1
Glutamate and other amino acids are the main excitatory neurotransmitters in many brain regions, including the hippocampus, by activating ion channel-coupled glutamate receptors, as well as metabotropic receptors linked to G proteins and second messenger systems. Several conditions which promote the release of glutamate, like frequency stimulation and hypoxia, also lead to an increase in the extracellular levels of the important neuromodulator, adenosine. We studied whether the activation of different subgroups of metabotropic glutamate receptors (mGluR) could modify the known inhibitory effects of a selective adenosine A1 receptor agonist on synaptic transmission in the hippocampus. The experiments were performed on hippocampal slices taken from young (12–14 days old) rats. Stimulation was delivered to the Schaffer collateral/commissural fibres, and evoked field excitatory postsynaptic potentials (fe.p.s.p.) recorded extracellularly from the stratum radiatum in the CA1 area.

2
The concentration-response curve for the inhibitory effects of the selective adenosine A1 receptor agonist, N6-cyclopentyladenosine (CPA; 2–50 nM), on the fe.p.s.p. slope (EC50=12.5 (9.2–17.3; 95% confidence intervals)) was displaced to the right by the group I mGluR selective agonist, (R,S)-3,5-dihydroxyphenylglycine (DPHG; 10 μM) (EC50=27.2 (21.4–34.5) nM, n=4). The attenuation of the inhibitory effect of CPA (10 nM) on the fe.p.s.p. slope by DHPG (10 μM) was blocked in the presence of the mGluR antagonist (which blocks group I and II mGluR), (R,S)-α-methyl-4-carboxyphenylglycine (MCPG; 500 μM). DHPG (10 μM) itself had an inhibitory effect of 20.1±1.9% (n=4) on the fe.p.s.p. slope.

3
The concentration-response curves for the inhibitory effects of CPA (2–20 nM) on the fe.p.s.p. slope were not modified either in the presence of the group II mGluR selective agonist, (2S,3S,4S)-α-(carboxycyclopropyl)glycine (L-CCG-I; 1 μM), or in the presence of the non-selective mGluR agonist (which activates both group I and II mGluR), (1S,3R)-1-aminocyclopentyl-1,3-dicarboxylate (ACPD; 100 μM). L-CCG-I had no consistent effects and ACPD (100 μM) decreased by 19.4±1.8% (n=4) the fe.p.s.p. slope.

4
The concentration-response curve for the inhibitory effects of CPA (2–100 nM) on the fe.p.s.p. slope (EC50=8.2 (6.9–9.6) nM) was displaced to the right by the group III mGluR selective agonist, L-2-amino-4-phosphonobutyrate (L-AP4; 25 μM) (EC50=17.7 (13.1–21.9) nM, n=4). The attenuation of the inhibitory effect of CPA (10 nM) on the fe.p.s.p. slope by L-AP4 (25 μM) was blocked in the presence of the mGluR antagonist (selective for the group III mGluR), (R,S)-α-methyl-4-phosphonophenylglycine (MPPG; 200 μM).

5
Both the direct effect of DHPG on synaptic transmission and the attenuation of the inhibitory effect of CPA (10 nM) were prevented in the presence of the protein kinase C selective inhibitors, staurosporine (1 μM) or chelerythrine (5 μM), and thus attributed to activation of protein kinase C.

6
The attenuation by L-AP4 (25 μM) of the inhibitory effect of CPA (10 nM) on the fe.p.s.p. slope was also prevented by the protein kinase C selective inhibitors, staurosporine (1 μM) or chelerythrine (5 μM), and thus attributed to activation of protein kinase C. But this effect seemed to be distinct from the direct effect of L-AP4 (25 μM) on synaptic transmission, which was not modified by the protein kinase C selective inhibitors.

7
We conclude that agonists of metabotropic glutamate receptors (Groups I and III) are able to attenuate the inhibitory effects of adenosine A1 receptor activation in the hippocampus. This interaction may have pathophysiological relevance in hypoxia, in which there is marked release of both excitatory amino acids and the important endogenous neuroprotective substance, adenosine.





