Pacemaker activity in hydra is modulated by glycine receptor ligands

In the mammalian central nervous system, the neurotransmitter, glycine, acts both on an inhibitory, strychnine-sensitive receptor (GlyR) and an excitatory, strychnine-insensitive site at the NMDA receptor. Here we present electrophysiological evidence that the strychnine-sensitive glycine agonists, glycine and taurine, and the antagonist, strychnine, affect the endodermal rhythmic potential (RP) system and that the ectodermal contraction burst (CB) pacemaker system is modulated by glycine and strychnine in hydra. The RP and CB pacemaker systems are responsible for the respective elongation and contraction of hydra's body column. Activity of the CB system, quantified by the rate of contraction bursts (CBs), the number of pulses per contraction burst (P/CB), and the duration of bursts, was decreased by glycine. Glycine, coadministered with the strychnine-insensitive glycine site blocker, indole-2-carboxylic acid (I2CA), decreased RPs but not CBs or P/CB. The effect was mimicked by taurine. Strychnine increased the duration of RP production, and decreased CB duration. The effect of glycine with I2CA was counteracted by strychnine. The results support the idea that a vertebrate-like GlyR may be involved in modulating activity of the endodermal RP system and suggest that a glycine site on an NMDA receptor may be involved in the CB system.     

Ionotropic glutamate receptors are involved in malondialdehyde production in anesthetized rat brain cortex: a microdialysis study

Elevated extracellular glutamate levels can increase malondialdehyde production in the brains of anesthetized rats. Thus, we investigated whether ionotropic glutamate receptors are involved in glutamate-induced malondialdehyde production. A microdialysis probe was implanted in the brain cortex of anesthetized rats. The malondialdehyde level in microdialysates was analyzed using an HPLC system. Three different ionotropic glutamate receptor agonists were used. At a concentration of 1.5 mM alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid hydrobromide (AMPA, a selective AMPA receptor agonist) induced a dramatic increase in extracellular malondialdehyde production (as much as 14-fold relative to the basal value). N-Methyl-D-aspartic acid (NMDA, a selective NMDA receptor agonist) also induced an increase in extracellular malondialdehyde production; however, the increase was not as much as that observed in the perfusion of AMPA receptor agonist. Kainic acid (a selective kainate receptor agonist) did not significantly increase malondialdehyde production. When co-perfused with L-trans-pyrrolidine-2,4-dicarboxylate (PDC; 31.4 mM), a glutamate uptake transport inhibitor that can increase the extracellular glutamate levels, AMPA receptor antagonist [1-(4-aminophenyl)4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine hydrochloride, 1.0 mM] can significantly reduce PDC-induced malondialdehyde production. Although NMDA receptor antagonist [(5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate, MK801] also can decrease the PDC-induced malondialdehyde production, it was not as effective as the AMPA receptor antagonist. These results suggest that ionotropic receptors are involved in the glutamate-induced increase in malondialdehdye production. Specifically, AMPA receptor seems to be predominant in the glutamate-induced malondialdehdye production in anesthetized rat brain cortex.     

Glutamatergic and GABAnergic control in the tentacle effector systems of Hydra vulgaris

In addition to their role in orchestrating body and tentacle contractions, hydra’s nerves control the behavior of nematocysts; precisely how is still a work in progress. There are strong indications that the classical neurotransmitters, glutamate and GABA (γ-amino-butyric acid), play an essential role in effecting stenotele and desmoneme discharge. In experiments on isolated tentacles of Hydra vulgaris, in which cnidocils were mechanically deflected with a piezo-electrically-driven glass micropipette, stenoteles and desmonemes respond to differences in applied force in a dose-dependent manner. GABA, working through its metabotropic receptor, appears to be involved with the recruitment of desmonemes. Desmonemes in distant battery cells or in another part of a given battery cell were discharged by stimulating a desmoneme cnidocil in the presence of bath-applied GABA or its metabotropic agonist, baclofen. The effect was blocked by phaclofen, its metabotropic antagonist. Neither GABA nor baclofen affected stenotele discharge. GABA_A agonists had no effect on nematocyst discharge. Glutamate caused a significant increase in number of stenoteles responding to direct mechanical stimuli, but did not effect desmoneme discharge. The effect was mimicked by NMDA (n-methyl-d-aspartate) together with kainate, or by NMDA plus AMPA (amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid), but not with any ionotropic agonist alone. The effect was blocked by D-AP 5 (d- (−)–2-amino–5-phosphopentanoic acid), a specific NMDA antagonist, or CNQX (6-cyano-7-nitroquinoxaline-2,3-dione), a specific kainate/AMPA antagonist. A glutamatergic mechanism working through ionotropic glutamate receptors appears to lower the firing threshold of stenoteles, perhaps␣by permitting the entry of Ca²⁺ into the cell through the early evolved NMDA/kainite/AMPA mechanism.     

