while the GABA-C receptor antagonist imidazol-4-acetic acid prevented LTPG. Glutamatergic synaptic transmission was found to be required, as LTPG was partially use-dependent and did not emerge when glutamate receptors of the non-NMDA type were blocked during GABA application. Moreover, LTPG declined to baseline values in the presence of the NMDA antagonist D,L-2-amino-5-phosphonovaleric acid (APV). In addition, the L-type calcium channel blocker nifedipine inhibited the induction of LTPG. It is suggested that activation of excitatory GABA non-A, non-B receptors can lead to LTP in the SC, which may be of major importance for plastic events since the content of GABA and GABA receptors are particularly high in this brain area.
1. The pharmacological features of the pre- and postsynaptic metabotropic glutamate receptors (mGluRs) present in the guinea-pig olfactory cortex, were examined in brain slices in vitro by use of a conventional intracellular current clamp/voltage clamp recording technique. 2. Bath-application of trans-aminocyclopentane-1,3-dicarboxylic acid (trans-ACPD) (50 microM) produced a sustained membrane depolarization, increase in cell excitability and induction of a post-stimulus inward (after depolarizing) tail current (IADP) (measured under 'hybrid' voltage clamp) similar to those evoked by the muscarinic receptor agonist oxotremorine-M (OXO-M, 2 microM). 3. L-Glutamate (0.25 1 mM. in the presence of 20 microM 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and 100 microM-DL-amino-5-phosphono valeric acid (DL-APV)) or the broad spectrum mGluR agonists 1S,3R-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD, 10 microM), 1S,3S-ACPD (50 microM), ibotenate (Ibo; 25 microM. in the presence of 100 microM DL-APV), the selective mGluR I agonists (S)-3,5-dihydroxyphenylglycine ((S)-3,5-DHPG, 10 microM), (S)-3-hydroxyphenylglycine ((S)-3HPG, 50 microM), or quisqualate (10 microM, in the presence of 20 microM CNQX), but not the mGluR II agonist 2S,1'S,2'S-2-(2'-carboxycyclopropyl)-glycine (L-CCG1,1 microM) or mGluR III agonist L(+)-2-amino-4-phosphonobutyric acid (L-AP4, 1 mM), were all effective in producing membrane depolarization and inducing a post-stimulus IADP. Unexpectedly, the proposed mGluR II-selective agonist (2S,1'R,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)-glycine (DCG-IV, 10 microM, in the presence of 100 microM DL-APV) was also active. 4. The excitatory effects induced by 10 microM 1S,3R-ACPD were reversibly antagonized by the mGluR I/II antagonist (1)-alpha-methyl-4-carboxyphenylglycine ((+)-MCPG, 0.5 1 mM), as well as the selective mGluR I antagonists (S)-4-carboxyphenylglycine ((S)-4CPG) and (S)-4-carboxy-3-hydroxyphenyl glycine ((S)-4C3HPG) (both at 1 mM), but not the nonselective mGluR antagonist L(+)-2-amino-3-phosphonopropionic acid (L-AP3, 1 mM) or the selective mGluR III antagonist (S)-alpha-methyl-L-AP4 (MAP4, 1 mM). 5. The excitatory postsynaptic potentials (e.p.s.ps), induced by single focal stimulation of cortical excitatory fibre tracts, were markedly reduced by 1S,3R-ACPD or L-AP4 (both at 10 microM), and by the selective mGluR II agonists (mGluR 1 antagonists) (S)-4CPG or (S)-4C3HPG (both at 1 mM) but not (S)-3,5-DHPG or (S)-3HPG (both at 100 microM). 6. The inhibitory effects of 1S-3R-ACPD, but not L-AP4, were reversibly blocked by (+)-MCPG (1 mM), whereas those produced by L-AP4, but not 1S,3R-ACPD, were blocked by the selective mGluR III antagonist MAP4 (1 mM). 7. It is concluded that a group I mGluR is most likely involved in mediating excitatory postsynaptic effects, whereas two distinct mGluRs (e.g. group II and III) might serve as presynaptic inhibitory autoreceptors in the guinea-pig olfactory cortex.
Fast glutamatergic and GABAergic transmission in the central nucleus of the inferior colliculus (ICC), a major auditory midbrain structure, is mediated respectively by alpha-amino-3-hydroxy-5-methylisoxazole-4 propionic acid (AMPA) and gamma-aminobutyric acid (GABA)(A) receptors. In this study, we used whole-cell patch clamp recordings in brain slices to investigate the effects of activation of metabotropic glutamate receptors (mGluRs) on synaptic responses mediated by AMPA and GABA(A) receptors in ICC neurons of young rats. Excitatory and inhibitory postsynaptic currents (EPSCs and IPSCs) mediated respectively by AMPA and GABA(A) receptors were elicited by stimulation of the lateral lemniscus, the major afferent pathway to the ICC. The agonists for groups I and II mGluRs, (+/-)-1-aminocyclopentane-trans-1,3-dicarboxylic acid (ACPD), and for group III mGluRs, L-2-amino-3-hydroxypropanoic acid 3-phosphate (L-SOP), did not affect intrinsic membrane properties of the ICC neurons. The agonist for group II mGluRs, (1R,4R,5S,6R)-4-amino-2-oxabicyclo[3.1.0] hexane-4,6-dicarboxylic acid (LY379268), significantly reduced the AMPA receptor-mediated EPSCs and GABA(A) receptor-mediated IPSCs. The effects were reversed by the group II mGluR antagonist, (2S)-2-amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl) propanoic acid (LY341495). The agonists for groups I and III, (RS)-3,5-dihydroxyphenylglycine (DHPG) and L-SOP, respectively, did not affect AMPA or GABA(A) receptor-mediated responses. The reduction of the synaptic responses by LY379268 was accompanied by a substantial increase in a ratio of the second to the first AMPA receptor-mediated EPSCs and GABA(A) receptor-mediated IPSCs to paired-pulse stimulation. The results suggest that group II mGluRs regulate both fast glutamatergic and GABAergic synaptic transmission in the ICC, probably through a presynaptic mechanism due to reduction of transmitter release.
Intracellular calcium concentrations in individual rat motoneurones in enriched primary cultures were measured by Indo-1 fluorimetry. Motoneurones in the cultures were characterized morphometrically and by cholineacetyltransferase immunocytochemistry. Depolarization of the cells with glutamic acid or veratridine increased intracellular calcium levels, which returned to baseline only slowly after removal of the depolarizing agent. The use of selective agonists (N-methyl-D-aspartic acid, AMPA, kainic acid, quisqualic acid and 1R-3S-ACPD) and antagonists (MK 801 and CNQX) showed that the excitatory amino acid-evoked responses were mediated by AMPA/kainate receptors rather than by NMDA receptors. Depolarization-evoked calcium transients in motoneurones are blocked by the neuroprotective drug riluzole Calcium transients reflected entry of calcium from without the cell, and their blockade by nitrendipine and lanthanum chloride suggested that this entry took place primarily through voltage-dependent calcium channels. These findings may be relevant for understanding the selective vulnerability of motoneurones to excitotoxicity in amyotrophic lateral sclerosis, and the therapeutic activity of riluzole in the treatment of this disease.
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