British Journal of Pharmacology (1997) 121, 1541–1548; doi:10.1038/sj.bjp.0701291

Influence of metabotropic glutamate receptor agonists on the inhibitory effects of adenosine A1 receptor activation in the rat hippocampus

Glutamate, the major excitatory amino acid, activates a wide variety of signal transduction cascades. This neurotransmitter is involved in photic entrainment of circadian rhythms, which regulate physiological and behavioral functions. The circadian clock in vertebrates is based on a transcription-translation feedback loop in which Brain and muscle aryl hydrocarbon receptor nuclear translocator (ARNT)-like protein 1 (BMAL1) acts as transcriptional activator of others clock genes. This protein is expressed in nearly all suprachiasmatic nucleus neurons, as well as in the granular layer of the cerebellum. In this context, we decided to investigate the role of glutamate in the molecular mechanisms involved in the processes of transcription/translation of BMAL1 protein. To this end, primary cultures of chick cerebellar Bergmann glial cells were stimulated with glutamatergic ligands and we found that BMAL1 levels increased in a dose- and time dependent manner. Additionally, we studied the phosphorylation of serine residues in BMAL1 under glutamate stimulation and we were able to detect an increase in the phosphorylation of this protein. The increased expression of BMAL1 is most probably the result of a stabilization of the protein after it has been phosphorylated by the cyclic AMP-dependent protein kinase and/or the Ca2+/diacylglycerol dependent protein kinase. The present results strongly suggest that glutamate participates in regulating BMAL1 in glial cells and that these cells might prove to be important in the control of circadian rhythms in the cerebellum.

Glutamate-Dependent BMAL1 Regulation in Cultured Bergmann Glia Cells.

Das Gehirn bezieht die fur seine Funktion notwendige Energie fast ausschlieslich aus dem oxidativen Abbau von Glukose. Bei normaler Korpertemperatur betragt der Sauerstoffverbrauch des Primatengehirns etwa 4 ml/100g/min und der Glukoseverbrauch etwa 30 μmol/ 100g/min. In der absteigenden Tierreihe nimmt der Glukose- und Sauerstoffverbrauch wegen der hoheren Zelldichte des Gehirns zu und betragt bei der Katze etwa das l,5fache und bei der Ratte und der Maus das 2- bis 3fache des Stoffumsatzes beim Primaten.

Experimentelle Pathophysiologie zerebraler Durchblutungsstörungen

Epilepsy is a disease of high prevalence, being well known since thousands of years as “morbus sacer.” In spite of intensive investigations, the pathophysiology of epilepsy is still poorly understood. Studies with various animal models have provided ample evidence for heterogeneity in the mechanisms of epileptogenesis. New evidence derives from investigations of kindling, which involves the delivery of brief, initially subliminal, electrical, or chemical stimuli to various areas of the brain. After 10–15 days of once-daily stimulation, the duration and intensity of afterdischarges reach a stable maximum, and a characteristic seizure is produced. Subsequent stimulation then regularly elicits seizures. Surveys of methods being used to test compounds with anticonvulsant properties have been provided by Toman and Everett (1964), Woodbury (1972), Hout et al. (1973), Swinyard (1973), Koella (1985), Meldrum (1986), Rump and Kowalczyk (1987), Loscher and Schmidt (1988), Fisher (1989), Rogawski and Porter (1990), and Porter and Rogawski (1992). Epilepsy becomes drug resistant in 20–30 % of patients. Out of the animal models, the amygdalakindled rat seems to be a suitable approach (Loscher 1997, 1998, 2002a, b). Furthermore, the rat cortical dysplasia model is recommended (Smyth et al. 2002). Several biochemical hypotheses have been advanced, involving the inhibitory GABAergic system and the system of the excitatory amino acids glutamate and aspartate. Excitatory receptors have been divided into subtypes according to the actions of specific agonists or antagonists. Agents which reduce GABAA synaptic function provoke convulsions. A convulsive state is induced by the direct blockade of GABAA receptors (e.g., to the action of bicuculline) or a reduction in the GABA-mediated opening of the chloride ion channel (e.g., by picrotoxin). One major factor in epileptogenesis seems to be a decreased function of GABAA synapses. More recently, research has focused on the therapeutic potential of blocking excitatory amino acids, in particular, glutamate. Of the three receptors of glutamate, the NMDA (N-methyl-D-aspartate) receptor is considered one of the most interested in epilepsy, and competitive NMDA receptor antagonists are proposed as potential antiepileptic drugs. Excessive excitatory amino acid neurotransmission is thought to be associated with the neuropathologies of epilepsy, stroke, and other neurodegenerative disorders. Antagonism of NMDA receptor function appears to be the mechanism of action of some novel anticonvulsant and neuroprotective agents. Excitatory amino acid receptors have been classified into at least three subtypes by electrophysiological criteria: NMDA, quisqualic acid (QA), and kainic acid (KA) (Cotman and Iversen 1987; Watkins and Olverman 1987). Fabene and Sbarbati (2004) underlined the value of in vivo MRI in different models of experimental epilepsy.