Functional Consequences of Natural Substitutions in the GluR6 Kainate Receptor Subunit Ligand-Binding Site

Differences in binding-site residues of GluR2 (AMPAR) and GluR6 (KAR) subunits have been identified that might account for their functional and pharmacological differences. Specifically, residues A518, A689 and N721 in GluR6 replace highly conserved threonine and serine residues found in other ionotropic glutamate receptor (iGluR) subunits. To define how these natural substitutions impact GluR6 function, we used patch clamp recording with ultrafast perfusion to characterize the effects of A518T, A689S, and N721T on agonist potency, efficacy and response kinetics. We find these natural substitutions impact GluR6 function less than would be expected from reverse mutations in other iGluRs. There was little effect of individual or combined mutations on glutamate potency, deactivation or desensitization kinetics. Altered recovery kinetics were seen that were greatest after combined mutations. Kainate potency and response kinetics were also unchanged in the mutants, whereas kainate efficacy was reduced in A518T and increased the T/S/T mutant relative glutamate. Notably, A518T and A689S mutation permitted AMPA to bind as a weak competitive antagonist and the effects of these mutations were additive. N721T mutation further enhanced AMPA binding, allowing AMPA to activate and fully desensitize the receptors. Alternative mutations altering side chain length at position 518 produced far greater changes in glutamate affinity and response kinetics than did the natural mutations. We conclude that these non-conserved residues in GluR6 define the size of the agonist-binding pocket, exerting a steric influence on the bound agonist and the extent of binding-domain closure that can influence agonist potency, deactivation, desensitization and recovery kinetics.     

Functional consequences of natural substitutions in the GluR6 kainate receptor subunit ligand-binding site

Differences in binding-site residues of GluR2 (AMPAR) and GluR6 (KAR) subunits have been identified that might account for their functional and pharmacological differences. Specifically, residues A518, A689 and N721 in GluR6 replace highly conserved threonine and serine residues found in other ionotropic glutamate receptor (iGluR) subunits. To define how these natural substitutions impact GluR6 function, we used patch clamp recording with ultrafast perfusion to characterize the effects of A518T, A689S and N721T on agonist potency, efficacy and response kinetics. We find these natural substitutions impact GluR6 function less than would be expected from reverse mutations in other iGluRs. There was little effect of individual or combined mutations on glutamate potency, deactivation or desensitization kinetics. Altered recovery kinetics were seen that were greatest after combined mutations. Kainate potency and response kinetics were also unchanged in the mutants, whereas kainate efficacy was reduced in A518T and increased the T/S/T mutant relative glutamate. Notably, A518T and A689S mutation permitted AMPA to bind as a weak competitive antagonist and the effects of these mutations were additive. N721T mutation further enhanced AMPA binding, allowing AMPA to activate and fully desensitize the receptors. Alternative mutations altering side chain length at position 518 produced far greater changes in glutamate affinity and response kinetics than did the natural mutations. We conclude that these nonconserved residues in GluR6 define the size of the agonist-binding pocket, exerting a steric influence on the bound agonist and the extent of binding-domain closure that can influence agonist potency, deactivation, desensitization and recovery kinetics.     

