The anterior retrosplenial cortex is required for short-term object in place recognition memory retrieval: Role of ionotropic glutamate receptors in male and female Long-Evans rats.

The anterior retrosplenial cortex (aRSC) integrates multimodal sensory information into cohesive associative recognition memories. Little is known about how information is integrated during different learning phases (i.e., encoding and retrieval). Additionally, sex differences are observed in performance of some visuospatial memory tasks; however, inconsistent findings warrant more research. We conducted three experiments using the 1-h delay object-in-place (1-h OiP) test to assess recognition memory retrieval in male and female Long-Evans rats. (i) We found both sexes performed equally in three repeated 1-h OiP test sessions. (ii) We showed infusions of a mixture of muscimol/baclofen (GABAA/B receptor agonists) into the aRSC ~15-min prior to the test phase disrupted 1-h OiP in both sexes. (iii) We assessed the role of aRSC ionotropic glutamate receptors in 1-h OiP retrieval using another squad of cannulated rats and confirmed that infusions of either the competitive AMPA/Kainate receptor antagonist CNQX (3 mM) or competitive NMDA receptor antagonist AP-5 (30 mM) (volumes = 0.50 uL/side) significantly impaired 1-h OiP retrieval in both sexes compared to controls. Taken together, findings challenge reported sex differences and clearly establish a role for aRSC ionotropic glutamate receptors in short-term visuospatial recognition memory retrieval. Thus, modulating neural activity in the aRSC may alleviate some memory processing impairments in related disorders.

Subunit-selective iGluR antagonists can potentiate heteromeric receptor responses by blocking desensitization.

Ionotropic glutamate receptors (iGluRs) are key molecules for synaptic signaling in the central nervous system, which makes them promising drug targets. Intensive efforts are being devoted to the development of subunit-selective ligands, which should enable more precise pharmacologic interventions while limiting the effects on overall neuronal circuit function. However, many AMPA and kainate receptor complexes in vivo are heteromers composed of different subunits. Despite their importance, little is known about how subunit-selective ligands affect the gating of heteromeric iGluRs, namely their activation and desensitization properties. Using fast ligand application experiments, we studied the effects of competitive antagonists that block glutamate from binding at part of the four subunits. We found that UBP-310, a kainate receptor antagonist with high selectivity for GluK1 subunits, reduces the desensitization of GluK1/GluK2 heteromers and fully abolishes the desensitization of GluK1/GluK5 heteromers. This effect is mirrored by subunit-selective agonists and heteromeric receptors that contain binding-impaired subunits, as we show for both kainate and GluA2 AMPA receptors. These findings are consistent with a model in which incomplete agonist occupancy at the four receptor subunits can provide activation without inducing desensitization. However, we did not detect significant steady-state currents during UBP-310 dissociation from GluK1 homotetramers, indicating that antagonist dissociation proceeds in a nonuniform and cooperativity-driven manner, which disfavors nondesensitizing occupancy states. Besides providing mechanistic insights, these results have direct implications for the use of subunit-selective antagonists in neuroscience research and envisioned therapeutic interventions.

Ionotropic Glutamate Receptors in Epilepsy: A Review Focusing on AMPA and NMDA Receptors.

It is widely accepted that glutamate-mediated neuronal hyperexcitation plays a causative role in eliciting seizures. Among glutamate receptors, the roles of N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors in physiological and pathological conditions represent major clinical research targets. It is well known that agonists of NMDA or AMPA receptors can elicit seizures in animal or human subjects, while antagonists have been shown to inhibit seizures in animal models, suggesting a potential role for NMDA and AMPA receptor antagonists in anti-seizure drug development. Several such drugs have been evaluated in clinical studies; however, the majority, mainly NMDA-receptor antagonists, failed to demonstrate adequate efficacy and safety for therapeutic use, and only an AMPA-receptor antagonist, perampanel, has been approved for the treatment of some forms of epilepsy. These results suggest that a misunderstanding of the role of each glutamate receptor in the ictogenic process may underlie the failure of these drugs to demonstrate clinical efficacy and safety. Accumulating knowledge of both NMDA and AMPA receptors, including pathological gene mutations, roles in autoimmune epilepsy, and evidence from drug-discovery research and pharmacological studies, may provide valuable information enabling the roles of both receptors in ictogenesis to be reconsidered. This review aimed to integrate information from several studies in order to further elucidate the specific roles of NMDA and AMPA receptors in epilepsy.