Anti-Epileptic Activity

Psychotropic and neurotropic activity

Metabotropic glutamate (mGlu) receptors are becoming increasingly interesting as potential drug targets for the treatment of a variety of central nervous system (CNS) disorders including epilepsy and chronic and acute neurodegeneration. In contrast to the ionotropic glutamate (iGlu) receptors of the N-methyl-D-aspartate (NMDA), 2-amino-3-[5-methyl-3-hydroxyisoxazol-4-yl]propionic acid (AMPA) and kainate types that form ion channels, mGlu receptors couple to G-proteins and modulate a variety of membrane enzymes and ion channels. The eight mGlu receptor subtypes revealed to date by molecular cloning exhibit not only distinct pharmacological properties, but also different functions in the brain. This article describes the potential disease targets of compounds acting at the various mGlu receptor subtypes, and the development of such compounds by reviewing both the primary and patent literature.

Metabotropic glutamate receptors

Handle everyday research tasks with reliable, citation-backed results

Your personal Research Agent to handle research tasks with citation-backed results

Popular Tasks used by Researchers

How can I help with your research?

Meet SciSpace

Get more enhanced response by uploading the PDFs you want me to reference.

No relevant PDFs in your library

SciSpace is the AI research assistant for academics. Run systematic literature reviews on 280M+ papers, and write papers with cited sources. Trusted by 1M+ students, PhDs & researchers.

SciSpace | AI for Research

Analyze PDFs

Code & Manuscripts

Funding & Grants

Literature & Patents

Medical & Clinical Data

Systematic Review

Visualize & Present

Web & Data

Build a Google Scholar-like website for your research.

Build a website

Create charts and images for your research

Create a Chart

Write a paper for submission to a journal

Draft a manuscript

Patent Search

Design eye-catching scientific posters in minutes.

Scientific Poster Generation

Systematic Literature Review

One task is running at the moment. Your messages will be shown right after.

Drag and drop or click here to browse

Loved by <highlight>1 million+</highlight> researchers

Extract a list of specific topics and their sources from unstructured text

Topics

Compare and analyze relevant papers that matches with your search

Papers

Get insights from PDFs and bookmarked papers from your library

My library

Recent searches

Try searching for:

Catch AI-generated content in scholarly and non-scholarly content

{ai} Detector

Ai Writer

Get PDF Summaries, highlighted text explanations 

Chat with PDF

Effortlessly create in-text citations and bibliographies in APA and 2,500 other formats

Citation generator

Get explanations, summaries, and answers on academic papers

Ease up your research workflow with {scispace}'s cohort of exciting AI tools

Elevate your academic writing skills and convey your ideas the way you want

Paraphraser

Explore our range of reading and writing tools

Your file is being prepared and should be ready in a few minutes. If it's a large file, it might take a bit longer. You can close this window, and we'll email you the file when it's done.

You have reached a maximum limit of <strong>{limit}</strong> columns in the table. Remove at least <strong>1</strong> column to add or create another one.

Ferdinando Nicoletti

Author Tools

Chat about Author

Papers

Metabotropic glutamate receptors