Negative allosteric modulators of AMPA-preferring receptors inhibit [(3)H]GABA release in rat striatum

The effect of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), a selective glutamate receptor agonist, on the release of previously incorporated [(3)H]GABA was examined in superfused striatal slices of the rat. The slices were loaded with [(3)H]GABA in the presence of beta-alanine (1 mM) and superfused with Krebs-bicarbonate buffer containing nipecotic acid (0.1 mM) and aminooxyacetic acid (0.1 mM) to inhibit GABA uptake and metabolism. AMPA (0.01 to 3 mM) increased basal [(3)H]GABA outflow and nipecotic acid potentiated this effect. The [(3)H]GABA releasing effect of AMPA was an external Ca(2+)-dependent process in the absence but not in the presence of nipecotic acid. Cyclothiazide (0.03 mM), a positive modulator of AMPA receptors, failed to evoke [(3)H]GABA release by itself, but it dose-dependently potentiated the [(3)H]GABA releasing effect of AMPA. The AMPA (0.3 mM)-induced [(3)H]GABA release was antagonized by NBQX (0.01 mM) in a competitive fashion (pA(2) 5.08). The negative modulator of AMPA receptors, GYKI-53784 (0.01 mM) reversed the AMPA-induced [(3)H]GABA release by a non-competitive manner (pD'(2) 5.44). GYKI-53784 (0. 01-0.1 mM) also decreased striatal [(3)H]GABA outflow on its own right, this effect was stereoselective and was not influenced by concomitant administration of 0.03 mM cyclothiazide. GYKI-52466 (0. 03-0.3 mM), another negative modulator at AMPA receptors, also inhibited basal [(3)H]GABA efflux whereas NBQX (0.1 mM) by itself was ineffective in alteration of [(3)H]GABA outflow.The present data indicate that AMPA evokes GABA release from the vesicular pool in neostriatal GABAergic neurons. They also confirm that multiple interactions may exist between the agonist binding sites and the positive and negative modulatory sites but no such interaction was detected between the positive and negative allosteric modulators. Since GYKI-53784, but not NBQX, inhibited [(3)H]GABA release by itself, AMPA receptors located on striatal GABAergic neurons may be in sensitized state and phasically controlled by endogenous glutamate. It is also postulated that these AMPA receptors are located extrasynaptically on GABAergic striatal neurons.     

Zinc has opposite effects on NMDA and non-NMDA receptors expressed in Xenopus oocytes

Pharmacological characterization of Zn2+ effects on glutamate ionotropic receptors was investigated in Xenopus oocytes injected with rat brain mRNA, using a double microelectrode, voltage-clamp technique. At low concentration, Zn2+ inhibited NMDA currents (IC50 = 42.9 +/- 1.3 microM) and potentiated both AMPA (EC50 = 30.0 +/- 1.2 microM) and desensitized kainate responses (EC50 = 13.0 +/- 0.1 microM). At higher concentrations, Zn2+ inhibited non-NMDA responses with IC50 values of 1.3 +/- 0.1 mM and 1.2 +/- 0.3 mM for AMPA and kainate, respectively. The potentiation of AMPA or quisqualate currents by Zn2+ was more than 2-fold, whereas that of the kainate current was only close to 30%. This potentiating effect of Zn2+ on AMPA current modified neither the affinity of the agonist for its site nor the current-voltage relationship. In addition, 500 microM Zn2+ differentially affected NMDA and non-NMDA components of the glutamate-induced response. The possible physiological relevance of Zn2+ modulation is discussed.     

Effects of NMDA and non-NMDA ionotropic glutamate receptors in the medial preoptic area on body temperature in awake rats

Glutamate when microinjected at the medial preoptic area (mPOA) influences brain temperature (T_br) and body temperature (T_b) in rats. Glutamate and its various receptors are present at the mPOA. The aim of this study was to identify the contribution of each of the ionotropic glutamatergic receptors at the mPOA on changes in T_br and T_b in freely moving rats. Adult male Wistar rats (n=40) were implanted with bilateral guide cannula with indwelling styli above the mPOA. A telemetric transmitter was implanted at the peritoneum to record T_b and locomotor activity (LMA). A precalibrated thermocouple wire implanted near the hypothalamus was used to assess T_br. Specific agonist for each ionotropic glutamate receptor was microinjected into the mPOA and its effects on temperature and LMA were measured in the rats. The rats were also microinjected with the respective ionotropic receptor antagonists, 15 min prior to the microinjection of each agonist. Amongst amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), N-methyl-d-aspartate (NMDA) and kainic acid, AMPA increased T_b and LMA when injected at the mPOA. Specific antagonists for AMPA receptors was able to attenuate this increase (p<0.005). Pharmacological blockade of NMDA was able to lower T_br only. Microinjection of kainic acid and its antagonist had no effect on the variables. The finding of the study suggests that activation of the AMPA receptors at the mPOA, leads to the rise in body temperature.     