C1 neurons are part of the circuitry that recruits active expiration in response to the activation of peripheral chemoreceptors.

Breathing results from the interaction of two distinct oscillators: the pre-Bötzinger Complex (preBötC), which drives inspiration; and the lateral parafacial region (pFRG), which drives active expiration. The pFRG is silent at rest and becomes rhythmically active during the stimulation of peripheral chemoreceptors, which also activates adrenergic C1 cells. We postulated that the C1 cells and the pFRG may constitute functionally distinct but interacting populations for controlling expiratory activity during hypoxia. We found in rats that: a) C1 neurons are activated by hypoxia and project to the pFRG region; b) active expiration elicited by hypoxia was blunted after blockade of ionotropic glutamatergic receptors at the level of the pFRG; and c) selective depletion of C1 neurons eliminated the active expiration elicited by hypoxia. These results suggest that C1 cells may regulate the respiratory cycle, including active expiration, under hypoxic conditions.

Activation and desensitization of ionotropic glutamate receptors by selectively triggering pre-existing motions.

Ionotropic glutamate receptors (iGluRs) are ligand-gated ion channels that are key players in synaptic transmission and plasticity. They are composed of four subunits, each containing four functional domains, the quaternary packing and collective structural dynamics of which are important determinants of their molecular mechanism of function. With the explosion of structural studies on different members of the family, including the structures of activated open channels, the mechanisms of action of these central signaling machines are now being elucidated. We review the current state of computational studies on two major members of the family, AMPA and NMDA receptors, with focus on molecular simulations and elastic network model analyses that have provided insights into the coupled movements of extracellular and transmembrane domains. We describe the newly emerging mechanisms of activation, allosteric signaling and desensitization, as mainly a selective triggering of pre-existing soft motions, as deduced from computational models and analyses that leverage structural data on intact AMPA and NMDA receptors in different states.

Polyamine-mediated channel block of ionotropic glutamate receptors and its regulation by auxiliary proteins.

Most excitatory neurotransmission in the mammalian brain is mediated by a family of plasma membrane-bound signaling proteins called ionotropic glutamate receptors (iGluRs). iGluRs assemble at central synapses as tetramers, forming a central ion-channel pore whose primary function is to rapidly transport Na+ and Ca2+ in response to binding the neurotransmitter l-glutamic acid. The pore of iGluRs is also accessible to bulkier cytoplasmic cations, such as the polyamines spermine, spermidine, and putrescine, which are drawn into the permeation pathway, but get stuck and block the movement of other ions. The degree of this polyamine-mediated channel block is highly regulated by processes that control the free cytoplasmic polyamine concentration, the membrane potential, or the iGluR subunit composition. Recently, an additional regulation by auxiliary proteins, most notably transmembrane AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor regulatory proteins (TARPs), cornichons, and neuropilin and tolloid-like proteins (NETOs), has been identified. Here, I review what we have learned of polyamine block of iGluRs and its regulation by auxiliary subunits. TARPs, cornichons, and NETOs attenuate the channel block by enabling polyamines to exit the pore. As a result, polyamine permeation occurs at more negative and physiologically relevant membrane potentials. The structural basis for enhanced polyamine transport remains unresolved, although alterations in both channel architecture and charge-screening mechanisms have been proposed. That auxiliary subunits can attenuate the polyamine block reveals an unappreciated impact of polyamine permeation in shaping the signaling properties of neuronal AMPA- and kainate-type iGluRs. Moreover, enhanced polyamine transport through iGluRs may have a role in regulating cellular polyamine levels.

Ionotropic and metabotropic glutamate receptors regulate protein translation in co-cultured nucleus accumbens and prefrontal cortex neurons.