Inhibition of Forskolin-Stimulated Cyclic AMP Formation by 1-Aminocyclopentane-trans-1,3-Dicarboxylate in Guinea-Pig Cerebral Cortical Slices

The effects of the selective metabotropic glutamate receptor agonist 1-aminocyclopentane-trans-1,3-dicarboxylate (t-ACPD) on forskolin-stimulated cyclic AMP formation in guinea-pig cerebral cortex slices were determined. t-ACPD inhibited the accumulation of [3H]cyclic AMP by approximately 80%, with an IC50 value of 35 +/- 4 microM. The effect was reversible and stereoselective, with the 1S,3R isomer being approximately 400-fold more potent than the 1R,3S isomer. L-Glutamate (over a restricted concentration range) also partially inhibited the response to forskolin, but quisqualate, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA), and N-methyl-D-aspartate (NMDA) were ineffective. The effect of t-ACPD was not blocked by antagonists of the phospholipase C-linked metabotropic glutamate receptor, the AMPA ionotropic glutamate receptor, or the NMDA receptor. In summary, our results indicate the presence of a glutamate receptor in guinea-pig brain that is activated selectively by t-ACPD and that is negatively linked to adenylyl cyclase.     

Synaptic Neurotransmitter-Gated Receptors

Since the discovery of the major excitatory and inhibitory neurotransmitters and their receptors in the brain, many have deliberated over their likely structures and how these may relate to function. This was initially satisfied by the determination of the first amino acid sequences of the Cys-loop receptors that recognized acetylcholine, serotonin, GABA, and glycine, followed later by similar determinations for the glutamate receptors, comprising non-NMDA and NMDA subtypes. The last decade has seen a rapid advance resulting in the first structures of Cys-loop receptors, related bacterial and molluscan homologs, and glutamate receptors, determined down to atomic resolution. This now provides a basis for determining not just the complete structures of these important receptor classes, but also for understanding how various domains and residues interact during agonist binding, receptor activation, and channel opening, including allosteric modulation. This article reviews our current understanding of these mechanisms for the Cys-loop and glutamate receptor families.To understand how neurons communicate with each other requires a fundamental understanding of neurotransmitter receptor structure and function. Neurotransmitter-gated ion channels, also known as ionotropic receptors, are responsible for fast synaptic transmission. They decode chemical signals into electrical responses, thereby transmitting information from one neuron to another. Their suitability for this important task relies on their ability to respond very rapidly to the transient release of neurotransmitter to affect cell excitability.In the central nervous system (CNS), fast synaptic transmission results in two main effects: neuronal excitation and inhibition. For excitation, the principal neurotransmitter involved is glutamate, which interacts with ionotropic (integral ion channel) and metabotropic (second-messenger signaling) receptors. The ionotropic glutamate receptors are permeable to cations, which directly cause excitation. Acetylcholine and serotonin can also activate specific cation-selective ionotropic receptors to affect neuronal excitation. For controlling cell excitability, inhibition is important, and this is mediated by the neurotransmitters GABA and glycine, causing an increased flux of anions. GABA predominates as the major inhibitory transmitter throughout the CNS, whereas glycine is of greater importance in the spinal cord and brainstem. They both activate specific receptors—for GABA, there are ionotropic and metabotropic receptors, whereas for glycine, only ionotropic receptors are known to date.Together with acetylcholine- and serotonin-gated channels, GABA and glycine ionotropic receptors form the superfamily of Cys-loop receptors, which differs in many aspects from the superfamily of ionotropic glutamate receptors. Over the last two decades, our knowledge of the structure and function of ionotropic receptors has grown rapidly. In this article, we summarize our current understanding of the molecular operation of these receptors and how we can now begin to interpret the role of receptor structure in agonist binding, channel activation, and allosteric modulation of Cys-loop and glutamate receptor families. Further details on the regulation and trafficking of neurotransmitter receptors in synaptic structure and plasticity can be found in accompanying articles.     

Hyperactivity following injection of a glutamate agonist and 6,7-ADTN into rat nucleus accumbens and its inhibition by THIP

The potent glutamate receptor agonist AMPA induced a dose related hyperactivity after bilateral injection of 0.025–0.5 μg into rat nucleus accumbens. The dopamine agonist 6, 7-ADTN (2.5–10 μg) induced a similar effect. The hyperactivity induced by AMPA and 6, 7-ADTN was antagonized by cis-Z-flupentixol (0.31 mg/kg). Reserpine (7.5 mg/kg) plus α-methyltyrosine (200 mg/kg) inhibited AMPA but not 6, 7-ADTN induced motility. Furthermore, AMPA and 6, 7-ADTN induced motility was antagonized by the GABA agonist THIP after systemic administration (5 mg/kg) and intraaccumbens injection (0.125–0.5 μg). The results suggest that glutamatergic mechanisms are important in regulation of locomotor activity by influencing mechanisms afferent to dopamine receptors. Both glutamate and dopamine systems are under inhibitory GABAergic control.     

Inhibitory glutamate receptor channels

Inhibitory glutamate receptors (IGluRs) are a family of ion channel proteins closely related to ionotropic glycine and γ-aminobutyric acid (GABA) receptors; They are gated directly by glutamate; the open channel is permeable to chloride and sometimes potassium. Physiologically and pharmacologically, IGluRs most closely resemble GABA receptors; they are picrotoxin-sensitive and sometimes crossdesensitized by GABA. However, the amino acid sequences of cloned IGluRs are most similar to those of glycine receptors. Ibotenic acid, a conformationally restricted glutamate analog closely related to muscimol, activates all IGluRs. Quisqualate is not an IGluR agonist except among pulmonate molluscs and for a unique multiagonist receptor in the crayfishAustropotamobius torrentium. Other excitatory amino acid agonists are generally ineffective. Avermectins have several effects on IGluRs, depending on concentration: potentiation, direct gating, and blockade, both reversible and irreversible. Since IGluRs have only been clearly described in protostomes and pseudocoelomates, these effects may mediate the powerful antihelminthic and insecticidal action of avermectins, while explaining their low toxicity to mammals. IGluRs mediate synaptic inhibition in neurons and are expressed extrajunctionally in striated muscles. The presence of IGluRs in a neuron or muscle is independent of the presence or absence of excitatory glutamate receptors or GABA receptors in the cell. Generally, extrajunctional IGluRs in muscle have a higher sensitivity to glutamate than do neuronal synaptic receptors. Some extrajunctional receptors are sensitive in the range of circulating plasma glutamate levels, suggesting a role for IGluRs in regulating muscle excitability. The divergence of the IGlu/GABA/Gly/ACh receptor superfamily in protostomes could become a powerful model system for adaptive molecular evolution. Physiologically and pharmacologically, protostome receptors are considerably more diverse than their vertebrate counterparts. Antagonist profiles are only loosely correlated with agonist profiles (e.g., curare-sensitive GABA receptors, bicuculline-sensitive AChRs), and pharmacologically identical receptors may be either excitatory or inhibitory, and permeable to different ions. The assumption that agonist sensitivity reliably connotes discrete, homologous receptor families is contraindicated. Protostome ionotropic receptors are highly diverse and straightforward to assay; they provide an excellent system in which to study and integrate fundamental questions in molecular evolution and adaptation.     

DNQX-induced toxicity in cultured rat hippocampal neurons: an apparent AMPA receptor-independent effect?

To evaluate the involvement of AMPA receptor activation in neuronal cell death and survival, rat hippocampal neurons in culture were treated with AMPA receptor antagonists. A 46 h treatment with 6,7-dinitroquinoxaline-2,3-dione (DNQX), added 2 h after cell plating, induces a dose-dependent neurotoxicity. Similar effects are also observed in more mature hippocampal neurons (treatment at 14 days in vitro). DNQX toxic effect is neuron-specific since cultured hippocampal glial cells are unaffected. Attempts to characterise the site of action of DNQX suggest that ionotropic glutamate receptors would not be implicated. Indeed, (i) other AMPA receptor antagonists are either ineffective or only moderately efficient in mimicking DNQX effects; (ii) AMPA alone or in the presence of cyclothiazide, as well as, other AMPA receptor agonists, do not reverse DNQX action; (iii) DNQX neurotoxicity is not likely to involve blockade of NMDA receptor glycine site, since this effect is neither mimicked by 7-chlorokynurenate nor reversed by D-serine. Thus, DNQX toxicity in cultured hippocampal neurons is apparently mediated through an ionotropic glutamate receptor-independent way.     