The regulation of protein translation by glutamate receptors and its role in plasticity have been extensively studied in the hippocampus. In contrast, very little is known about glutamatergic regulation of translation in nucleus accumbens (NAc) medium spiny neurons (MSN), despite their critical role in addiction-related plasticity and recent evidence that protein translation contributes to this plasticity. We used a co-culture system, containing NAc MSNs and prefrontal cortex (PFC) neurons, and fluorescent non-canonical amino acid tagging (FUNCAT) to visualize newly synthesized proteins in neuronal processes of NAc MSNs and PFC pyramidal neurons. First, we verified that the FUNCAT signal reflects new protein translation. Next, we examined the regulation of translation by group I metabotropic glutamate receptors (mGluRs) and ionotropic glutamate receptors by incubating co-cultures with agonists or antagonists during the 2-h period of non-canonical amino acid labeling. In NAc MSNs, basal translation was modestly reduced by blocking Ca2+-permeable AMPARs whereas blocking all AMPARs or suppressing constitutive mGluR5 signaling enhanced translation. Activating group I mGluRs with dihydroxyphenylglycine increased translation in an mGluR1-dependent manner in NAc MSNs and PFC pyramidal neurons. Disinhibiting excitatory transmission with bicuculline also increased translation. In MSNs, this was reversed by antagonists of mGluR1, mGluR5, AMPARs or NMDARs. In PFC neurons, AMPAR or NMDAR antagonists blocked bicuculline-stimulated translation. Our study, the first to examine glutamatergic regulation of translation in MSNs, demonstrates regulatory mechanisms specific to MSNs that depend on the level of neuronal activation. This sets the stage for understanding how translation may be altered in addiction.

Pre- and Postsynaptic Effects of Glutamate in the Frog Labyrinth.

The role of glutamate in quantal release at the cytoneural junction was examined by measuring mEPSPs and afferent spikes at the posterior canal in the intact frog labyrinth. Release was enhanced by exogenous glutamate, or dl-TBOA, a blocker of glutamate reuptake. Conversely, drugs acting on ionotropic glutamate receptors did not affect release; the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA-R) blocker CNQX decreased mEPSP size in a dose-dependent manner; the NMDA-R blocker d-AP5 at concentrations <200 µM did not affect mEPSP size, either in the presence or absence of Mg and glycine. In isolated hair cells, glutamate did not modify Ca currents. Instead, it systematically reduced the compound delayed potassium current, IKD, whereas the metabotropic glutamate receptor (mGluR)-II inverse agonist, (2S)-2-amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl)propanoic acid (LY341495), increased it. Given mGluR-II decrease cAMP production, these finding are consistent with the reported sensitivity of IKD to protein kinase A (PKA)-mediated phosphorylation. LY341495 also enhanced transmitter release, presumably through phosphorylation-mediated facilitation of the release machinery. The observed enhancement of release by glutamate confirms previous literature data, and can be attributed to activation of mGluR-I that promotes Ca release from intracellular stores. Glutamate-induced reduction in the repolarizing IKD may contribute to facilitation of release. Overall, glutamate exerts both a positive feedback action on mGluR-I, through activation of the phospholipase C (PLC)/IP3 path, and the negative feedback, by interfering with substrate phosphorylation through Gi/0-coupled mGluRs-II/III. The positive feedback prevails, which may explain the increase in overall rates of release observed during mechanical stimulation (symmetrical in the excitatory and inhibitory directions). The negative feedback may protect the junction from over-activation.

Inhibition of non-NMDA ionotropic glutamate receptors delays the retinal degeneration in rd10 mouse.

Retinitis pigmentosa (RP) is a hereditary blinding disease characterized by neurodegeneration of photoreceptors. Retinal ganglion cells (RGCs) in animal models of RP exhibit an abnormally high spontaneous activity that interferes with signal processing. Blocking AMPA/Kainate receptors by bath application of CNQX decreases the spontaneous firing, suggesting that inhibiting these receptors in vivo may help maintain the function of inner retinal neurons in rd10 mice experiencing photoreceptor degeneration. To test this, rd10 mice were i.p. injected with CNQX or GYKI 52466 (an AMPA receptor antagonist) for 1-2 weeks, and examined for their retinal morphology (by immunocytochemistry), function (by MEA recordings) and visual behaviors (using a black/white box). Our data show that iGluRs were up-regulated in the inner plexiform layer (IPL) of rd10 retinas. Application of CNQX at low doses both in vitro and in vivo, attenuated the abnormal spontaneous spiking in RGCs, and increased the light-evoked response of ON RGCs, whereas GYKI 52466 had little effect. CNQX application also improved the behavioral performance. Interestingly, in vivo administration of CNQX delayed photoreceptor degeneration, evidenced by the increased cell number and restored structure. CNQX also improved the structure of bipolar cells. Together, we demonstrated that during photoreceptor degeneration, blockade of the non-NMDA iGluRs decelerates the progression of RGCs dysfunction, possibly by dual mechanisms including slowing photoreceptor degeneration and modulating signal processing within the IPL. Accordingly, this strategy may effectively extend the time window for treating RP.

Differentiating Cerebellar Impact on Thalamic Nuclei.

The cerebellum plays a role in coordination of movements and non-motor functions. Cerebellar nuclei (CN) axons connect to various parts of the thalamo-cortical network, but detailed information on the characteristics of cerebello-thalamic connections is lacking. Here, we assessed the cerebellar input to the ventrolateral (VL), ventromedial (VM), and centrolateral (CL) thalamus. Confocal and electron microscopy showed an increased density and size of CN axon terminals in VL compared to VM or CL. Electrophysiological recordings in vitro revealed that optogenetic CN stimulation resulted in enhanced charge transfer and action potential firing in VL neurons compared to VM or CL neurons, despite that the paired-pulse ratio was not significantly different. Together, these findings indicate that the impact of CN input onto neurons of different thalamic nuclei varies substantially, which highlights the possibility that cerebellar output differentially controls various parts of the thalamo-cortical network.

Disrupted Ionic Homeostasis in Ischemic Stroke and New Therapeutic Targets.

BACKGROUND: Stroke is a leading cause of long-term disability. All neuroprotectants targeting excitotoxicity have failed to become stroke medications. In order to explore and identify new therapeutic targets for stroke, we here reviewed present studies of ionic transporters and channels that are involved in ischemic brain damage. METHOD: We surveyed recent literature from animal experiments and clinical reports in the databases of PubMed and Elsevier ScienceDirect to analyze ionic mechanisms underlying ischemic cell damage and suggest promising ideas for stroke therapy. RESULTS: Dysfunction of ionic transporters and disrupted ionic homeostasis are most early changes that underlie ischemic brain injury, thus receiving sustained attention in translational stroke research. The Na+/K+-ATPase, Na+/Ca2+ Exchanger, ionotropic glutamate receptor, acid-sensing ion channels (ASICs), sulfonylurea receptor isoform 1 (SUR1)-regulated NCCa-ATP channels, and transient receptor potential (TRP) channels are critically involved in ischemia-induced cellular degenerating processes such as cytotoxic edema, excitotoxicity, necrosis, apoptosis, and autophagic cell death. Some ionic transporters/channels also act as signalosomes to regulate cell death signaling. For acute stroke treatment, glutamate-mediated excitotoxicity must be interfered within 2 hours after stroke. The SUR1-regulated NCCa-ATP channels, Na+/K+-ATPase, ASICs, and TRP channels have a much longer therapeutic window, providing new therapeutic targets for developing feasible pharmacological treatments toward acute ischemic stroke. CONCLUSION: The next generation of stroke therapy can apply a polypharmacology strategy for which drugs are designed to target multiple ion transporters/channels or their interaction with neurotoxic signaling pathways. But a successful translation of neuroprotectants relies on in-depth analyses of cell death mechanisms and suitable animal models resembling human stroke.

Ionotropic receptors signal host recognition in the salmon louse (Lepeophtheirus salmonis, Copepoda).

A remarkable feature of many parasites is a high degree of host specificity but the mechanisms behind are poorly understood. A major challenge for parasites is to identify and infect a suitable host. Many species show a high degree of host specificity, being able to survive only on one or a few related host species. To facilitate transmission, parasite's behavior and reproduction has been fine tuned to maximize the likelihood of infection of a suitable host. For some species chemical cues that trigger or attract the parasite in question have been identified but how metazoan parasites themselves receive these signals remains unknown. In the present study we show that ionotropic receptors (IRs) in the salmon louse are likely responsible for identification of a specific host. By using RNAi to knock down the expression level of different co-receptors, a significant change of infectivity and settlement of lice larvae was achieved on Atlantic salmon. More remarkably, knock down of the IRs changed the host specificity of the salmon louse and lice larvae settled at a significant rate on host that the wild type lice rejected within minutes. To our knowledge, this has never before been demonstrated for any metazoan parasite. Our results show that the parasites are able to identify the host quickly upon settlement, settle and initiate the parasitic life style if they are on the right host. This novel discovery opens up for utilizing the host recognition system for future parasite control.

Excessive activation of ionotropic glutamate receptors induces apoptotic hair-cell death independent of afferent and efferent innervation.