Glutamate receptors on human melanocytes regulate the expression of MiTF

Glutamate is the major excitatory neurotransmitter in the central nervous system but has also important functions in the epidermis. It is involved in keratinocyte barrier function and in re-epithelialization processes after wounding. Recently, glutamate signalling has been suggested to be implicated in the development of melanoma. The present study examined the expression and functionality of metabotropic and ionotropic glutamate receptors on normal human melanocytes. We found that cultured melanocytes expressed the ionotropic glutamate receptors GluR2 and 4 [alpha-amino-3-hydroxy-5-methyl-4-isoxsazolepropionic acid (AMPA) receptors] and N-methyl-d-aspartate (NMDA) receptors 2A and 2C and possibly the metabotropic glutamate receptor 1. Melanocytes were also found to express specific glutamate transporters and decarboxylases, but appeared neither to produce nor to release l-glutamate. Stimulation with 10 or 100 microM AMPA or NMDA elevated intracellular calcium concentrations in melanocytes, and thus demonstrated the functionality of the glutamate receptors. Millimolar concentrations of l-glutamate did not induce melanocyte toxicity and had no stimulating effect on melanin production. However, blockage of AMPA and NMDA receptors with CFM-2, memantine or MK801 caused a rapid and reversible change in melanocyte morphology, which was associated with disorganisation of actin and tubulin microfilaments. After 24 h of treatment with the AMPA receptor inhibitor CFM-2, there was a sharp reduction in the expression of the crucial melanocyte differentiation and proliferation factor MiTF. The results of this study demonstrate a role for glutamate in melanocyte regulation that may have implications in melanocyte associated disorders.     

N-Methyl-d-aspartate and α-amino-3-hydroxy-5-methyl-4- isoxazolepropionate receptors involved in the induction of sedative effects under an acute stress in neonatal chicks

Glutamate, an excitatory amino acid, acts at several glutamate receptor subtypes. Recently, we reported that central administration of glutathione induced hypnosis under stressful conditions in neonatal chicks. Glutathione appears to bind to the N-methyl-d-aspartate (NMDA) receptor. To clarify the involvement of each glutamate receptor subtype during stressful conditions, intracerebroventricular (i.c.v.) injection of several glutamate receptor agonists was given to chicks under social separation stress. Glutamate dose-dependently induced a hypnotic effect. NMDA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) and kainate are characterized as ionotropic glutamate receptors (iGluRs). Although NMDA also induced sleep-like behavior or sedative effects, the potency of NMDA was less than that of glutamate. AMPA tended to decrease distress vocalizations induced by acute stress and brought about a sedative effect. Kainate and (S)-3, 5-dehydroxyphenylglycine, which is a metabotropic glutamate receptor agonist, had no influence on chick behavior. Thus, it is suggested that the iGluRs, NMDA and AMPA, are important in inducing hypnosis and sedation under acute stress in chicks.     

N-Methyl-<Emphasis Type="SmallCaps">d</Emphasis>-aspartate and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptors involved in the induction of sedative effects under an acute stress in neonatal chicks

Glutamate, an excitatory amino acid, acts at several glutamate receptor subtypes. Recently, we reported that central administration of glutathione induced hypnosis under stressful conditions in neonatal chicks. Glutathione appears to bind to the N-methyl-d-aspartate (NMDA) receptor. To clarify the involvement of each glutamate receptor subtype during stressful conditions, intracerebroventricular (i.c.v.) injection of several glutamate receptor agonists was given to chicks under social separation stress. Glutamate dose-dependently induced a hypnotic effect. NMDA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) and kainate are characterized as ionotropic glutamate receptors (iGluRs). Although NMDA also induced sleep-like behavior or sedative effects, the potency of NMDA was less than that of glutamate. AMPA tended to decrease distress vocalizations induced by acute stress and brought about a sedative effect. Kainate and (S)-3, 5-dehydroxyphenylglycine, which is a metabotropic glutamate receptor agonist, had no influence on chick behavior. Thus, it is suggested that the iGluRs, NMDA and AMPA, are important in inducing hypnosis and sedation under acute stress in chicks.     