Accumulation of excess glutamate plays a central role in eliciting the pathological events that follow intensely loud noise exposures and ischemia-reperfusion injury. Glutamate excitotoxicity has been characterized in cochlear nerve terminals, but much less is known about whether excess glutamate signaling also contributes to pathological changes in sensory hair cells. I therefore examined whether glutamate excitotoxicity damages hair cells in zebrafish larvae exposed to drugs that mimic excitotoxic trauma. Exposure to ionotropic glutamate receptor (iGluR) agonists, kainic acid (KA) or N-methyl-D-aspartate (NMDA), contributed to significant, progressive hair cell loss in zebrafish lateral-line organs. To examine whether hair-cell loss was a secondary effect of excitotoxic damage to innervating neurons, I exposed neurog1a morphants-fish whose hair-cell organs are devoid of afferent and efferent innervation-to KA or NMDA. Significant, dose-dependent hair-cell loss occurred in neurog1a morphants exposed to either agonist, and the loss was comparable to wild-type siblings. A survey of iGluR gene expression revealed AMPA-, Kainate-, and NMDA-type subunits are expressed in zebrafish hair cells. Finally, hair cells exposed to KA or NMDA appear to undergo apoptotic cell death. Cumulatively, these data reveal that excess glutamate signaling through iGluRs induces hair-cell death independent of damage to postsynaptic terminals.

A Molecular and Cellular Context-Dependent Role for Ir76b in Detection of Amino Acid Taste.

Amino acid taste is expected to be a universal property among animals. Although sweet, bitter, salt, and water tastes have been well characterized in insects, the mechanisms underlying amino acid taste remain elusive. From a Drosophila RNAi screen, we identify an ionotropic receptor, Ir76b, as necessary for yeast preference. Using calcium imaging, we identify Ir76b+ amino acid taste neurons in legs, overlapping partially with sweet neurons but not those that sense other tastants. Ir76b mutants have reduced responses to amino acids, which are rescued by transgenic expression of Ir76b and a mosquito ortholog AgIr76b. Co-expression of Ir20a with Ir76b is sufficient for conferring amino acid responses in sweet-taste neurons. Notably, Ir20a also serves to block salt response of Ir76b. Our study establishes the role of a highly conserved receptor in amino acid taste and suggests a mechanism for mutually exclusive roles of Ir76b in salt- and amino-acid-sensing neurons.

Ionotropic glutamate receptor antagonists and cancer therapy: time to think out of the box?

Glutamate has a trophic function in the development of the central nervous system, regulating the proliferation and migration of neuronal progenitors. The resemblance between neuronal embryonic and tumor cells has paved the way for the investigation of the effects of glutamate on tumor cells. Indeed, tumor cells derived from neuronal tissue express ionotropic glutamate receptor (iGluRs) subunits and iGluR antagonists decrease cell proliferation. Likewise, iGluRs subunits are expressed in several peripheral cancer cells and blockade of the N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) ionotropic glutamate receptor subtypes decreases their proliferation and migration. Although these mechanisms are still being investigated, the inhibition of the mitogen-activated protein kinase pathway was shown to play a key role in the antiproliferative activity of iGluR antagonists. Importantly, MK-801, a NMDAR channel blocker, was effective and well tolerated in animal models of melanoma, lung, and breast cancers, suggesting that the blockade of iGluR signaling may represent a new strategy for cancer treatment. In this review, we focus on the significance of NMDA and AMPA receptor expression in tumor cells, as well as possible therapeutic strategies targeting these receptors.

Metabotropic and ionotropic glutamate receptors mediate the modulation of acetylcholine release at the frog neuromuscular junction.

There is some evidence that glutamate (Glu) acts as a signaling molecule at vertebrate neuromuscular junctions where acetylcholine (ACh) serves as a neurotransmitter. In this study, performed on the cutaneous pectoris muscle of the frog Rana ridibunda, Glu receptor mechanisms that modulate ACh release processes were analyzed. Electrophysiological experiments showed that Glu reduces both spontaneous and evoked quantal secretion of ACh and synchronizes its release in response to electrical stimulation. Quisqualate, an agonist of ionotropic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic receptors and metabotropic Group I mGlu receptors, also exerted Glu-like inhibitory effects on the secretion of ACh but had no effect on the kinetics of quantal release. Quisqualate's inhibitory effect did not occur when a blocker of Group I mGlu receptors (LY 367385) or an inhibitor of phospholipase C (U73122) was present. An increase in the degree of synchrony of ACh quantal release, such as that produced by Glu, was obtained after application of N-methyl-D-aspartic acid (NMDA). The presence of Group I mGlu and NMDA receptors in the neuromuscular synapse was confirmed by immunocytochemistry. Thus, the data suggest that both metabotropic Group I mGlu receptors and ionotropic NMDA receptors are present at the neuromuscular synapse of amphibians, and that the activation of these receptors initiates different mechanisms for the regulation of ACh release from motor nerve terminals. © 2016 Wiley Periodicals, Inc.

Design and Synthesis of a Series of l-trans-4-Substituted Prolines as Selective Antagonists for the Ionotropic Glutamate Receptors Including Functional and X-ray Crystallographic Studies of New Subtype Selective Kainic Acid Receptor Subtype 1 (GluK1) Antagonist (2S,4R)-4-(2-Carboxyphenoxy)pyrrolidine-2-carboxylic Acid.

Ionotropic glutamate receptor antagonists are valuable tool compounds for studies of neurological pathways in the central nervous system. On the basis of rational ligand design, a new class of selective antagonists, represented by (2S,4R)-4-(2-carboxyphenoxy)pyrrolidine-2-carboxylic acid (1b), for cloned homomeric kainic acid receptors subtype 1 (GluK1) was attained (Ki = 4 µM). In a functional assay, 1b displayed full antagonist activity with IC50 = 6 ± 2 µM. A crystal structure was obtained of 1b when bound in the ligand binding domain of GluK1. A domain opening of 13-14° was seen compared to the structure with glutamate, consistent with 1b being an antagonist. A structure-activity relationship study showed that the chemical nature of the tethering atom (C, O, or S) linking the pyrrolidine ring and the phenyl ring plays a key role in the receptor selectivity profile and that substituents on the phenyl ring are well accommodated by the GluK1 receptor.

[The kynurenic acid hypothesis - a new look at etiopathogenesis and treatment of schizophrenia]. / Koncepcja kynureninowa ­ nowe spojrzenie na etiopatogeneze i leczenie schizofrenii.

Kynurenic acid (KYNA) is a neuroactive metabolite of tryptophan formed in the brain and in the periphery, known to block ionotropic glutamate receptors and α7 nicotinic receptors, and to act as a ligand of G protein-coupled GPR35 receptors and human aryl hydrocarbon (AHR) receptors. KYNA seems to modulate a number of mechanisms involved in the pathogenesis of schizophrenia including dopaminergic transmission in mesolimbic and mesocortical areas or glutamatemediated neurotransmission. The kynurenine hypothesis of schizophrenia links the occurrence of positive and negative symptoms of schizophrenia and cognitive impairments characteristic for the disease with the disturbances of kynurenine pathway function. Available data suggest that antipsychotic drugs may restore balance among kynurenine pathway metabolites, and that co-administration of glycine with antipsychotics may reduce extrapyramidal symptoms in patients suffering from schizophrenia. Central level of KYNA may increase in the course of inflammation, which is consistent with the inflammatory hypothesis of schizophrenia. Alterations of immune response and disturbed functioning of kynurenine pathway may lead to disproportion between neuroprotective and neurotoxic mechanisms in the brain. Currently, intense research efforts are focused on the role of kynurenine pathway metabolites in pathogenesis of schizophrenia, their association with the response to antipsychotic treatment, and search for novel medications modulating the function of kynurenine pathway.

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 (Tbr) and body temperature (Tb) 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 Tbr and Tb 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 Tb and locomotor activity (LMA). A precalibrated thermocouple wire implanted near the hypothalamus was used to assess Tbr. 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, 15min 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 Tb 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 Tbr 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.

Amide of Lambertian Acid Suppresses Hyperactivation of Inotropic Glutamate Receptors, but not Synaptic Potentiation in Hippocampal Sections.

Amide of lambertian acid suppresses hyperactivation of inotropic glutamate receptors in hippocampal sections induced by a decrease in the level of magnesium ions (a selective blocker of glutamate NMDA receptors). Treatment of the sections with amide of lambertian acid in standard physiological saline does not prevent development of NMDA-dependent synaptic potentiation. Lambertian acid isolated from needles and turpentine of Siberian pine (Pinus sibirica R. Mayr), and its derivatives may become a source of substances with glutamatergic mechanism of action for treatment of cognitive and neurodegenerative disorders.