NMDA receptors in nucleus tractus solitarii are linked to soluble guanylate cyclase

We sought to test the hypothesis that cardiovascular responses to activation of ionotropic, but not metabotropic, glutamate receptors in the nucleus tractus solitarii (NTS) depend on soluble guanylate cyclase (sGC) and that inhibition of sGC would attenuate baroreflex responses to changes in arterial pressure. In adult male Sprague-Dawley rats anesthetized with chloralose, the ionotropic receptor agonists N-methyl-d-aspartate (NMDA) and dl-alpha-amino-3-hydroxy-5-methylisoxazole-propionic acid (AMPA) and the metabotropic receptor agonist trans-dl-amino-1,3-cyclopentane-dicarboxylic acid (ACPD) were microinjected into the NTS before and after microinjection of sGC inhibitors at the same site. Inhibition of sGC produced significant dose-dependent attenuation of cardiovascular responses to NMDA but did not alter responses produced by injection of AMPA or ACPD. Bilateral inhibition of sGC did not alter arterial pressure, nor did it attenuate baroreflex responses to pharmacologically induced changes in arterial pressure. This study links sGC with NMDA, but not AMPA or metabotropic, receptors in cardiovascular signal transduction through NTS.     

GABA and glutamate signaling: homeostatic control of adult forebrain neurogenesis

The neurotransmitter GABA exerts a strong negative influence on the production of adult-born olfactory bulb interneurons via tightly regulated, non-synaptic GABAergic signaling. After discussing some findings on GABAergic signaling in the neurogenic subventricular zone (SVZ), we provide data suggesting ambient GABA clearance via two GABA transporter subtypes and further support for a non-vesicular mechanism of GABA release from neuroblasts. While GABA works in cooperation with the neurotransmitter glutamate during embryonic cortical development, the role of glutamate in adult forebrain neurogenesis remains obscure. Only one of the eight metabotropic glutamate receptors (mGluRs), mGluR5, has been reported to tonically increase the number of proliferative SVZ cells in vivo, suggesting a local source of glutamate in the SVZ. We show here that glutamate antibodies strongly label subventricular zone (SVZ) astrocytes, some of which are stem cells. We also show that some SVZ neuroblasts express one of the ionotropic glutamate receptors, AMPA/kainate receptors, earlier than previously thought. Collectively, these findings suggest that neuroblast-to-astrocyte GABAergic signaling may cooperate with astrocyte-to-neuroblast glutamatergic signaling to provide strong homeostatic control on the production of adult-born olfactory bulb interneurons. An erratum to this article can be found at     

Role of Glutamate Receptors and Glutamate Transporters in the Regulation of the Glutamate-Glutamine Cycle in the Awake Rat

In the present study we investigate the effects of a specific glutamate reuptake blocker, L-trans-pyrrolidine-3,4-dicarboxylic acid (PDC), on extracellular concentrations of glutamine and glutamate in the striatum of the freely moving rat. Intracerebral infusions of PDC (1, 2 and 4 mM) produced a dose-related increase in extracellular concentrations of glutamate and a dose-related decrease in extracellular concentrations of glutamine. These increases in extracellular glutamate and decreases in extracellular glutamine were significantly correlated. To investigate the involvement of ionotropic glutamate receptors in the decreases of extracellular glutamine produced by PDC, N-methyl-D-aspartate (NMDA) receptor antagonist and -amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA)/kainate receptor antagonist were used. Perfusion of the NMDA receptor antagonist blocked the decrease of extracellular glutamine but had no effect on the increase of extracellular glutamate, both produced by PDC. Perfusion of the AMPA/kainate receptor antagonist attenuated the increase of extracellular glutamate and not only blocked the decrease of extracellular glutamine but also produced a significant increase of extracellular glutamine. The results reported in this study suggest that both NMDA and AMPA/kainate glutamatergic receptors are involved in the regulation of extracellular glutamine.